Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression.

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Recombinant hirudin attenuates pulmonary hypertension and thrombosis in acute pulmonary embolism rat model.

Background: Acute pulmonary embolism (APE) is classified as a subset of diseases that are characterized by lung obstruction due to various types of emboli. Current clinical APE treatment using anticoagulants is frequently accompanied by high risk of bleeding complications. Recombinant hirudin (R-hirudin) has been found to have antithrombotic properties. However, the specific impact of R-hirudin on APE remains unknown. Methods: Sprague-Dawley (SD) rats were randomly assigned to five groups, with thrombi injections to establish APE models. Control and APE group rats were subcutaneously injected with equal amounts of dimethyl sulfoxide (DMSO). The APE+R-hirudin low-dose, middle-dose, and high-dose groups received subcutaneous injections of hirudin at doses of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, respectively. Each group was subdivided into time points of 2 h, 6 h, 1 d, and 4 d, with five animals per point. Subsequently, all rats were euthanized, and serum and lung tissues were collected. Following the assessment of right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP), blood gas analysis, enzyme-linked immunosorbnent assay (ELISA), pulmonary artery vascular testing, hematoxylin-eosin (HE) staining, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, immunohistochemistry, and Western blot experiments were conducted. Results: R-hirudin treatment caused a significant reduction of mPAP, RVP, and Malondialdehyde (MDA) content, as well as H2O2 and myeloperoxidase (MPO) activity, while increasing pressure of oxygen (PaO2) and Superoxide Dismutase (SOD) activity. R-hirudin also decreased wall area ratio and wall thickness to diameter ratio in APE rat pulmonary arteries. Serum levels of endothelin-1 (ET-1) and thromboxaneB2 (TXB2) decreased, while prostaglandin (6-K-PGF1α) and NO levels increased. Moreover, R-hirudin ameliorated histopathological injuries and reduced apoptotic cells and Matrix metalloproteinase-9 (MMP9), vascular cell adhesion molecule-1 (VCAM-1), p-Extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P65/P65 expression in lung tissues. Conclusion: R-hirudin attenuated pulmonary hypertension and thrombosis in APE rats, suggesting its potential as a novel treatment strategy for APE.

Clot time ratio (CTR) and treatment outcomes in Apixaban-treated atrial fibrillation patients.

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.

Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation.

Salvia miltiorrhiza Bunge. (DS), as an important traditional Chinese medicine (TCM), has a long history of usage for promoting blood circulation and removing blood stasis. Modern studies have shown that the chemical components of DS have many biological activities such as cardiovascular protection, anti-arrhythmia, anti-atherosclerosis, improvement of microcirculation, protection of myocardium, inhibition and removal of platelet aggregation. Nevertheless, the action mechanism of DS as well its active compounds on platelet activation has not been fully uncovered. This study aimed to find out the potential targets and mechanisms of DS in the modulation of platelet activation and thrombosis, using network pharmacology and biological experimental. These compounds with anti-thrombotic activity in DS, cryptotanshinone (CPT), isoeugenol (ISO) and tanshinone IIA (TSA), together with the corresponding targets being Src, Akt and RhoA are screened by network pharmacology. We confirmed that ISO, CPT and TSA dose-dependently inhibited platelet activation in vitro, mainly by inhibiting agonist-induced clot retraction, aggregation and P-selectin and ATP release. The western blot findings indicated that ISO, CPT, and TSA led to reduced levels of p-Akt and p-ERK in activated platelets. Additionally, ISO and TSA were observed to decrease p-cSrc expression while increasing RhoA expression. ISO, CPT, and TSA demonstrated a potential to restrict the advancement of carotid arterial thrombosis in vivo. We confirm that ISO, CPT and TSA are the key anti-thrombotic active compounds in DS. These active compounds exhibit unique inhibitory effects on platelet activation and thrombus formation by modulating the Akt/ERK and cSrc/RhoA signaling pathways.

Fingerprint analysis of dang-gui-Si-Ni decoction and its anticoagulant activity in vivo-in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Dang-Gui-Si-Ni (DGSN) decoction is a classic prescription in the clinical practice of traditional Chinese Medicine (TCM). DGSN decoction is often used to relieve symptoms of cold coagulation and blood stasis recorded by Treatise on Febrile Diseases (Shang Han Lun) and treat Raynaud's disease, dysmenorrhea, arthritis, migraine in TCM clinic. Accumulated evidences have suggested that this diseases are related to microcirculation disturbance. However, the anticoagulant activity and underlying mechanisms of DGSN decoction responsible for the therapeutic not well understood. AIM OF THE STUDY: The fingerprint and anticoagulant activity in vivo-in vitro of DGSN decoction were evaluated to strengthen the quality control and activity study of formulas. MATERIALS AND METHODS: The chemical components of DGSN decoction were analyzed by HPLC and its fingerprint similarity were evaluated by "Chinese Medicine Chromatographic Fingerprint Similarity Evaluation Software (2012 Edition)". The anticoagulant activity of DGSN decoction was assessed by measuring four coagulation factors (PT, TT, APTT, FIB) in vitro. Zebrafish thrombosis model induced by punatinib was established to evaluate the activity of improving microvascular hemodynamics in vivo. Quantitative real-time polymerase chain reaction (q-PCR) were adopted to compare the changes in the RNA expression levels of coagulation factor II (FII), VII (FVII), IX (FIX) and X (FX) in zebrafish thrombosis model. RESULTS: The fingerprint similarity evaluation method of DGSN decoction was established. The results showed that 18 samples had higher similarity (S1-S18 > 0.878). Pharmacodynamic results showed that DGSN decoction could extend PT, TT and APTT, and reduce FIB content in vitro. Meanwhile, it markedly enhanced the cardiac output and blood flow velocity at low dosage (500 µg mL-1) in vivo. q-PCR data demonstrated that DGSN decoction (500 µg mL-1) could downregulate the RNA expression of FII, FVII, FIX and FX. Interestingly, there were a bidirectional regulation of FII, FIX and FX in a certain concentration range. In general, DGSN decoction can significantly improve hemodynamics and downregulate coagulation factors, and the results were consistent both in vitro - in vivo. CONCLUSION: The fingerprint study provide a new perspective for improving the quality control of DGSN decoction. DGSN decoction possess anticoagulant activity by regulating multiple coagulation factors simultaneously. Thus, it has the potential to develop into the novel raw material of anticoagulant drugs.

Hypolipidemic and Antithrombotic Effect of 6'-O-Caffeoylarbutin from Vaccinium dunalianum Based on Zebrafish Model, Network Pharmacology, and Molecular Docking.

Vaccinium dunalianum leaf buds make one of the most commonly used herbal teas of the Yi people in China, which is used to treat articular rheumatism, relax tendons, and stimulates blood circulation in the body. In addition, 6'-O-caffeoylarbutin (CA) is a standardized extract of V. dunalianum, which has been found in dried leaf buds, reaching levels of up to 31.76%. Because of the uncommon phenomenon, it is suggested that CA may have a potential therapeutic role in hyperlipidemia and thrombosis. This study was designed to study the efficacy of CA on treating hyperlipidemia and thrombosis and the possible mechanisms behind these effects. Hyperlipidemia and thrombosis zebrafish models were treated with CA to observe variations of the integrated optical density within the vessels and the intensity of erythrocyte staining within the hearts. The possible mechanisms were explored using network pharmacology and molecular docking. The results demonstrate that CA exhibits an excellent hypolipidemic effect on zebrafish at concentrations ranging from 3.0 to 30.0 µg/mL and shows thrombosis inhibitory activity in zebrafish at a concentration of 30.0 µg/mL, with an inhibition rate of 44%. Moreover, network pharmacological research shows that MMP9, RELA, MMP2, PRKCA, HSP90AA1, and APP are major targets of CA for therapy of hyperlipidemia and thrombosis, and may relate to pathways in cancer, chemical carcinogenesis-receptor activation, estrogen signaling pathway, and the AGE-RAGE signaling pathway in diabetic complications.

Therapeutic effects and molecular mechanisms of natural products in thrombosis.

Thrombotic disorders, such as myocardial infarction and stroke, are the leading cause of death in the global population and have become a health problem worldwide. Drug therapy is one of the main antithrombotic strategies, but antithrombotic drugs are not completely safe, especially the risk of bleeding at therapeutic doses. Recently, natural products have received widespread interest due to their significant efficacy and high safety, and an increasing number of studies have demonstrated their antithrombotic activity. In this review, articles from databases, such as Web of Science, PubMed, and China National Knowledge Infrastructure, were filtered and the relevant information was extracted according to predefined criteria. As a result, more than 100 natural products with significant antithrombotic activity were identified, including flavonoids, phenylpropanoids, quinones, terpenoids, steroids, and alkaloids. These compounds exert antithrombotic effects by inhibiting platelet activation, suppressing the coagulation cascade, and promoting fibrinolysis. In addition, several natural products also inhibit thrombosis by regulating miRNA expression, anti-inflammatory, and other pathways. This review systematically summarizes the natural products with antithrombotic activity, including their therapeutic effects, mechanisms, and clinical applications, aiming to provide a reference for the development of new antithrombotic drugs.

Qihuang Zhuyu formula alleviates coronary microthrombosis by inhibiting PI3K/Akt/αIIbß3-mediated platelet activation.

BACKGROUND: Coronary microembolism (CME) is commonly seen in the peri-procedural period of Percutaneous Coronary Intervention (PCI), where local platelet activation and endothelial cell inflammation crosstalk may lead to micro thrombus erosion and rupture, with serious consequences. Qihuang Zhuyu Formula (QHZYF) is a Chinese herbal compound with high efficacy against coronary artery disease, but its antiplatelet mechanism is unclear. HYPOTHESIS/PURPOSE: This study aimed to elucidate the effects and mechanisms of QHZYF on sodium laurate-induced CME using network pharmacology and in vitro and in vivo experiments. METHODS: We employed high-performance liquid chromatography mass spectrometry to identify the main components of QHZYF. Network pharmacology analysis, molecular docking and surface plasmon resonance (SPR) were utilized to predict the primary active components, potential therapeutic targets, and intervention pathways mediating the effects of QHZYF on platelet activation. Next, we pretreated a sodium laurate-induced minimally invasive CME rat model with QHZYF. In vivo experiments were performed to examine cardiac function in rats, to locate coronary arteries on heart sections to observe internal microthrombi, to extract rat Platelet-rich plasma (PRP) for adhesion assays and CD62p and PAC-1 (ITGB3/ITGA2B) flow assays, and to measure platelet-associated protein expression in PRP. In vitro clot retraction and Co-culture of HUVECs with PRP were performed and the gene pathway was validated through flow cytometry and immunofluorescence. RESULTS: Combining UPLC-Q-TOF/MS technology and database mining, 78 compounds were finally screened as the putative and representative compounds of QHZYF, with 75 crossover genes associated with CME. QHZYF prevents CME mainly by regulating key pathways of the inflammation and platelets, including Lipid and atherosclerosis, Fluid shear stress, platelet activation, and PI3K-Akt signaling pathways. Five molecules including Calyson, Oroxin A, Protosappanin A,Kaempferol and Geniposide were screened and subjected to molecular docking and SPR validation in combination with Lipinski rules (Rule of 5, Ro5). In vivo experiments showed that QHZYF not only improved myocardial injury but also inhibited formation of coronary microthrombi. QHZYF inhibited platelet activation by downregulating expression of CD62p receptor and platelet membrane protein αIIbß3 and reduced the release of von Willebrand Factor (vWF), Ca2+ particles and inflammatory factor IL-6. Further analysis revealed that QHZYF inhibited the activation of integrin αIIbß3, via modulating the PI3K/Akt pathways. In in vitro experiments, QHZYF independently inhibited platelet clot retraction. Upon LPS induction, the activation of platelet membrane protein ITGB3 was inhibited via the PI3K/Akt pathway, revealing an important mechanism for attenuating coronary microthrombosis. We performed mechanistic validation using PI3K inhibitor LY294002 and Akt inhibitor MK-2206 to show that QHZYF inhibited platelet membrane protein activation and inflammation to improved coronary microvessel embolism by regulating PI3K/Akt/αIIbß3 pathways, mainly by inhibiting PI3K and Akt phosphorylation. CONCLUSION: QHZYF interferes with coronary microthrombosis through inhibition of platelet adhesion, activation and inflammatory crosstalk, thus has potential in clinical anti-platelet applications. Calyson, Oroxin A, Protosappanin A, Kaempferol and Geniposide may be the major active ingredient groups of QHZYF that alleviate coronary microthrombosis.

Alleviation of endothelial dysfunction of Pheretima guillemi (Michaelsen)-derived protein DPf3 in ponatinib-induced thrombotic zebrafish and mechanisms explored through ox-LDL-induced HUVECs and TMT-based proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Thrombus generation is one of the leading causes of death in human, and vascular endothelial dysfunction is a major contributor to thrombosis. Pheretima guillemi (Michaelsen), a traditional medicinal animal known as "Dilong", has been utilized to cure thrombotic disorders for many years. DPf3, a group of functional proteins extracted from P. guillemi, has been characterized and identified to possess antithrombotic bioactivity via in vitro and ex vivo experiments. AIM OF THE STUDY: This study is aimed to investigate the vascular-protection activity and related mechanism of antithrombotic protein DPf3 purified from Pheretima guillelmi systematically. MATERIALS AND METHODS: The antithrombotic activity and vascular endothelium protection effect of DPf3 was explored in vivo using ponatinib-induced vascular endothelial injury zebrafish thrombus model. Then, (hi) ox-LDL-induced HUVECs was applied to investigate the protection mechanism of DPf3 against the injury of vascular endothelium. In addition, TMT-based proteomics analysis was used to study the biomarkers, biological processes and signal pathways involved in the antithrombotic and vascular protective effects of DPf3 holistically. RESULTS: DPf3 exerted robust in vivo antithrombosis and vascular endothelial protection ability. DPf3 was identified to prevent HUVECs from damage by reducing ROS production, and to reduce monocyte adhesion by decreasing the protein content of adhesion factor VCAM 1. DPf3 was also observed to weaken the migration ability of injured cells and inhibit abnormal angiogenesis. The mechanism of DPf3's antithrombotic and vascular protective activity was mainly related to the regulation of lipid metabolism, energy metabolism, complement and coagulation system, ECM receptor interaction, MAPK signal pathway, etc. CONCLUSIONS: This study demonstrates that DPf3 has strong antithrombotic and endothelial protective effects. The endothelial protective ability and related mechanisms of DPf3 provide a scientific reference for the traditional use of earthworms in the treatment of thrombosis.

Antarctic Krill Oil from Euphausia superba Ameliorates Carrageenan-Induced Thrombosis in a Mouse Model.

FJH-KO obtained from Antarctic krill, especially Euphausia superba, has been reported to contain high amounts of omega-3 polyunsaturated fatty acids (n-3 PUFA) and to exhibit anticancer and anti-inflammatory properties. However, its antithrombotic effects have not yet been reported. This study aimed to investigate the antithrombotic effects of FJH-KO in carrageenan-induced thrombosis mouse models and human endothelial cells. Thrombosis was induced by carrageenan injection, whereas the mice received FJH-KO pretreatment. FJH-KO attenuated carrageenan-induced thrombus formation in mouse tissue vessels and prolonged tail bleeding. The inhibitory effect of FJH-KO was associated with decreased plasma levels of thromboxane B2, P-selectin, endothelin-1, ß-thromboglobulin, platelet factor 4, serotonin, TNF-α, IL-1ß, and IL-6. Meanwhile, FJH-KO induced plasma levels of prostacyclin I2 and plasminogen. In vitro, FJH-KO decreased the adhesion of THP-1 monocytes to human endothelial cells stimulated by TNF-α via eNOS activation and NO production. Furthermore, FJH-KO inhibited the expression of TNF-α-induced adhesion molecules such as ICAM-1 and VCAM-1 by suppressing the NF-κB signaling pathway. Taken together, our study demonstrates that FJH-KO protects against carrageenan-induced thrombosis by regulating endothelial cell activation and has potential as an antithrombotic agent.

Treatment of cancer-associated venous thromboembolism: A focus on special populations.

Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and rivaroxaban) as first-line options for the treatment of venous thromboembolism (VTE) in patients with cancer. However, most of these guidelines refer to the general cancer patient population and provide limited guidance for specific subgroups of patients at particularly high risk of bleeding, such as those with gastrointestinal cancers, primary or metastatic brain tumors, thrombocytopenia, or renal impairment. In these complex populations, the management of cancer-associated thrombosis (CAT) poses unique challenges and requires a nuanced approach based on the primum non nocere principle. This comprehensive review critically examines the relevant literature and discusses the therapeutic options currently available for the management of CAT in these special situations.

Biomimetic platelet-camouflaged drug-loaded polypyrrole for the precise targeted antithrombotic therapy.

Lower extremity deep venous thrombosis (LEDVT) affects patient's quality of life for a long time, and even causes pulmonary embolism, which threatens human health. Current anticoagulant drugs in clinical treatment are hampered by the risk of bleeding due to poor targeting and low drug penetration. Here, we used platelet (PLT)-like biological targeting to enhance the delivery and accumulation of nanomedicines in thrombus and reduce the risk of bleeding. Meanwhile, the parallel strategy of "thrombus thermal ablation and anticoagulation" was applied to increase the permeability of drugs in thrombus and achieve the optimal antithrombotic effect. Polypyrrole (PPy) and rivaroxban (Riv, an anticoagulant drug) were co-assembled into platelet membrane-coated nanoparticles (NPs), PLT-PPy/Riv NPs, which actively targeted the thrombotic lesion at multiple targets in the platelet membrane and were thermally and drug-specific thrombolysed by 808 nm laser irradiation. The combination therapy resulted in up to 90% thrombolysis in a femoral vein thrombosis model compared to single phototherapy or drug therapy. The results showed that the nanoformulation provided a new direction for remote precise and controlled sustained thrombolysis, which was in line with the trend of nanomedicine towards clinical translation.

Supplementation with Ashitaba (Angelica keiskei) Yellow Stem Exudate Prevents Aging-Induced Thrombotic Tendencies and Systemic Inflammation Without Affecting Body Weight Gain in Mice.

Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine and health supplement in Japan. Ashitaba yellow stem exudate (AYE) contains abundant chalcones and thus has the potential to treat and prevent many pathological states such as cancer, inflammation, obesity, diabetics, thrombosis, and hypertension. Levels of plasminogen activator inhibitor 1 (PAI-1), a key regulator of the fibrinolytic system, increase with age in mouse plasma. Therefore, we aimed to determine the effects of AYE on plasma thrombotic parameters in aging mice. Long-term (52 weeks) AYE supplementation significantly decreased age-induced increases of PAI-1 in mouse plasma. Supplementation with AYE decreased levels of the acute-phase and fibrinolytic protein plasma plasminogen, and significantly decreased those of tumor necrosis factor α. These results suggested that continuous intake of AYE throughout life decreases age-induced systemic inflammation and prevents thrombotic tendencies without affecting body weight gain in aged mice. Our findings showed that supplementing diets with AYE might help to prevent thrombotic diseases in elderly individuals.

P-Selectin mediates targeting of a self-assembling phototherapeutic nanovehicle enclosing dipyridamole for managing thromboses.

Thrombotic vascular disorders, specifically thromboembolisms, have a significant detrimental effect on public health. Despite the numerous thrombolytic and antithrombotic drugs available, their efficacy in penetrating thrombus formations is limited, and they carry a high risk of promoting bleeding. Consequently, the current medication dosage protocols are inadequate for preventing thrombus formation, and higher doses are necessary to achieve sufficient prevention. By integrating phototherapy with antithrombotic therapy, this study addresses difficulties related to thrombus-targeted drug delivery. We developed self-assembling nanoparticles (NPs) through the optimization of a co-assembly engineering process. These NPs, called DIP-FU-PPy NPs, consist of polypyrrole (PPy), dipyridamole (DIP), and P-selectin-targeted fucoidan (FU) and are designed to be delivered directly to thrombi. DIP-FU-PPy NPs are proposed to offer various potentials, encompassing drug-loading capability, targeted accumulation in thrombus sites, near-infrared (NIR) photothermal-enhanced thrombus management with therapeutic efficacy, and prevention of rethrombosis. As predicted, DIP-FU-PPy NPs prevented thrombus recurrence and emitted visible fluorescence signals during thrombus clot penetration with no adverse effects. Our co-delivery nano-platform is a simple and versatile solution for NIR-phototherapeutic multimodal thrombus control.

Alpha-ketoglutarate supplementation reduces inflammation and thrombosis in type 2 diabetes by suppressing leukocyte and platelet activation.

The interplay between platelets and leukocytes contributes to the pathogenesis of inflammation, thrombosis, and cardiovascular diseases (CVDs) in type 2 diabetes (T2D). Our recent studies described alpha-ketoglutarate (αKG), a Krebs cycle intermediate metabolite as an inhibitor to platelets and leukocytes activation by suppressing phosphorylated-Akt (pAkt) through augmentation of prolyl hydroxylase-2 (PHD2). Dietary supplementation with a pharmacological concentration of αKG significantly inhibited lung inflammation in mice with either SARS-CoV-2 infection or exposed to hypoxia treatment. We therefore investigated if αKG supplementation could suppress hyperactivation of these blood cells and reduce thromboinflammatory complications in T2D. Our study describes that dietary supplementation with αKG (8 mg/100 g body wt. daily) for 7 days significantly reduced the activation of platelets and leukocytes (neutrophils and monocytes), and accumulation of IL1ß, TNFα, and IL6 in peripheral blood of T2D mice. αKG also reduced the infiltration of platelets and leukocytes, and accumulation of inflammatory cytokines in lungs by suppressing pAkt and pP65 signaling. In a cross-sectional investigation, our study also described the elevated platelet-leukocyte aggregates and pro-inflammatory cytokines in circulation of T2D patients. T2D platelets and leukocytes showed an increased aggregation and thrombus formation in vitro. Interestingly, a pre-incubation of T2D blood samples with octyl αKG significantly suppressed the activation of these blood cells and ameliorated aggregate/thrombus formation in vitro. Thus, suggesting a potential therapeutic role of αKG against inflammation, thrombosis, and CVDs in T2D.

Secondary right atrial thrombosis in three dogs: Antithrombotics therapy and echocardiographic follow-up.

Three dogs were diagnosed with right atrial thrombosis, thought to be secondary to systemic diseases. Specifically, two cases had hyperadrenocorticism and one case was diagnosed with pancreatitis with acute renal injury. In all cases, the thrombi were found within the right atrium, necessitating a differentiation from cardiac neoplasia. In all three cases, the structures assumed to be thrombi had irregular margins with interspersed hypoechoic regions, which were later confirmed as thrombi based on the responsiveness to therapy. All three cases were prescribed with the combination of clopidogrel and rivaroxaban.The thrombi gradually disappeared after initiation of the combination therapy. Complete resolution of right atrial thrombosis was noted in each dog treated with clopidogrel and rivaroxaban. This combination therapy appears to be safe and well tolerated. Diligent observation of the echocardiographic findings and clinical course allows the diagnosis of thrombosis.

The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers. AIM OF THE REVIEW: We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer. MATERIALS AND METHODS: Relevant studies about BSAT were collected from PubMed and Web of science. RESULTS: Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors. CONCLUSIONS: BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy.

Preventive effect and mechanism of Tibetan tea extract on thrombosis in arachidonic acid-induced zebrafish determined via RNA-seq transcriptome profiles.

Thrombosis is a key pathological event in cardiovascular diseases and is also the most important targeting process for their clinical management. In this study, arachidonic acid (AA) was used to induce thrombus formation in zebrafish larvae. Blood flow, red blood cell (RBCs) aggregation and cellular oxidative stress were measured to evaluate the antithrombotic effect of Tibetan tea (TT). Meanwhile, the potential molecular mechanism was further explored by transcriptome sequencing (RNA-seq). The results indicated that TT could significantly restore heart RBCs intensity of thrombotic zebrafish, whilst decreasing RBCs accumulation in the caudal vein. The transcriptome analysis revealed that the preventive effect of TT on thrombosis could be mostly attributed to changes in lipid metabolism related signaling pathways, such as fatty acid metabolism, glycerollipid metabolism, ECM-receptor interaction and steroid biosynthesis signaling pathway. This study demonstrated that Tibetan tea could alleviate thrombosis by reducing oxidative stress levels and regulating lipid metabolism.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Effect of high-dose statin therapy on coagulation factors: Lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease.

BACKGROUND: Multiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients. OBJECTIVES: We investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties. METHODS: We studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6-12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential. RESULTS: At baseline LDL-C (median 3.2, interquartile range 2.7-3.7 mmol/L) was independently associated solely with FXI (ß = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (ß = -0.41, P < 0.001), LDL-C (ß = -0.26, P = 0.001), and FXI (ß = -0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (ß = 0.19, P = 0.043) and FXI (ß = 0.17, P = 0.049). CONCLUSIONS: High-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.