Antithrombotic Effects Research Articles

Effect of exercise-based cardiac rehabilitation on the ischemic threshold in patients with high-risk ischemic heart disease

Abstract Introduction Coronary artery disease is a complex condition and is not always resolved after an interventional or surgical procedure, due to the remaining obstructions in the coronary tree or the severity of the atherosclerosis, leaving anginal symptoms, ischemic threshold (IU) in the exercise, decreased cardiorespiratory fitness, and poor quality of life (QoL). Exercise-based cardiac rehabilitation programs (Ex-CRP) usually develop ischemic preconditioning mechanisms thanks to their direct anti-inflammatory, antioxidant, antithrombotic and coronary neovascularization effects, thus improving coronary reserve flow. We hypothesize that an Ex-CRP is capable of favorably impacting the UI in these patients. Therefore, the objective of this study is to evaluate the effects of an Ex-CRP on the UI in patients with high-risk ischemic heart disease. Methods Quasi-experimental study with 121 patients with ischemic threshold due to high-risk ischemic heart disease (with perfusion defects in nuclear medicine, complex coronary anatomy or partially revascularized) and presence of ischemic threshold in the exercise test. An Ex-CRP of 4–6 weeks duration was performed, consisting of supervised and monitored training concurrent with 30-minute aerobic exercise sessions at 70% of heart rate reserve, 3 times per week, supplemented with resistance exercise. and an educational understanding program for the control of risk factors and nutritional and psycho-emotional care. At the end of the program, a stress test was performed to compare the post-intervention effects and ischemic threshold was defined as the presence of angina or electrocardiographic changes of ischemia with negative ST-segment depression in 2 consecutive beats more than 80 ms from the J point. and in more than two contiguous leads. Results The 121 patients with ischemic threshold were 61±10 years old and 75% were male. On the other hand, 29.7% had a diagnosis of heart failure and an average LVEF of 53.1±12.9%. After Ex-CRP, an improvement was found in calculated VO2p (24.7±7.8 vs 34.23±7.5; p=0.000), METs at maximum effort from 7.06±2.15 to 9.78±1.14 (p<0.0001) and submaximal load in watts from 44±21.32 to 61±24.49; p<0.0001. 40.5% of the patients who were admitted with UI resolved it (absence of post-intervention ischemic diagnosis) after Ex-CRP and the remaining percentage with UI (59.5%) displaced it by 2.62 METs (p<0.0001). With this, the cardiovascular risk calculated by the Duke Score also decreased from −7 to −2 (p<0.0001), and the myocardial efficiency index improved from 8 to 6 (p<0.0001), strength (79±15 to 92±8%; p<0.0001) and QoL (65±17 vs 82±12; p<0.0001). Conclusions Ex-CRP had a significant effect on the resolution or displacement of the UI in patients with high-risk ischemic heart disease. In addition, it improved muscle strength, quality of life, myocardial efficiency, and reduced the cardiovascular risk index calculated by the Duke score. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Centro de Estudios e Investigaciόn FISICOL. Cúcuta, ColombiaCardioFit. CDMX, México

Antiplatelet therapy and risk of adverse cardiovascular events in peripheral artery disease

Abstract Background Antiplatelet therapy has been shown to reduce adverse cardiovascular (CV) events in patients with PAD, but despite the well-established medication benefit, large-scale epidemiological data evaluating antiplatelet agent of choice with low bleeding risk and high antithrombotic effect is sparse. Purpose We explored Danish healthcare registers to examine guideline-recommended antiplatelet therapy and associated risk of adverse CV outcomes in patients with PAD. Methods All patients with a first-time diagnosis of PAD between January 1, 1997 and December 31, 2016 were identified. Patients alive six months after diagnosis were divided into four treatment groups: aspirin, clopidogrel, dual therapy (DAPT), and no antiplatelet therapy. Logistic regression models were used to estimate 1-year risk of myocardial infarction (MI), stroke, CV death, all-cause mortality, and gastrointestinal (GI) bleeding. Results We identified a total of 85,771 PAD patients [median age 70.6 (IQR 63–77 years), 52% male]. The results suggest that compared to no antiplatelet therapy, use of clopidogrel alone significantly decreased 1-year risk of incident MI, stroke, CV death and all-cause mortality with odds ratios 0.56 (CI 0.46–0.68), 0.69 (CI 0.59–0.81), 0.72 (CI 0.56–0.94), and 0.79 (CI 0.65–0.97) respectively. Likewise, aspirin monotherapy was associated with only a marginal reduction in 1-year risk of stroke by 11% and all-cause mortality by 7%. Odds ratios for GI bleeding were estimated to be 1.18 (CI 1.04–1.34), 1.34 (CI 0.94–1.91), and 1.54 (CI 1.05–2.26) for aspirin, clopidogrel, and DAPT groups, respectively. Conclusion In this nationwide study, clopidogrel is associated with significantly reduced risk of MI, stroke, CV death and all-cause mortality with low risk of bleeding and appears to support clopidogrel as antiplatelet agent of choice for CV risk reduction in patients with PAD. Funding Acknowledgement Type of funding sources: None.

Heparin-Peptide Nanogranules for Thrombosis-Actuated Anticoagulation.

Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported. Biophysical studies demonstrate this responsive behavior is due to the sequestration of heparin within self-assembling peptide nanofibrils and its mechanically actuated decoupling to elicit antithrombotic effects at the clotting site. In vivo studies show these unique properties converge to allow subcutaneous nanogranule depots to extend heparin serum concentrations for an order of magnitude longer than standard dosing regimens while enabling prolonged and controlled anticoagulant activity. This biohybrid delivery system demonstrates a potentially scalable platform for the development of safer, easier to administer, and more effective antithrombotic nanotechnologies.

Dexamethasone improves cardiovascular outcomes in critically ill COVID-19, a real world scenario multicenter analysis

Abstract Background Severe COVID-19 pneumonia requiring intensive care treatment remains a clinical challenge to date. Dexamethasone was reported as a promising treatment option, leading to a reduction of mortality rates in severe COVID-19 disease. However, the effect of dexamethasone treatment on cardiac injury and pulmonary embolism remains largely elusive. Methods In total 178 critically ill COVID-19 patients requiring intensive care treatment and mechanical ventilation were recruited in three European medical centres and included in the present retrospective study. 113 patients (63.5%) were treated with dexamethasone for a median duration of 10 days (IQR 9–10). 65 patients (36.5%) constituted the non-dexamethasone control group. Results While peak inflammatory markers were reduced by dexamethasone treatment, the therapy also led to a significant reduction in peak troponin levels (231% vs. 700% indicated as relative to cut off value, p=0.001). Similar, dexamethasone resulted in significantly decreased peak D-Dimer levels (2.16 mg/l vs. 6.14mg/l, p=0.002) reflected by a significant reduction in pulmonary embolism rate (4.4% vs. 20.0%, p=0.001). The antithrombotic effect of dexamethasone treatment was also evident in the presence of therapeutic anticoagulation (pulmonary embolism rate: 6% vs. 34.4%, p<0.001). Of note, no significant changes in baseline characteristics were observed between the dexamethasone and non-dexamethasone group. Conclusion In severe COVID-19, antiinflammatory effects of dexamethasone treatment seem to be associated with a significant reduction in myocardial injury. Similar, a significant decrease in pulmonary embolism, independent of anticoagulation, was evident, emphasizing the beneficial effect of dexamethasone treatment in severe COVID-19. Funding Acknowledgement Type of funding sources: None.

Impact of poor below-the-knee run-off on stent failure of femoro-popliteal arteries in healthy swine model

Abstract Background Poor below-the-knee (BTK) run-off is reported to be one of the predictors of stent failure after endovascular treatment to femoro-popliteal arteries (1), however, the mechanism of stent failure has never been characterized before. The aim of the current study was to evaluate impact of poor BTK run-off on stent failure in healthy swine femoro-popliteal (FP) lesions, and to compare the outcome of a bare-metal stent (BMS) and two drug-eluting stents (DES) in the arteries with poor BTK run-off. Method Fluoropolymer-coated paclitaxel-eluting stents (FP-PES, Eluvia) and BMS were implanted in bilateral femoral arteries of 6 healthy swine following coil embolization in both tibial arteries to induce poor BTK run-off. FP-PES and polymer-free paclitaxel-coated stents (PF-PCS, Zilver-PTX) were also implanted in 6 swine with the same fashion. Angiography with an optical coherence tomography (OCT) at one month followed by histological analysis was performed for each lesion. Result Angiography demonstrated that in-stent restenosis was observed exclusively in BMS, and percent stenosis was significantly less in FP-PES compared with BMS (FP-PES vs. BMS, median [interquartile range (IQR)], 17.8% [16.6–28.7] vs. 79.3% [64.2–87.2], respectively, p=0.03). FP-PES also demonstrated significantly less percent stenosis compared with PF-PCS (FP-PES vs. PF-PCS, 8.9% [4.7–44.7] vs. 31.2% [23.3–51.2], respectively, p=0.03). Histopathological evaluation demonstrated that organizing and/or organized fibrin thrombus was the main feature of the restenotic lesions, suggesting a risk of thrombus attachment in the FP lesions with poor BTK run-off. Biologic drug effect such as medial smooth muscle cell (SMC) loss score was significantly greater in FP-PES compared with BMS (4.0 [3.3–4.0] vs. 2.0 [1.0–3.0], respectively, p<0.01), whereas, similar between FP-PES and PF-PCS (4.0 [3.0–4.0] vs. 4.0 [3.0–4.0], respectively, p=0.88). Conclusion Thrombus attachment would be the main causes of restenosis in FP lesions with poor BTK runoff. The results of the current study suggest that not only paclitaxel drug effect, but also anti-thrombotic effect of fluoropolymer might be needed to prevent stent failure. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study is supported by Boston Scientific.

CANNABIS USE DISORDER: FRIEND OR FOE IN PULMONARY EMBOLISM AND ASSOCIATED MORTALITY IN YOUNG ADULTS (AGED 18-44 YEARS)?

CANNABIS USE DISORDER: FRIEND OR FOE IN PULMONARY EMBOLISM AND ASSOCIATED MORTALITY IN YOUNG ADULTS (AGED 18-44 YEARS)?

Antiapoptotic Effects of Hydroxychloroquine on Hypoxic-Ischemic Injury in Neonatal Rat Brain: May Hydroxychloroquine Be an Adjuvant Theraphy?

Hydroxychloroquine (HCQ) has immunomodulatory, antithrombotic, cardiovascular, antimicrobial, and antineoplastic effects. In this study, we aimed to investigate the antiapoptotic and immunomodulator effects of intraperitoneal HCQ on hypoxic-ischemic (HI) injury in newborn rats. Wistar albino rats, 7 to 10 days old, were randomly divided into three groups: hypoxic-ischemic encephalopathy (HIE) group, HIE treated with HCQ group, and Sham group. Left common carotid artery ligation and hypoxia model were performed in HIE and HCQ groups. The HCQ group was treated with 80 mg/kg intraperitoneal HCQ every 24 hours for 3 days, while Sham and HIE groups were given physiological saline. After 72 hours, rats were decapitated and brain tissues were stained with hematoxylin and eosin, TUNEL, and IL-1β for histopathological grading and neuronal cell injury. Neuronal apoptosis was statistically lower in all neuroanatomical areas in the HCQ group compared with the HIE group. IL-1β-stained areas were similar in both HCQ and HIE groups but significantly higher compared with the Sham group. Histopathological grading scores were found to be lower in the HCQ group on the left parietal cortex and hippocampus region. In this study, we have shown for the first time that HCQ treatment decreased apoptosis in HI newborn rat model in both hemispheres. HCQ may be a promising adjuvant therapy in neonatal HIE. · HCQ decreased neuronal apoptosis in the ischemic penumbra of the rat brain.. · HCQ attenuates hypoxia-ischemia-induced brain injury in neonatal rats.. · HCQ has no anti-inflammatory effect on HI injury..

Effects and mechanisms of 6-hydroxykaempferol 3,6-di-O-glucoside-7-O-glucuronide from Safflower on endothelial injury in vitro and on thrombosis in vivo.

Background: The florets of Carthamus tinctorius L. (Safflower) is an important traditional medicine for promoting blood circulation and removing blood stasis. However, its bioactive compounds and mechanism of action need further clarification. Objective: This study aims to investigate the effect and possible mechanism of 6-hydroxykaempferol 3,6-di-O-glucoside-7-O-glucuronide (HGG) from Safflower on endothelial injury in vitro, and to verify its anti-thrombotic activity in vivo. Methods: The endothelial injury on human umbilical vein endothelial cells (HUVECs) was induced by oxygen-glucose deprivation followed by reoxygenation (OGD/R). The effect of HGG on the proliferation of HUVECs under OGD/R was evaluated by MTT, LDH release, Hoechst-33342 staining, and Annexin V-FITC apoptosis assay. RNA-seq, RT-qPCR, Enzyme-linked immunosorbent assay and Western blot experiments were performed to uncover the molecular mechanism. The anti-thrombotic effect of HGG in vivo was evaluated using phenylhydrazine (PHZ)-induced zebrafish thrombosis model. Results: HGG significantly protected OGD/R induced endothelial injury, and decreased HUVECs apoptosis by regulating expressions of hypoxia inducible factor-1 alpha (HIF-1α) and nuclear factor kappa B (NF-κB) at both transcriptome and protein levels. Moreover, HGG reversed the mRNA expression of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, and reduced the release of IL-6 after OGD/R. In addition, HGG exhibited protective effects against PHZ-induced zebrafish thrombosis and improved blood circulation. Conclusion: HGG regulates the expression of HIF-1α and NF-κB, protects OGD/R induced endothelial dysfunction in vitro and has anti-thrombotic activity in PHZ-induced thrombosis in vivo.

Abciximab coated albumin nanoparticles of rutin for improved and targeted antithrombotic effect

In this work, we fabricated rutin (RTN)-loaded albumin nanoparticles (RTN-ALB-NPs) and abciximab (ABX) coated RTN-loaded albumin nanoparticles (ABX-RTN-ALB-NPs) for the targeted prevention and treatment of thrombosis. The prepared albumin nanoparticles were of 130–200 nm in particle size range with smooth and spherical surface morphology. The entrapment efficiency was achieved up to 73.08% with an in-vitro release rate of 34.49% in the first 4 h and 85.99% by the end of 72 h. The degree of ABX conjugation on the nanoparticle surface about 62% which was further confirmed by X-ray photoelectron spectroscopy analysis, energy-dispersive X-ray spectroscopy analysis and Bradford assay. The serum stability and biocompatibility study demonstrated that the antithrombotic property of RTN was maintained, indicative of good serum stability and hemocompatibility. Moreover, the in-vitro targeting efficiency study showed approximately 10 to 20-fold much higher intracellular fluorescence intensities of targeted formulation than non-targeted formulation towards the activated platelets. The in-vitro platelet aggregation assay and blood clot assay also revealed that the inhibition of thrombus formation was significantly higher when treated with ABX-RTN-ALB-NPs than RTN-ALB-NPs. The findings showed that the developed nanoformulation is a potential site-specific delivery system of RTN for targeted prevention and treatment of thrombosis.

Exploring the mechanism of the antithrombotic effects of Pueraria lobata and Pueraria lobata var. thomsonii based on network pharmacology

Ethnopharmacological relevancePueraria lobata (Willd.) Ohwi and Pueraria lobata var. thomsonii (Benth.) Maesen are nutritious medicine food homology plants that are widely used in the food and health products industry and are excellent natural materials for the development of new health foods, with great potential for domestic and foreign markets. Clinically, P. lobata and P. thomsonii are used to treat coronary heart disease, atherosclerosis, cerebral infarction and other cardiovascular diseases, and antithrombotic actions may be their core effect in the treatment of thrombotic diseases. However, the underlying mechanisms of the antithrombotic properties of P. lobata and P. thomsonii have not been clarified. MethodsFirst, P. lobata and P. thomsonii were identified by high-performance liquid chromatography (HPLC). An arteriovenous bypass thrombosis rat model was established. Thrombus dry‒wet weight, platelet accumulation rate and the four coagulation indices, including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB), were detected in plasma to manifest the P. lobata and P. thomsonii antithrombotic function. Network pharmacology and molecular docking methods were used to obtain key targets and verify reliability. David 6.8 was used for GO and KEGG analyses to explore pathways and potential targets for P. lobata and P. thomsonii antithrombotic functions. Prostaglandin I2 (PGI2), thromboxane A2 (TXA2), cyclooxygenase 2 (COX-2), myeloperoxidase (MPO) and endothelial nitric oxide synthase (eNOS) were tested by enzyme-linked immunosorbent assay (ELISA). ResultsThe results indicated that P. lobata and P. thomsonii can reduce thrombus dry‒wet weight and platelet accumulation in rats and inhibit TT, APTT, FIB, and PT. A comprehensive network pharmacology approach successfully identified 9 active ingredients in P. lobata and P. thomsonii. The main active ingredients include polyphenols, amino acids and flavonoids. A total of 15 antithrombotic function targets were obtained, including 3 key targets (PTGS2, NOS3, MPO). Pathway analysis showed 10 significant related pathways and 29 biological processes. P. lobata and P. thomsonii inhibited platelet aggregation by upregulating PGI2 and downregulating TXA2, inhibited PTGS2 to reduce inflammation, and increased the level of eNOS to promote vasodilation. In addition, P. lobata and P. thomsonii alleviated oxidative stress by increasing SOD levels and significantly decreasing MDA contents. ConclusionThe results of the study further clarify the antithrombotic mechanism of action of P. lobata and P. thomsonii, which provides a scientific basis for the development of new drugs for thrombogenic diseases and lays the foundation for the development of P. lobata and P. thomsonii herbal resources and P. lobata and P. thomsonii health products.

In Vitro Evidence of Statins' Protective Role against COVID-19 Hallmarks.

Despite the progressions in COVID-19 understanding, the optimization of patient-specific therapies remains a challenge. Statins, the most widely prescribed lipid-lowering drugs, received considerable attention due to their pleiotropic effects, encompassing lipid metabolism control and immunomodulatory and anti-thrombotic effects. In COVID-19 patients, statins improve clinical outcomes, reducing Intensive Care Unit admission, the onset of ARDS, and in-hospital death. However, the safety of statins in COVID-19 patients has been debated, mainly for statins’ ability to induce the expression of the ACE2 receptor, the main entry route of SARS-CoV-2. Unfortunately, the dynamic of statins’ mechanism in COVID-19 disease and prevention remains elusive. Using different in vitro models expressing different levels of ACE2 receptor, we investigated the role of lipophilic and hydrophilic statins on ACE2 receptor expression and subcellular localization. We demonstrated that the statin-mediated increase of ACE2 receptor expression does not necessarily coincide with its localization in lipid rafts domains, particularly after treatments with the lipophilic atorvastatin that disrupt lipid rafts’ integrity. Through a proteomic array, we analyzed the cytokine patterns demonstrating that statins inhibit the release of cytokines and factors involved in mild to severe COVID-19 cases. The results obtained provide additional information to dissect the mechanism underlying the protective effects of statin use in COVID-19.

Relationship between liver dysfunction, lipoprotein concentration and mortality during sepsis.

High-density lipoproteins (HDLs) are synthesized by the liver and display endothelioprotective properties, including anti-inflammatory, antiapoptotic, antithrombotic and antioxidant effects. In both septic and chronic liver failure patients, a low HDL cholesterol (HDL-C) concentration is associated with overmortality. Whereas sepsis-associated liver dysfunction is poorly defined, the aim of this study was to characterize the relationship between liver dysfunction, lipoprotein concentrations and mortality in septic patients in the intensive care unit (ICU). A prospective observational study was conducted in a university hospital ICU. All consecutive patients admitted for septic shock or sepsis were included. Total cholesterol, HDL-C, low-density lipoprotein-cholesterol (LDL-C), and triglyceride levels were assessed at admission. Sepsis-associated liver dysfunction was defined as a serum bilirubin≥ 2N or aspartate aminotransferase/alanine aminotransferase concentrations ≥ 2N. Short-term and one-year prognostic outcomes were prospectively assessed. A total of 219 septic patients were included, and 15% of them presented with sepsis-associated liver dysfunction at admission. Low concentrations of lipoproteins were associated with mortality at Day 28 in the overall population. Sepsis-associated liver dysfunction at admission was associated with overmortality. In this subgroup, patients had a lower HDL-C concentration than patients without hepatic dysfunction (HDL-C = 0.31 [0.25, 0.55] mmol/L vs. 0.48 [0.29, 0.73] mmol/L, p = 0.0079) but there was no relationship with the outcome. Interestingly, no correlation was observed between lipoprotein concentrations and liver dysfunction markers. Sepsis-associated liver dysfunction at ICU admission is strongly associated with overmortality and is associated with a lower HDL-C concentration. However, in this subgroup of patients, HDL-C concentration had no relationship with mortality. Further exploratory studies are needed to better understand the interaction between lipoproteins and liver dysfunction during sepsis.

Diallyl Disulfide: A Bioactive Garlic Compound with Anticancer Potential.

Cancer is a life-threatening disease caused by the uncontrolled division of cells, which culminates in a solid mass of cells known as a tumor or liquid cancer. It is the leading cause of mortality worldwide, and the number of cancer patients has been increasing at an alarming rate, with an estimated 20 million cases expected by 2030. Thus, the use of complementary or alternative therapeutic techniques that can help prevent cancer has been the subject of increased attention. Garlic, the most widely used plant medicinal product, exhibits a wide spectrum of biological activities, including antibacterial, hypo-lipidemic, antithrombotic, and anticancer effects. Diallyl disulfide (DADS) is a major organosulfur compound contained within garlic. Recently, several experimental studies have demonstrated that DADS exhibits anti-tumor activity against many types of tumor cells, including gynecological cancers (cervical cancer, ovarian cancer), hematological cancers (leukemia, lymphoma), lung cancer, neural cancer, skin cancer, prostate cancer, gastrointestinal tract and associated cancers (esophageal cancer, gastric cancer, colorectal cancer), hepatocellular cancer cell line, etc. The mechanisms behind the anticancer action of DADS include epithelial-mesenchymal transition (EMT), invasion, and migration. This article aims to review the available information regarding the anti-cancer potential of DADS, as well as summarize its mechanisms of action, bioavailability, and pharmacokinetics from published clinical and toxicity studies.

The loading of C-type natriuretic peptides improved hemocompatibility and vascular regeneration of electrospun poly(ε-caprolactone) grafts

As a result of thrombosis or intimal hyperplasia, synthetic artificial vascular grafts had a low success rate when they were used to replace small-diameter arteries (inner diameter < 6 mm). C-type natriuretic peptides (CNP) have anti-thrombotic effects, and can promote endothelial cell (EC) proliferation and inhibit vascular smooth muscle cell (SMC) over-growth. In this study, poly(ε-caprolactone) (PCL) vascular grafts loaded with CNP (PCL-CNP) were constructed by electrospinning. The PCL-CNP grafts were able to continuously release CNP at least 25 days in vitro. The results of scanning electron microscopy (SEM) and mechanical testing showed that the loading of CNP did not change the microstructure and mechanical properties of the PCL grafts. In vitro blood compatibility analysis displayed that PCL-CNP grafts could inhibit thrombin activity and reduce platelet adhesion and activation. In vitro cell experiments demonstrated that PCL-CNP grafts activated ERK1/2 and Akt signaling in human umbilical vein endothelial cells (HUVECs), as well as increased cyclin D1 expression, enhanced proliferation and migration, and increased vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production. The rabbit arteriovenous (AV)-shunt ex vitro indicated that CNP loading significantly improved the antithrombogenicity of PCL grafts. The assessment of vascular grafts in rat abdominal aorta implantation model displayed that PCL-CNP grafts promoted the regeneration of ECs and contractile SMCs, modulated macrophage polarization toward M2 phenotype, and enhanced extracellular matrix remodeling. These findings confirmed for the first time that loading CNP is an effective approach to improve the hemocompatibility and vascular regeneration of synthetic vascular grafts. Statement of significanceSmall-diameter (< 6 mm) vascular grafts (SDVGs) have not been made clinically available due to their prevalence of thrombosis, limited endothelial regeneration and intimal hyperplasia. The incorporation of bioactive molecules into SDVGs serves as an effective solution to improve hemocompatibility and endothelialization. In this study, for the first time, we loaded C-type natriuretic peptides (CNP) into PCL grafts by electrospunning and confirmed the effectiveness of loading CNP on improving the hemocompatibility and vascular regeneration of artificial vascular grafts. Regenerative advantages included enhancement of endothelialization, modulation of macrophage polarization toward M2 phenotypes, and improved contractile smooth muscle cell regeneration. Our investigation brings attention to CNP as a valuable bioactive molecule for modifying cardiovascular biomaterial.

Systemic lupus erythematosus and cardiovascular disease.

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non-mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.

Bromelain: A Potent Phytomedicine.

The commercially available protein-digesting enzyme bromelain is derived from the pineapple fruit or stem. Bromelain from fruit and stems are produced in different ways and has varied enzyme compositions. “Bromelain” often refers to the "stem bromelain". Bromelain is a combination of several thiol endopeptidases and others including various protease inhibitors, glucosidase, cellulase, phosphatase, peroxidase, and escharase. Studies conducted in both the lab and on animals show that bromelain has a variety of fibrinolytic, anti-edematous, antithrombotic, and anti-inflammatory effects. The body can absorb bromelain to a significant extent without it ceasing its proteolytic activity or having any negative side effects. Numerous therapeutic advantages of bromelain include wound debridement, improved drug absorption, and the management of sinusitis, bronchitis, angina pectoris, surgical trauma, and thrombophlebitis. Additionally, it treats numerous cardiovascular conditions, diarrhoea, and osteoarthritis. Bromelain also encourages apoptotic cell death and exhibits some anti-cancerous properties. This review compiles the crucial traits, medical and dental uses of bromelain as well as its potential mechanism of action.

Antineoplastic Effects of Ankaferd Hemostat.

Materials and Methods Up to June 2022, literature searches were performed using the internet search engines Medline, Google Scholar, and Embase: Ankaferd. PRISMA flow diagram described the Ankaferd search. Results ABS have important effects in several cellular processes, like control of the cell cycle, apoptosis, angiogenesis, signal transduction, inflammation, immunologic, and metabolic mechanisms. The molecular basis of antineoplastic roles of ABS depends on its proteomics, metabolomics, and transcriptomics features. ABS has antineoplastic effects on solid tumors like colon, bladder, breast, and osteosarcoma cancer cells. Also, ABS effects renal tubular apoptosis and has antitumoral roles on malign melanoma cells. ABS inhibits hematological tumors like myeloma and lymphoid cells. ABS induces apoptosis in retinal cells and has inhibitory effects on mesenchymal stem cells. It has an antiproliferative role on gastrointestinal tumors like hepatocellular carcinoma cells. Moreover, ABS has a treatment supportive role in cancer since it can prevent oxidative DNA damage and decrease the intestinal damage in necrotizing enterocolitis. Furthermore, it has chemopreventive and hepatoprotective features and can be used for prophylaxis and treatment of oral mucositis. Conclusion ABS alters cell metabolism and cell cycle. ABS has antineoplastic role on cancer cells. The expanding context of ABS compromises anti-infective, antineoplastic, and wound healing features. ABS may also be used for the palliative, adjuvant, neoadjuvant, or supportive use by interventional radiology procedures for the treatment of solid tumors. Future controlled studies are necessary to clarify the pleiotropic role of ABS like antineoplastic, antithrombotic, anti-inflammatory, anti-infective, antifungal, and antioxidative effects.

Guanxinning tablet inhibits the interaction between leukocyte integrin Mac-1 and platelet GPIbα for antithrombosis without increased bleeding risk.

Recent studies have showed that thrombosis is closely related to leucocytes involved in immunity. Interfering with the binding of leukocyte integrin Mac-1 and platelet GPIbα can inhibit thrombosis without affecting physiological coagulation. Mac-1-GPIbα is proposed as a potential safety target for antithrombotic agents. Guanxinning tablet (GXNT) is an oral Chinese patent medicine used for the treatment of angina pectoris, which contains phenolic acid active ingredients, such as salvianolic acids, ferulic acid, chlorogenic acid, caffeic acid, rosmarinic acid, tanshinol, and protocatechualdehyde. Our previous studies demonstrated that GXN exhibited significant antithrombotic effects, and clinical studies suggested that it did not increase bleeding risk. In addition, GXN exerted a significantly regulatory effect on immune inflammation. In the current study, we intended to evaluate the effects of GXN on bleeding events and explore the safety antithrombotic mechanism of GXN based on leukocyte-platelet interaction. First, we established a gastric ulcer model induced by acetic acid in rats and found that GXN not only did not increase the degree of gastrointestinal bleeding when gastric ulcer occurred, but also had a certain promoting effect on the healing of gastric ulcer. Second, in vitroexperiments showed that after pretreatment with GXN and activation by phorbol 12-myristate-13-acetate (PMA), the adhesion and aggregation of leukocytes with human platelets were reduced. It was also found that GXN reduced the expression and activation of Mac-1 in leucocytes, and inhibited platelet activation due to leukocyte engagement via Mac-1. Overall, the results suggest that GXN may be a safe antithrombotic agent, and its low bleeding risk mechanism is probably related to inhibited leukocyte-platelet aggregation and its interaction target Mac-1-GPIbα.

A Novel Polysaccharide from AuriculariaAuricula Alleviates Thrombosis Induced by Carrageenan in Mice.

The increasing incidence of cardiovascular diseases has created an urgent need for safe and effective antithrombotic agents. In this study, we aimed to elucidate the structural characteristics and antithrombotic activity of a novel polysaccharide isolated from Auricularia auricula fruiting bodies. The purified polysaccharide AAP-b2 (12.02 kDa) was composed of mannose, glucuronic acid, glucose and xylose, with a molar ratio of 89.25:30.50:4.25:1.00. Methylation and NMR analyses showed that AAP-b2 primarily consisted of →2,3)-Manp-(1→, →3)-Manp-(1→, →4)-GlcAp-(1→ and Manp-(1→. A thrombus mouse model induced by carrageenan was used in this research to evaluate its antithrombotic effect. AAP-b2 significantly inhibited platelet aggregation, reduced the black tail length and prolonged the coagulation time, including activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT), exerting a good inhibitory effect on thrombosis in mice. The antithrombotic activity of AAP-b2 was found to be related to the inhibition of platelet activation by regulation of endothelial nitric oxide synthases (eNOs), endothelin-1 (ET-1), prostacyclin (PGI2) and thromboxane B2 (TXB2), along with the enhancement of anticoagulant activity by affecting antithrombin III (AT-III) and protein C (PC) pathways.

Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions.

Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H···water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead molecule 2d in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor 3f (Ki = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.