Molecular Advances in Hypertension and Blood

Hematopoietic cells and their microvesicles have recently emerged as novel markers of cardiovascular risk. The crosstalk between these vesicles and endothelial dysfunction or vascular damage is a field of continuous progress. Additionally, thromboinflammation represents an emerging concept in cardiovascular diseases. In hypertension, the role of signaling pathways in hypertension remains also under investigation. Realizing the unmet needs of increased awareness of treating physicians and active researchers in this complex setting, we launched our Special Issue on “Molecular Advances in Hypertension and Blood”. Our issue has addressed both sides of the coin by publishing four articles that are summarized in this editorial. Firstly, we published an experimental study providing evidence that certain molecular pathways may be involved in myocardial remodeling in the settings of arterial hypertension and chronic kidney disease. Secondly, an in vitro study revealed a novel immune-modulatory effect of Ticagrelor, which is widely used in patients with hypertension and cardiovascular disease. Thirdly, another translational study assessed endothelial injury and pro-coagulant activity using circulating microvesicles in survivors of allogeneic hematopoietic cell transplantation, compared to a control population matched for traditional cardiovascular risk factors. Lastly, a review article delineated the role of Toll-like receptors in the pathogenesis of essential hypertension.

SARS-CoV-2 Spike protein activates TMEM16F-mediated platelet pro-coagulant activity

Background: Thrombosis of the lung micro-vasculature is a characteristic of COVID-19 disease, which is observed in large excess compared to other forms of acute respiratory distress syndrome and thus suggests a trigger for thrombosis endogenous to the lung. Our recent work has shown that the SARS-CoV-2 Spike protein activates the cellular TMEM16F chloride channel and scramblase. Through a screening on >3,000 FDA/EMA approved drugs, we identified Niclosamide and Clofazimine as the most effective molecules at inhibiting this activity. As TMEM16F plays an important role in the stimulation of the pro-coagulant activity of platelets, and considering that platelet abnormalities are common in COVID-19 patients, we investigated whether Spike directly affects platelet activation and pro-thrombotic function and tested the effect of Niclosamide and Clofazimine on these processes. Methods: We produced SARS-CoV-2 Spike or VSV-G protein-pseudotyped virions, or generated cells expressing Spike on their plasma membrane, and tested their effects on platelet adhesion (fluorescence), aggregation (absorbance), exposure of phosphatidylserine (flow cytometry for annexin V binding), calcium flux (flow cytometry for fluo-4 AM), and clot formation and retraction. These experiments were also conducted in the presence of the TMEM16F activity inhibitors Niclosamide and Clofazimine. Results: Here we show that exposure to SARS-CoV-2 Spike promotes platelet activation, adhesion and spreading, both when present on the envelope of virions or upon expression on the plasma membrane of cells. Spike was effective both as a sole agonist or by enhancing the effect of known platelet activators, such as collagen and collagen-related peptide. In particular, Spike exerted a noticeable effect on the procoagulant phenotype of platelets, by enhancing calcium flux, phosphatidylserine externalisation, and thrombin generation. Eventually, this resulted in a striking increase in thrombin-induced clot formation and retraction. Both Niclosamide and Clofazimine almost abolished this Spike-induced pro-coagulant response. Conclusions: Together, these findings provide a pathogenic mechanism to explain thrombosis associated to COVID-19 lung disease, by which Spike present in SARS-CoV-2 virions or exposed on the surface of infected cells, leads to local platelet stimulation and subsequent activation of the coagulation cascade. As platelet TMEM16F is central in this process, these findings reinforce the rationale of repurposing drugs targeting this protein, such as Niclosamide, for COVID-19 therapy.

Extracellular Vesicles in Human Milk

Milk supports the growth and development of infants. An increasing number of mostly recent studies have demonstrated that milk contains a hitherto undescribed component called extracellular vesicles (EVs). This presents questions regarding why milk contains EVs and what their function is. Recently, we showed that EVs in human milk expose tissue factor, the protein that triggers coagulation or blood clotting, and that milk-derived EVs promote coagulation. Because bovine milk, which also contains EVs, completely lacks this coagulant activity, important differences are present in the biological functions of human milk-derived EVs between species. In this review, we will summarize the current knowledge regarding the presence and biochemical composition of milk EVs, their function(s) and potential clinical applications such as in probiotics, and the unique problems that milk EVs encounter in vivo, including survival of the gastrointestinal conditions encountered in the newborn. The main focus of this review will be human milk-derived EVs, but when available, we will also include information regarding non-human milk for comparison.

Cytotoxicity and genotoxicity assessment of the extract and lectins from Moringa oleifera Lam. Seeds / Avaliação da citotoxicidade e genotoxicidade do extrato e lectinas das sementes de Moringa oleifera Lam

Moringa oleifera seeds are used globally as a treatment for water and contain the lectins cMoL and WSMoL, which display coagulant activity. In this study, we sought to determine the cytotoxicity and genotoxicity of the M. oleifera seed extract (SE), prepared with the same procedure that people use for treating water, as well as cMoL and WSMoL, in human peripheral blood mononuclear cells (PBMCs). Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, while genotoxicity was evaluated using the comet assay, with cell nucleoids categorized in classes ranging from 0 (without damage) to 4 (maximum damage). The PBMCs treated with SE, cMoL, and WSMoL displayed viability higher than 60% in treatments with concentrations up to 100 µg/mL. In addition, SE and cMoL displayed low genotoxicity owing to the detection of nucleoids in class 1. However, the number of nucleoids in all classes increased when 50 and 100 µg/mL of WSMoL was administered, reaching a damage frequency of 50.0%. Although M. oleifera SE, cMoL, and WSMoL were not cytotoxic to PBMCs after 24 h of exposure, dose-dependent genotoxic effects were observed, especially with WSMoL. These findings indicate that caution must be exercised when selecting a lectin/extract concentration for water treatment.

Endothelial dysfunction and hypercoagulability in severe sickle cell acute chest syndrome

RationaleAcute pulmonary hypertension (PH) may develop during sickle-cell acute chest syndrome (ACS), and is associated with an increased mortality. Its mechanisms remain poorly known. The question was to assess if there is an endothelial dysfunction and a hypercoagulability in severe ACS, with and without acute PH.MethodsIn a prospective monocenter cohort follow-up study, all sickle-cell adult patients with ACS admitted to the intensive care unit underwent a trans-thoracic echography (TTE), and measurements of biomarkers of coagulation, endothelial activation, and platelet and erythrocyte activation. Acute PH was defined as a high echocardiographic probability of PH. The biological profiles of sickle-cell patients were analysed at the time of ACS, contrasting the existence of acute PH, and compared with steady state and with non-sickle-cell controls (healthy subjects and community-acquired pneumonia (CAP)).ResultsMost patients (36 patients with 39 ACS episodes; 23 males; 27 years old) had thoracic pain, dyspnea and CT scan lung consolidation. Acute PH was diagnosed in 7 patients (19%). Erythrocyte and platelet-derived microparticles (MPs) and the pro-coagulant activity of MPs were higher in ACS patients with acute PH, as compared with their counterparts. As compared with healthy controls, ACS patients had higher levels of tissue factor, fibrin monomers, D-dimer, release of pro-coagulant microparticles, and erythrocyte and platelet-derived MPs. As compared with CAP patients, ACS patients had increased levels of fibrin monomers, and erythrocyte and platelet-derived MPs.ConclusionsSevere ACS is characterised by endothelial dysfunction and hypercoagulability state, with a marked pro-coagulant profile in case of associated PH.

A Review Article on Phytochemical Investigation and Pharmacological Activity of Various Parts of Dalbergia sissoo

Current study discussing the ethnobotanical importance of the different part of the plant Dalbergia sissoo its pharmacological activity and various formulation. Nature is like a treasure of medicine. From last thousands year nature give us several type of medicines which we use for the treatment of different type of diseases and valetudinarism. Dalbergia sissoo is one the most crucial/significant plant with full of medicinal attribute. Dalbergia sissoo (Fabaceae) has reported to possess different type pharmacological activity such as antinociceptive activity, anti-coagulant activity, antibacterial activity, anti-inflammatory activity, memory enhancing activity, antiulcer activity, nephro-protective activity, anti-spermatogenic activity, analgesic activity, antipyretic activity, antitermitic activity, antilithiatic activity, antidiabetic activity, anthelmintic activity, immunomodulation activity and so on. This study divulging the medicinal important and all pharmacological action of the different part of the plant Dalbergia sissoo.