Anti-platelet Aggregation Effects Research Articles

Evaluation of Antiplatelet Aggregation and Anticoagulant Effects of Oxalis Debilis Kunth Rhizome Extracts

Cardiovascular disease is one of the leading causes of death globally. The discovery and use of natural products in the prevention and treatment of cardiovascular diseases have achieved great interest. Oxalis debilis is traditionally used for the treatment of various ailments.  This study aimed to investigate the potential antiplatelet and anticoagulant properties of extracts derived from O. debilis rhizome. The rhizome of O. debilis was extracted with methanol and then fractionated to obtain four extracts: the total methanol extract, the n-hexane, ethyl acetate, and water fraction. These four extracts were then tested for their ability to inhibit platelet aggregation and blood coagulation in human blood samples. This report demonstrated for the first time that O. debilis had inhibitory effects on platelet aggregation induced by both adenosine diphosphate and collagen as well as blood coagulation. Moreover, the total methanol extract, the ethyl acetate, and the water fraction had strong antiplatelet aggregation effects. All tested extracts had mild anticoagulant activities. This plant could be a valuable natural source for searching for antithrombotic substances, or for the development of supplementary products for the treatment and prevention of heart diseases and thrombosis.
  

Thrombotic microenvironment responsive crosslinking cyclodextrin metal-organic framework nanocarriers for precise targeting and thrombolysis

Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO3/cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.

Discovery of Novel Hybrids of Edaravone and 6-Phenyl-4,5-dihydropyridazin-3(2H)-one with Antiplatelet Aggregation and Neuroprotection for Ischemic Stroke Treatment.

Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.

Platelet hyperactivity: a comparison of water-soluble, bioactive compound levels in commercial tomato products and water-soluble tomato concentrate, a supplement with an approved EFSA antiplatelet health effect

The aim of this study was to evaluate and compare the concentration of water-soluble bioactive compounds in tomato products (polyphenols profile, water-soluble vitamins and nucleophilic substances) with the concentration of the same bioactive molecules existing in a water-soluble patented tomato extract, water-soluble tomato extract (WSTC), commercially available as FruitFlow®. This patented tomato extract has been recognised by EFSA (European Food Safety Authority) in a specific Health Claim declaration as having an “Antiplatelet health effect”. More than 100 commercial tomato samples, coming from 18 different processing tomato companies worldwide, were analysed and compared with the FruitFlow® supplement. According to the multivariate statistical analyses applied to the data matrix, it is possible to conclude that the commercial tomato products measured (pastes, purees, others) show a significantly higher concentration of water-soluble bioactive molecules (nucleosides/nucleotides and polyphenols) responsible for an anti-platelet aggregation effect than the FruitFlow® dietary supplement.

Hydroxysafflor yellow A inhibits the hyperactivation of rat platelets by regulating the miR-9a-5p/SRC axis

Pathological platelet activation plays a vital role in the prevalence of cardiovascular diseases. Hydroxysafflor yellow A (HSYA) has been shown to have significant anti-platelet aggregation and anti-activation effects, but its mechanism of action is unclear. Our study showed that HSYA inhibited the expression of platelet surface glycoproteins IIβ/III α (GPIIβ/III α) and thromboxane A2 (TXA2) during platelet activation and reduced platelet Ca2+ accumulation. HSYA significantly reduced the number of platelets and inhibited adrenaline-induced platelet hyperaggregation in rats. Transcriptomic analysis of platelets suggested that HSYA significantly suppressed SRC and MAPK3 (ERK1/2) gene expression. YEEI peptide, an SRC activator, could significantly reverse the inhibition of HSYA on the phosphorylation of SRC/PLCγ2/PKCδ/MEK/ERK1/2 pathway proteins and reverse the effect of HSYA on platelet activation-related markers GPIIβ/IIIα protein, TXA2 and cAMP. The SRC genes were further predicted by transcriptome analysis of HSYA-regulated miRNAs combined with bioinformatics techniques. The results suggested that HSYA could significantly upregulate the expression level of the miR-9a-5p gene and further confirmed that miR-9a-5p had a targeted regulatory relationship with SRC by dual-luciferase activity reporter and cell transfection experiments. The inhibitory effect of HSYA on the SRC/PLCγ2/PKCδ/MEK/ERK1/2 pathway was significantly reversed after platelets were transfected with the miR-9a inhibitor, while SRC siRNA attenuated the effect of the miR-9a inhibitor. SRC siRNA was able to attenuate the effect of the miR-9a inhibitor. In conclusion, this study suggests that HSYA can inhibit the activation of the SRC/PLCγ2/PKC δ/MEK/ERK1/2 axis by upregulating platelet miR-9a-5p, thereby reducing the activation of platelets and inhibiting platelet aggregation.

Phytochemistry and Pharmacology of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu: A Review.

Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y.Hu (E. sessiliflorus), a member of the Araliaceae family, is a valuable plant widely used for medicinal and dietary purposes. The tender shoots of E. sessiliflorus are commonly consumed as a staple wild vegetable. The fruits of E. sessiliflorus, known for their rich flavor, play a crucial role in the production of beverages and fruit wines. The root barks of E. sessiliflorus are renowned for their therapeutic effects, including dispelling wind and dampness, strengthening tendons and bones, promoting blood circulation, and removing stasis. To compile a comprehensive collection of information on E. sessiliflorus, extensive searches were conducted in databases such as Web of Science, PubMed, ProQuest, and CNKI. This review aims to provide a detailed exposition of E. sessiliflorus from various perspectives, including phytochemistry and pharmacological effects, to lay a solid foundation for further investigations into its potential uses. Moreover, this review aims to introduce innovative ideas for the rational utilization of E. sessiliflorus resources and the efficient development of related products. To date, a total of 314 compounds have been isolated and identified from E. sessiliflorus, encompassing terpenoids, phenylpropanoids, flavonoids, volatile oils, organic acids and their esters, nitrogenous compounds, quinones, phenolics, and carbohydrates. Among these, triterpenoids and phenylpropanoids are the primary bioactive components, with E. sessiliflorus containing unique 3,4-seco-lupane triterpenoids. These compounds have demonstrated promising properties such as anti-oxidative stress, anti-aging, antiplatelet aggregation, and antitumor effects. Additionally, they show potential in improving glucose metabolism, cardiovascular systems, and immune systems. Despite some existing basic research on E. sessiliflorus, further investigations are required to enhance our understanding of its mechanisms of action, quality assessment, and formulation studies. A more comprehensive investigation into E. sessiliflorus is warranted to delve deeper into its mechanisms of action and potentially expand its pharmaceutical resources, thus facilitating its development and utilization.

Mechanisms of glabridin inhibition of integrin αIIbβ3 inside-out signals and NF-κB activation in human platelets

BackgroundPlatelets play a crucial role in cardiovascular diseases (CVDs) and are activated by endogenous agonists like collagen. These agonists initiate signal transduction through specific platelet receptors, resulting in platelet aggregation. Glabridin, a prenylated isoflavonoid found in licorice root, is known for its significance in metabolic abnormalities. Glabridin has been observed to inhibit collagen-induced platelet aggregation, but the precise mechanisms, specifically concerning NF-κB activation and integrin αIIbβ3 signaling, are not yet fully understood.MethodsIn this study, platelet suspensions were prepared from healthy human blood donors, and the aggregation ability was observed using a lumi-aggregometer. The inhibitory mechanisms of glabridin in human platelets were evaluated through immunoblotting and confocal microscopy. The anti-thrombotic effects of glabridin were assessed by histological analysis of lung sections in acute pulmonary thromboembolism and by examining fluorescein-induced platelet plug formation in mesenteric microvessels in mice.ResultsGlabridin inhibited integrin αIIbβ3 inside-out signals such as Lyn, Fyn, Syk, and integrin β3 activation and NF-κB-mediated signal events, with similar potency to classical inhibitors BAY11-7082 and Ro106-9920. Glabridin and BAY11-7082 inhibited IKK, IκBα, and p65 phosphorylation and reversed IκBα degradation, while Ro106-9920 only reduced p65 phosphorylation and reversed IκBα degradation. BAY11-7082 reduced Lyn, Fyn, Syk, integrin β3, phospholipase Cγ2 and protein kinase C activation. Glabridin reduced platelet plug formation in mesenteric microvessels and occluded vessels in thromboembolic lungs of mice.ConclusionOur study revealed a new pathway for activating integrin αIIbβ3 inside-out signals and NF-κB, which contributes to the antiplatelet aggregation effect of glabridin. Glabridin could be a valuable prophylactic or clinical treatment option for CVDs.

Improving Chuanxiong Rhizoma quality standards using an effect-constituent index based bioassay

Chuanxiong Rhizoma is a traditional Chinese medicine (TCM) that is used to promote blood circulation. We set out to improve Chuanxiong Rhizoma quality standards using a bioassay-based Effect-constituent Index (ECI). We performed high performance liquid chromatography (HPLC) analysis to determine the chemical constituents of 10 Chuanxiong Rhizoma samples from different locations. We then constructed a direct bioassay method to investigate each sample’s antiplatelet aggregation effects. To screen for active ingredients that promote antiplatelet aggregation, we carried out Pearson correlation analyses between biopotency and compounds identified in the HPLC data. We developed an ECI of platelet aggregation inhibition using a multi-indicator synthetic evaluation method based on the integration of biopotency and active constituents. To further assess the biopotency-based Chuanxiong Rhizoma quality evaluation result accuracy, we compared the ECI with the chemical indicator’ method. Eight common chemical fingerprints peaks indicated notable content variation among samples. Biological evaluation showed that all 10 samples could inhibit platelet aggregation, although they had significantly different biological potencies. Using spectrum-effect relationships, we determined that Ligustilide was the significant active constituent responsible for antiplatelet aggregation. Using correlation analysis, we found that ECI correlated with the Chuanxiong Rhizoma extract’s platelet aggregation inhibitory effect. Additionally, ECI proved to be a good indicator of Chuanxiong Rhizoma quality, whereas chemical indicators failed to distinguish and predict the biopotency-based quality grade. This work indicates that ECI is a useful tool for associating sample quality with chemical markers linked to TCM clinical effects. ECI also provides a paradigm for improving the quality control of other TCMs that invigorate blood circulation.

Tyrame [N-(3-hydroxy-1:3:5(10)-estratrien-17β-yl)-4-hydroxy-phenethylamine], antithrombotic aminoestrogen that decreases microvesicle formation.

Estrogens that are used as contraceptives or in replacement therapy are associated with an increase in the risk for developing thrombosis, mainly during the first year of treatment and in women with associated risk factors. To synthesize, characterize and identify the anticoagulant, antiplatelet aggregation and microvesicle-reducing effect of the new aminoestrogen Tyrame. CD1 strain mice were used, which had Tyrame (0, 1 and 2 mg/100 g) subcutaneously administered. At 24 h, a blood sample was obtained to determine whole-blood clotting time, microvesicles concentration and inhibitory effect on platelet aggregation. Blood clotting time increased up to 1.5 times in comparison with the control. Platelet aggregation inhibition had different magnitude depending on the agonist agent employed, and was complete with collagen. Both effects had a dose-dependent relationship. The microvesicles decreased up to six times with respect to the control. Tyrame reduces platelet aggregation and microvesicle formation, which emphasizes its potential therapeutic utility as an estrogen free of thrombotic effects.

Panax notoginseng saponins promote hair follicle growth in mice via Wnt/β-Catenin signaling pathway.

Panax notoginseng saponins (PNS), the active ingredients of the traditional Chinese medicine Panax notoginseng, have strong neuroprotective and anti-platelet aggregation effects. To investigate whether PNS can promote hair follicle growth in C57BL/6J mice, the optimal concentration of PNS was initially determined, followed by clarification of the mechanism underlying their effects. Twenty-five male C57BL/6J mice had the hair on a 2 × 3cm2 area of the dorsal skin shaved and were equally divided into five groups: control group, 5% minoxidil (MXD) group, and three PNS treatment groups [2% (10mg/kg), 4% (20 mg/kg), and 8% (40 mg/kg) PNS]. They were then intragastrically administered the corresponding drugs for 28 days. The effects of PNS on C57BL/6J mice were analyzed by subjecting their dorsal depilated skin samples to different assessments, including hematoxylin and eosin staining, immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting (WB). The group with 8% PNS exhibited the largest number of hair follicles from 14 days onwards. Compared with the control group, the number of hair follicles increased significantly in the mice treated with 8% PNS and 5% MXD, which significantly increased in a PNS-dose-dependent manner. Immunohistochemistry and immunofluorescence results revealed that treatment with 8% PNS activated the metabolism of hair follicle cells, with them showing higher rates of proliferation and apoptosis than those in the normal group. In qRT-PCR and WB analysis, the expression of β-catenin, Wnt10b, and LEF1 was upregulated in the PNS and MDX groups compared with that in the control group. Examination of the WB bands revealed that the greatest inhibitory effect of Wnt5a occurred in mice in the 8% PNS group. PNS may promote the growth of hair follicles in mice, with 8% PNS demonstrating the strongest effect. The mechanism behind this may be related to the Wnt/β-catenin signaling pathway.

Electrochemical Biosensor for Detection of the CYP2C19*2 Allele Based on Exonuclease Ⅲ

Currently, the therapeutic effect of clopidogrel differs considerably among individuals and is thought to be closely related to the genetic polymorphism of CYP2C19. The CYP2C19*2 gene can reduce the antiplatelet aggregation effect of clopidogrel, which increases the risk of major cardiovascular adverse events in patients. In this research, we report a new type of biosensor for the highly sensitive detection of the CYP2C19*2 gene based on exonuclease III assisted electric signal amplification and the use of calixarene to enrich electrical signal substances. Specifically, under the best conditions, the logarithmic concentrations of the analytes have a good linear relationship with the peak current in the range of 0.01 fM to 100 pM and the detection limit is 13.49 aM. The results have also shown that this method has good selectivity, high sensitivity, and stability, etc., and will provide a very promising application for the detection of the CYP2C19*2 gene and other biological molecules by replacing corresponding nucleic acid sequences.

Antithrombotic and Antioxidant Activities of Binahong [Anredera cordifolia (Ten.) Steenis] Leaf Ethanol Extract and Its Nanoemulsion Preparation in Swiss Webster Mice

Platelet aggregation has the potential to form thrombi and result in cardiovascular system diseases such as myocardial infarction and ischemic stroke - one of the leading causes of death globally. Traditionally, people use binahong leaves as blood thinners. Therefore, this study aims to obtain scientific data on the efficacy of binahong leaf  as antithrombotic. The efficacy test was carried out on male Swiss-Webster mice. The results showed that the ethanol extract of binahong leaves at doses of 50 (BLEE50) and 100 mg/kg bw (BLEE100) could increase bleeding time on H7 (7.61±1.79% and 3.72±1.76% vs 1.08±0.90%) and H14 (13.81±4.42% and 5.06±2.30% vs 1.66±1.09%) and coagulation time at H7 (5.01±1.36% and 4.18±1.67% vs 1.38±1.08%) and at H14 (7.92±1.97% and 7.19±1.96% vs 1.70±1.10%) significantly (p<0.05). The two doses of BLEE were formulated in the form of nanoemulsions with the Self Nano Emulsifying Drug Delivery System (NBLEE50 and NBLEE100) were also able to prolong bleeding time and coagulation time significantly (p<0.01) but only NBLEE50 prolonged bleeding time (p<0.05) significantly against BLEE50. In the test of the anti-platelet aggregation effect with ADP as an inducer, both doses of BLEE and the nanoemulsion preparation (NBLEE) could significantly (p<0.01)  inhibit platelet aggregation with a percentage of inhibition >70% which was not different from the standard (acetylsalicylic acid). In the antioxidant effect test using the DPPH method, BLEE has an IC50 = 66.08?g/mL which is classified as a strong antioxidant. Both doses of BLEE and its NBLEE could significantly (p<0.01) inhibit lipid peroxidation in plasma and liver and NO radicals formation. BLEE50 can significantly (p<0.05) reduce mean platelet volume (6.05±0.24fL vs 6.55±0.34fL) and platelet distribution width (8.52±0.36% vs 9.25±0.42%). Based on those results, BLEE has the potential to be used as an antiplatelet aggregation and antioxidant.

A comprehensive review of Rubia cordifolia L.: Traditional uses, phytochemistry, pharmacological activities, and clinical applications.

Rubia cordifolia (family: Rubiaceae) L (R. cordifolia) is a perennial botanical drug climbing vine. As the main part of the traditional Chinese medicine, the rhizome has a long history. A great number of literary studies have reported that it can be used for the improvement of blood circulation, hemostasis, activation of collaterals, etc. When it comes to the wide application of R. cordifolia in traditional medicine, we systematically review its traditional uses, phytochemistry and pharmacological effects. Literatures were systematically searched using several scientific databases, including China National Knowledge Infrastructure (CNKI), Baidu Scholar, PubMed, Web of Science, and other professional websites. Kew Botanical Garden and the iPlant were used for obtaining the scientific names and plant images of R. cordifolia. In addition, other information was also gathered from books including traditional Chinese herbal medicine, the Chinese Pharmacopoeia, and Chinese Materia Medica. So far, many prescriptions containing R. cordifolia have been widely used in the clinical treatment of abnormal uterine bleeding, primary dysmenorrhea and other gynecological diseases, allergic purpura, renal hemorrhage and other diseases. The phytochemistry studies have reported that more than 100 compounds are found in R. cordifolia, such as bicyclic peptides, terpenes, polysaccharides, trace elements, flavonoids, and quinones. Among them, quinones and peptides are the types of components with the highest contents in R. cordifolia. The modern pharmacological studies have revealed that R. cordifolia and its derived components have anti-tumor, anti-oxidative, anti-platelet aggregation, and anti-inflammatory effects. However, most studies are preclinical. The pharmacological mechanism of R. cordifolia has not been thoroughly studied. In addition, there are few pharmacokinetic and toxicity studies of R. cordifolia, therefore the clinical safety data for R. cordifolia is lacking. To sum up, this review for the first time summarizes a systemic and integrated traditional uses, chemical compositions, pharmacological actions and clinical applications of R. cordifolia, which provides the novel and full-scale insight for the drug development, medicinal value, and application of R. cordifolia in the future.

Kadsura longipedunculata Finet & Gagnepain (Schisandraceae): An Overview of Botany, Traditional Uses, Phytochemistry and Pharmacological Activities

Kadsura longipedunculata Finet & Gagnepain (Chinese Kadsura vine) is an evergreen climbing shrub that is widely found in the southwest province of China. The plant can be used as folk medicine to cure canker sores, dysmenorrhea, traumatic injury, insomnia, rheumatoid arthritis, gastrointestinal inflammation, menstrual disorders, and feminine condition. We conducted an open-ended, online database search with the help of Baidu Scholar, CNKI, Elsevier, Scopus, ScienceDirect, Google, Pubmed, and Web of Science for all publications accessible from 1986 to 2022, using the terms related to traditional uses, botany, phytochemistry, and pharmacological properties. A total of ca. 314 phytochemicals were reviewed and identified in K. longipedunculata, with lignans and terpenoids as the predominant groups. The isolated compounds of this plant possess cytotoxic, antioxidant, antitumor, anti-inflammatory, anti-insomnia, anti-trypanosomal, anti-platelet aggregation, hepatoprotective, and other pharmacological effects. This review offers primary data for further research needed to determine the chemical components responsible for its pharmacological effect in order to continue its traditional use. More clinical and preclinical evidence is required to determine the rationale and safety of using K. longipendunculata for medicinal and food purposes.

Synthesis of novel purine derivatives: Antiplatelet aggregation activity evaluation and 3D‐QSAR analysis

AbstractCardiovascular disease caused by platelet aggregation is a serious threat to human health, so antiplatelet aggregation has great significance to treat the disease. Since, purine derivatives are important molecules with antiplatelet aggregation activity, it is very essential to study the relationship between purine structure and antiplatelet aggregation effect, which could help us to find antithrombotic drugs. This article describes the modification of molecular substituents with purine structures as backbone and evaluates their antiplatelet aggregation activity. 3D‐QSAR analysis of a series of novel purine derivatives synthesized was performed based on self‐organized molecular field analysis (SOMFA). Significant correlation coefficients (SOMFA, r2 = 0.821, rcv2 = 0.807, F value = 283.500, SEE = 0.229) were obtained, and the model prediction ability was validated using the test set. The results suggest that rational modification of the substituent groups can provide a basis for the development of more effective drug molecules.

Preparation and pharmacological effects of minor ginsenoside nanoparticles: a review.

Ginseng (Panax ginseng) is a perennial herbaceous plant belonging to Panax genus of Araliaceae. Ginsenosides are a kind of important compounds in ginseng and minor ginsenosides are secondary metabolic derivatives of ginsenosides. Studies have shown that minor ginsenosides have many pharmacological effects, such as antioxidant, anti-tumor, anti-platelet aggregation, and neuroprotective effects. However, the therapeutic effects of minor ginsenosides are limited due to poor solubility in water, short half-life, and poor targeting accuracy. In recent years, to improve the application efficiency, the research on the nanocrystallization of minor ginsenosides have attracted extensive attention from researchers. This review focuses on the classification, preparation methods, pharmacological effects, and action mechanisms of minor ginsenoside nanoparticles, as well as existing problems and future direction of relevant research, which provides a reference for the in-depth research of minor ginsenoside nanoparticles.

Adenosine A2A receptor as a potential target for improving cancer immunotherapy.

The adenosine nucleoside performs a wide range of actions on various human tissues by activating four cell surface receptors. Adenosine A2A receptors (A2ARs) are widely expressed in the striatum, olfactory bulb, platelets, leukocytes, spleen, and thymus. They promote vasodilatation, platelet antiaggregatory effect, protection from ischemic damage, and regulation of sensorimotor neurons in basal ganglia. Adenosine signaling plays a vital part in modulating in vivo pathophysiological responses. A2ARs are potent negative regulators of the antitumor and proinflammatory actions of activated T cells. This axis offers several therapeutic targets, the most important of which are A2ARs, HIF-1α, and CD39/CD73. Downregulation of this axis increases the effectiveness of modern immunotherapeutic approaches against cancer, such as αCTLA-4/αPD-1. These discoveries have led to a promising novel role of antagonists of A2AR in blocking angiogenesis in immunotherapy of cancer. A small molecule, AZD4635, strongly inhibits A2AR, lowering cancer volume and increasing anticancer immunity. Deletion of A2AR with CRISPR/Cas9 in both human and murine CAR T cells produces a substantial increase in the efficiency of these cells. This review asserts that inhibition of the adenosinergic pathway can boost antitumor immunity, and this axis should be a target for future immunotherapeutic strategies.

Effective components and mechanism analysis of anti-platelet aggregation effect of Justicia procumbens L.

Ethnopharmacological relevanceJusticia procumbens L. is a traditional Chinese medicine, first recorded in "Shen Nong's Herbal Classic", for the treatment of lumbar pain and fever. As a widely distributed herb, it has also been documented in India, Nepal, and Malaysia. In “Tang Materia Medica”, a famous medicinal book of Tang Dynasty in ancient China, it was first used to treat diseases associated with blood stasis. Blood stasis syndrome is closely related to thrombus formation and platelet aggregation. Although some compounds isolated from this plant have anti-platelet aggregation effects, the main chemical components and mechanism of J. procumbens in terms of these effects are little known. Aims of the studyThrough in vivo and in vitro experiments, this studsy revealed the characteristic components and action mechanism of anti-platelet aggregation by J. procumbens from an overall perspective. Materials and methodsThe effective crude extracts of the whole plant were screened via an in vitro anti-platelet aggregation test. After incubating these extracts with apheresis platelets, high affinity compounds were detected by HPLC-MS and regulatory genes were detected using gene chips. The effective components and potential target proteins were analyzed using computational docking technology. Furthermore, the compound with the strongest predicted activity was evaluated in vivo via an anti-thrombotic test. ResultsIntegrin aⅡbβ3, PKCα, PI3Kγ, and mitogen-activated protein kinase 14 were found to be potential targets. Justicidin B, tuberculatin, chinensinaphthol methyl ether, and neojusticin B were effective compounds that inhibited human platelet aggregation by suppressing Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways. Among the compounds that bind to platelets, justicidin B showed the strongest virtual binding force. The test of carotid artery thrombosis induced by ferric chloride in SD rats confirmed that justicidin B inhibited thrombus formation. ConclusionExperimental investigation showed that arylnaphthalene lignan aglycones with one methylenedioxy group and two methoxy groups are effective components for anti-platelet aggregation by J. procumbens. These compounds inhibit Gq-PLC-PKC and Gi-PI3K-MAPK signaling pathways by suppressing the expression of genes such as ITGB3, PRKCA, PIK3CG, and MAPK14. These results reflected the characteristics of multi-component and multi-target synergistic treatment of Chinese medicine.

Assessment of Polyunsaturated Fatty Acids on COVID-19-Associated Risk Reduction.

Pooled evidence conveys the association between polyunsaturated fatty acids and infectious disease. SARS-CoV-2, an enveloped mRNA virus, was also reported to interact with polyunsaturated fatty acids. The present review explores the possible mode of action, immunology, and consequences of these polyunsaturated fatty acids during the viral infection. Polyunsaturated fatty acids control protein complex formation in lipid rafts associated with the function of two SARS-CoV-2 entry gateways: angiotensin-converting enzyme-2 and cellular protease transmembrane protease serine-2. Therefore, the viral entry can be mitigated by modulating polyunsaturated fatty acids contents in the body. α-Linolenic acid is the precursor of two clinically important eicosanoids eicosapentaenoic acid and docosahexaenoic acid, the members of ω-3 fats. Resolvins, protectins, and maresins derived from docosahexaenoic acid suppress inflammation and augment phagocytosis that lessens microbial loads. Prostaglandins of 3 series, leukotrienes of 5 series, and thromboxane A3 from eicosapentaenoic acid exhibit anti-inflammatory, vasodilatory, and platelet anti-aggregatory effects that may also contribute to the control of pre-existing pulmonary and cardiac diseases. In contrast, ω-6 linoleic acid-derived arachidonic acid increases the prostaglandin G2, lipoxins A4 and B4, and thromboxane A2. These cytokines are pro-inflammatory and enhance the immune response but aggravate the COVID-19 severity. Therefore, the rational intake of ω-3-enriched foods or supplements might lessen the complications in COVID-19 and might be a preventive measure.Graphic

Preparation of injectable clopidogrel loaded submicron emulsion for enhancing physicochemical stability and anti-thrombotic efficacy

Due to the superior safety and therapeutic efficacy, clopidogrel (CLP) has been widely used to prevent postoperative thrombosis. However, limitations of delayed absorption and metabolic activation of clopidogrel after oral administration hinder its clinic use for acute thrombosis treatment in percutaneous coronary intervention (PCI). Although clopidogrel aqueous injection systems were designed and developed, chemical instability under physiological condition or vascular irritation remains to be solved. In this study, we aim to prepare an injectable clopidogrel loaded submicron emulsion to overcome the drawbacks of conventional clopidogrel aqueous formulation and improve the antiplatelet aggregation effects. Results showed that this delivery system exerted inspiring features including uniform particle size, higher drug loading capacity and sustained drug release behavior. It can dramatically upgrade the formulation stability and prevent the drug degradation under sterilization or higher pH environments. No remarkable droplet size increase or drug content decrease was observed during storage. Compared to CLP tablet, the peak drug concentration (Cmax) and area under the curve (AUC) of CLP emulsion increased by 12.01-fold and 4.69-fold, respectively. Most importantly, it exerted excellent in vivo anti-thrombotic effect on numerous designed animal models. Conclusively, submicron emulsion is a promising delivery system for improving clopidogrel stability and anti-thrombotic efficacy.