Tangeretin regulates platelet function through inhibition of phosphoinositide 3-Kinase and cyclic nucleotide signaling

OBJECTIVE: Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis. APPROACH AND RESULTS: Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239. CONCLUSIONS: This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease

Pharmacological actions of nobiletin in the modulation of platelet function

Background and Purpose The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin in the modulation of platelet function. Experimental Approach The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. The fibrinogen binding, α-granule secretion and calcium mobilisation assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Key Results Nobiletin was shown to supress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilisation and thrombus formation. Nobiletin was shown to extend bleeding time in mice and reduce the phosphorylation of Akt and PLCγ2 within the collagen receptor (GPVI) - stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of VASP, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. Conclusions and Implications This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore nobiletin may represent a potential antithrombotic agent of dietary origins

Intracellular trafficking, localization, and mobilization of platelet-borne thiol isomerases

OBJECTIVE: Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation. APPROACH AND RESULTS: Immunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13dJinx mice). CONCLUSIONS: Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide-sensitive fusion protein attachment receptor/Munc13-4-dependent vesicular-plasma membrane fusion

Farnesoid X Receptor and its ligands inhibit the function of platelets

Objective - While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results - FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin alphaIIbbeta3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion – This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease

Information uncertainty and investors’ under-reaction

This study investigates the relation between information uncertainty and investors’ under reaction, in other words, whether information uncertainty results in higher investors' under-reaction which is one of the abnormalities of efficient capital market. The sample includes 106 firms listed in Tehran Stock Exchange over the period from 2007 to 2011. We used a sample of 106 companies to test hypotheses. In this research, we used abnormal return volatility, earning forecast dispersion, and earning forecast error as three proxies for measuring information uncertainty. These three criterions are weighted by using factor analysis method and applied as one single factor. We used Equality of Tow Means Test for statistical analysis of research hypothesis. The results indicate that information uncertainty has a positive relationship with investors’ under-reaction

Large anomalous transverse transport properties in atomically thin 2D Fe3GaTe2

Abstract Anomalous transverse conductivities, such as anomalous Hall conductivity (AHC), anomalous Nernst conductivity (ANC), and anomalous thermal Hall conductivity (ATHC), play a crucial role in the emerging field of spintronics. Motivated by the recent fabrication of two-dimensional (2D) ferromagnetic thin film Fe3GaTe2, we investigate the thickness-dependent anomalous transverse conductivities of the 2D Fe3GaTe2 system (from one to four layers). The atomically ultrathin 2D Fe3GaTe2 system shows above-room-temperature ferromagnetism with a large perpendicular magnetic anisotropy energy. Furthermore, we obtain a large AHC of −485 S/cm in the four-layer thickness, and this is further enhanced to −550 S/cm with small electron doping. This AHC is seven times larger than the measured AHC in thicker 2D Fe3GaTe2 (178 nm). The ANC also reaches 0.55 A/K.m in the four-layer structure. Along with these, the four-layer system exhibits a large ATHC (−0.105 ~ −0.135 W/K.m). This ATHC is comparable to the large ATHC found in Weyl semimetal Co3Sn2S2. Based on our results, the atomically ultrathin 2D Fe3GaTe2 system shows outstanding anomalous transverse conductivities and can be utilized as a potential platform for future spintronics and spin caloritronic device applications

Graphene Induced High Thermoelectric Performance in ZnO/Graphene Heterostructure

Abstract Despite the low thermoelectric (TE) efficiency of graphene, its flexibility features are attractive for flexible and wearable next‐generation thermoelectric applications. So, it will be highly desirable to synthesize graphene‐based high TE material. Hence, the possibility of significant enhancement of the TE performance in ZnO/graphene heterostructure is investigated. The ZnO monolayer has a direct band gap of 3.3 eV, while a band gap of 5 meV in the ZnO/graphene heterostructure is found. The highest ZT ≈ 2.4 in the n‐doped ZnO/graphene heterostructure at 500 K is obtained, whereas the ZnO monolayer shows ZT ≈ 1.3 at 700 K. Particularly, this giant ZT in the ZnO/graphene heterostructure is found even at a low carrier concentration (≈1011 carrier cm−2). Besides, the ZnO/graphene heterostructure also displays a ZT ≈ 0.8 even at 300 K with a very low carrier concentration (≈1010 carrier cm−2). This outstanding TE performance originates from the TE coefficient advantages of each layer; high electrical conductivity from graphene and high Seebeck coefficient from ZnO incorporate with reduced thermal conductivity in the heterostructure. The findings will stimulate further studies to confirm the results as well as the development of flexible TE generators based on graphene for Internet of things thermoelectric applications

The impact of internal supply chain integration on perceived product quality: A case study of Moulin de Laghouat Spa

تبحث هذه الدراسة العلاقة بين التكامل الداخلي لسلسلة الامداد و الجودة المدركة للمنتج في شركة  مطاحن الاغواط  بالجزائر. حيث يعتبر كل من التنسيق، التعاون و المشاركة ابعاد للتكامل الداخلي.  تحليل مسار البيانات تم باستخدام طريقة نمذجة المعادلات الهيكلية باستخدام المربعات الصغرى الجزئية وذلك بالاعتماد على برنامج SmartPLS 3. و اسفر تحليل البيانات المجمعة بواسطة الاستبيان لعينة مكونة من ثلاثون عامل الى وجود تاثير للتكامل الداخلي لسلسلة الامداد و التنسيق على الجودة المدركة للمنتج. بينما كل من التعاون و المشاركة  لم يكن لهم اثر على الجودة المدركة للمنتج. بينت نتائج الدراسة انه يتوجب على مؤسسة مطاحن الاغواط اعتماد نظام معلومات فعال يعزز التنسيق، التعاون و المشاركة بين اقسامها و وظائفها،  و يكون ذلك من خلال تبني نظام لتخطيط موارد المؤسساتERP  للوصول الى سلسلة امداد داخلية متكاملة. This study examines the relationship between internal Supply chain integration (ISCI) and Perceived product quality (PPQ) in Moulin de Laghouat company. Inter-functional Coordination (CRD), cooperation (COP), and collaboration (CLB) are introduced as dimensions of the ISCI. In this research, A path model analysis was used to evaluate the model through partial least squares structural equation modeling (PLS-SEM). The analysis of collected data from thirty employees of Moulin de Laghouat company in Algeria was performed using SmartPLS 3. Findings indicate that ISCI and CRD had an impact on PPQ. Simultaneously, both COP and CLB as dimensions of (ISCI) have no significant effect on PPQ. Results show that Moulins de Laghouat should adopt an efficient information system by implementing an ERP system to help different departments coordinating their activities. Moreover, reach a higher level of cooperation and collaboration within ISCI.      &nbsp

Improving seed germination of native species for camel rangeland restoration: effects of cold stratification and temperature

International audienceNative plants of the Sahara are remarkably resistant to prolonged droughts and are important sources of forage, food, and medicine. Their regeneration from seeds after strong anthropogenic disturbances is a challenging step toward their conservation and to mitigate desertification. We studied the germination responses of 43 dominant native species of the Sahara desert that could be propagated from seeds for future ecological restoration projects, exploring the effects of cold stratification and temperatures on seed germination. Seeds were stratified at 4°C for 3 days and then tested for germination at 5, 10, 15, 20, 25, 30, 35, and 40°C. While cold stratification negatively affected four species, it improved the germination of 36 species. Five of these species required cold stratification to germinate. Temperatures during the germination trial significantly influenced seed germinability. Twenty-three species (54%) germinated to higher percentages at intermediate temperatures (20 to 30°C) similar to the maximum temperatures of the rainiest months, when germination in the field is high. Thirteen species (30%) also germinated at a higher temperature (40°C). Seven species (16%) germinated best at low temperatures (5 to 10°C). Our results suggest that cold stratification is an efficient and easy treatment to apply prior to sowing seeds in the field for restoration