Coumarin derivates have been known for their antithrombotic, anti‐inflammatory, and antioxidant activities and daphnetin is one of the natural coumarin derivatives isolated from Daphne Korean Nakai. ...Although the pharmacological value of daphnetin is well documented in diverse biological activities, its antithrombotic effect is not studied till date.
We investigated the functional role of daphnetin and its molecular basis on the regulation of platelet activation using murine platelets.
In order to check the effect of daphnetin on GPVI‐mediated platelet response, we first measured the effect of daphnetin on collagen‐induced platelet aggregation and secretion. Collagen‐induced platelet aggregation and dense granule secretion were partially inhibited in the presence of daphnetin. Interestingly, 2‐MeSADP‐induced secondary wave of aggregation and secretion were completely inhibited in the presence of daphnetin. It has been known that 2‐MeSADP‐induced secretion and the resultant secondary wave of aggregation are mediated by positive‐feedback effect of thromboxane A2 (TxA2) generation, suggesting the important role of daphnetin on TxA2 generation in platelets. Consistently, daphnetin did not affect the 2‐MeSADP‐induced platelet aggregation in aspirin‐treated platelets where the contribution of TxA2 generation is blocked. Additionally, AYPGKF‐induced platelet aggregation and secretion were inhibited in the presence of daphnetin by blocking the positive‐feedback effect of TxA2 generation. Moreover, 2‐MeSADP‐induced TxA2 generation was completely inhibited in the presence of daphnetin confirming the role of daphnetin on TxA2 generation. Finally, 2‐MeSADP‐induced ERK phosphorylation was inhibited in the presence of daphnetin.
We conclude that daphnetin plays a role in platelet function by inhibiting the TxA2 generation through the regulation of ERK phosphorylation.
Endogenous hypercortisolism is associated with increased risk of blood‐related diseases such as high blood pressure and hyperglycemia that result in fatal cardiovascular disorders. Platelet plays a ...major role in hemostasis and thrombosis. Although it is well known that glucocorticoids exert a significant effect on hemostasis, the effect of endogenous cortisol on platelet function is much less clear.
We aimed to characterize the in vitro effect of prednisolone and its molecular basis on regulation of platelet function using murine platelets.
We first evaluated the concentration‐dependent effect of prednisolone on 2‐MeSADP‐induced platelet function and found that 2‐MeSADP‐induced secondary wave of aggregation and dense granule secretion were completely inhibited from 500 nM prednisolone. Since 2‐MeSADP‐induced secretion and the resultant secondary wave of aggregation is mediated by thromboxane A2 (TxA2) generation, this result suggested a role of prednisolone on TxA2generation in platelets. Consistently, prednisolone did not affect the 2‐MeSADP‐induced aggregation in aspirin‐treated platelets, where the secondary wave of aggregation and secretion were blocked by eliminating the contribution of TxA2 generation by aspirin. In addition, AYPGKF‐ and thrombin‐induced platelet aggregation and secretion were inhibited in the presence of prednisolone by inhibiting the positive‐feedback effect of TxA2 generation on platelet function. Furthermore, prednisolone completely inhibited 2‐MeSADP‐induced TxA2 generation confirming the role of prednisolone on TxA2 generation. Finally, Western blot analysis revealed that prednisolone inhibited the 2‐MeSADP‐induced ERK phosphorylation.
In conclusion, prednisolone affects platelet function by the inhibition of TxA2 generation through the regulation of ERK phosphorylation, thereby shedding light on the clinical characterization and its treatment efficacy in patients with cardiovascular disorders in the future.
Nanocrystalline pure and gadolinium (Gd) doped zinc oxide (Zn
1−
x
Gd
x
O) films were synthesized on a glass substrate by unconventional sol–gel screen-printing process. The prepared samples were ...then fired (sintered) at 500 °C to get the desired stoichiometry. The samples thus prepared were analyzed for their structural, morphological, optical and electrical features by exploiting x-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive x-ray (EDX), UV–visible spectroscopy, photoluminescence (PL) spectroscopy and dark (DC) electrical resistivity appraised by two-probe unit. XRD analysis exposed that all the samples were polycrystalline in character exhibiting single-phase hexagonal wurtzite structure. Fiber-like surface morphology was exhibited by the samples. EDX technique indicates that the samples have the prerequisite constituent elements in stoichiometric ratio. The optical band gap (E
g
) showed an increment from 3.24 to 3.45 eV on increasing the doping concentration of gadolinium from
x
= 0 to
x
= 0.05 illustrating a band gap tuning of 6.48%. PL spectra of prepared samples displayed a strong near band edge emission along with a weak green emission. Dark (DC) electrical resistivity was found to decrease with the increase in gadolinium doping concentration.
Increased risk of fungal diseases in immunocompromised patients, emerging fungal pathogens, limited repertoire of antifungal drugs and resistance development against the drugs demands for development ...of new and effective antifungal agents. With greater knowledge of fungal metabolism efforts are being made to inhibit specific enzymes involved in different biochemical pathways for the development of antifungal drugs. Chitin synthase is one such promising target as it is absent in plants and mammals. Nikkomycin Z, a chitin synthase inhibitor is under clinical development. Chitin synthesis in fungi, chitin synthase as a target for antifungal agent development, different chitin synthase inhibitors isolated from natural sources, randomly synthesized and modified from nikkomycin and polyoxin are discussed in this review.
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. ...Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients.
G protein-coupled receptor kinases (GRKs) are protein kinases that function in concert with arrestins in the regulation of a diverse class of G protein-coupled receptors (GPCRs) signaling. Although ...GRKs and arrestins are key participants in the regulation of GPCR cascades, the complex regulatory mechanisms of GRK expression, its alternation, and their function are not thoroughly understood. Several studies together with the work from our lab in recent years have revealed the critical role of these kinases in various physiological and pathophysiological processes, including cardiovascular biology, inflammation and immunity, neurodegeneration, thrombosis, and hemostasis. A comprehensive understanding of the mechanisms underlying functional interactions with multiple receptor proteins and how these interactions take part in the development of various pathobiological processes may give rise to novel diagnostic and therapeutic strategies. In this review, we summarize the current research linking the role of GRKs to various aspects of cell biology, pathology, and therapeutics, with a particular focus on thrombosis and hemostasis.
Platelets play a variety of roles in vascular biology and are best recognized as primary hemostasis and thrombosis mediators. Platelets have a large number of receptors and secretory molecules that ...are required for platelet functionality. Upon activation, platelets release multiple substances that have the ability to influence both physiological and pathophysiological processes including inflammation, tissue regeneration and repair, cancer progression, and spreading. The involvement of platelets in the progression and seriousness of a variety of disorders other than thrombosis is still being discovered, especially in the areas of inflammation and the immunological response. This review represents an integrated summary of recent advances on the function of platelets in pathophysiology that connects hemostasis, inflammation, and immunological response in health and disease and suggests that antiplatelet treatment might be used for more than only thrombosis.
In this study, Gd
0.02
Zn
0.98
O (GZO) film was coated onto ordinary glass substrate by unusual sol–gel screen printing procedure. Gadolinium was successfully integrated into ZnO lattice as confirmed ...by XRD study. The developed film was polycrystalline in nature and displayed hexagonal (wurtzite) structure with favored orientation in (101) direction. SEM picture exposed the formation of fibrous structure on whole glass substrate. The direct nature of band gap with a value of 3.35 eV was determined by UV-Visible spectrum in reflectance mode. A strong emission peak near the band edge along with weak green emission were exposed by PL spectra. The electrical features of the film were scrutinized by Hall measurement and it was observed that the film showed
n
-type conductivity with low resistivity value of about 1.07 × 10
–3
Ω cm.
Introduction This study was aimed to investigate the effect of multimodal intervention on the cognitive functions of older adults with subjective cognitive impairment (SCI). Materials and methods ...Sixty subjects were randomized 1:1:1:1 to receive either computer based cognitive therapy (CBCT) or CBCT+Mediterranean equivalent diet (MED) or CBCT+MED+ Exercise regime and the control group. The intervention group received supervised CBCT twice a week to have 40 sessions, each of 40 minutes duration, and/ or supervised aerobic and resistive exercise twice a week for 24 weeks and or MED at home under the supervision of a dietician. The control group was provided with health awareness instructions for brain stimulating activities such as sudoku, mental maths, and learning music and new skills. Results Cognitive functions which was the primary outcome measure were assessed using the Post Graduate Institute Memory Scale (PGI-MS), and Stroop Colour and Word Test at baseline and after 6 months intervention period. As assessed by the PGI-MS, there was significant improvement in domains such as mental balance, attention and concentration, delayed recall, immediate recall, verbal retention of dissimilar pairs, Visual retention, and total score both in the unimodal and multimodal intervention groups. However, the improvement was observed to be the highest in the multimodal intervention group as compared to unimodal group. All the participants completed the trial. Conclusion This pilot randomized control trial indicated that multimodal intervention could be an effective non-pharmacological intervention in individuals with SCI for improving their cognitive functions.
Platelet activation has a major role in hemostasis and thrombosis. Various agonists including adenosine diphosphate (ADP) and thrombin interact with G protein-coupled receptors (GPCRs) which ...transduce signals through various G proteins. Recent studies have elucidated the role of GPCRs and their corresponding G proteins in the regulation of events involved in platelet activation. However, agonist-induced platelet activation in companion animals has not been elucidated. This study was designed to characterize the platelet response to various agonists in dog platelets. We found that 2-methylthio-ADP-induced dog platelet aggregation was blocked in the presence of either P2Y₁ receptor antagonist MRS2179 or P2Y₁₂ receptor antagonist AR-C69931MX, suggesting that co-activation of both the P2Y₁ and P2Y₁₂ receptors is required for ADP-induced platelet aggregation. Thrombin-induced dog platelet aggregation was inhibited in the presence of either AR-C69931MX or the PKC inhibitor GF109203X, suggesting that thrombin requires secreted ADP to induce platelet aggregation in dog platelets. In addition, thrombin-mediated Akt phosphorylation was inhibited in the presence of GF109203X or AR-C69931MX, indicating that thrombin causes G
stimulation through the P2Y₁₂ receptor by secreted ADP in dog platelets. Unlike human and murine platelets, protease-activated receptor 4 (PAR4)-activating peptide AYPGKF failed to cause dog platelet aggregation. Moreover, PAR1-activating peptide SFLLRN or co-stimulation of SFLLRN and AYPGKF failed to induce dog platelet aggregation. We conclude that ADP induces platelet aggregation through the P2Y₁ and P2Y₁₂ receptors in dogs. Unlike human and murine platelets, selective activation of the PAR4 receptor may be insufficient to cause platelet aggregation in dog platelets.
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