We have previously demonstrated that cyclic ADP-ribose (cADPR) is a calcium signaling messenger in interleukin 8 (IL-8)-induced lymphokine-activated killer (LAK) cells. In this study we examined the possibility that IL-8 activates CD38 to produce another messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), in LAK cells, and we showed that IL-8 induced NAADP formation after cADPR production. These calcium signaling messengers were not produced when LAK cells prepared from CD38 knock-out mice were treated with IL-8, indicating that the synthesis of both NAADP and cADPR is catalyzed by CD38 in LAK cells. Application of cADPR to LAK cells induced NAADP production, whereas NAADP failed to increase intracellular cADPR levels, confirming that the production of cADPR precedes that of NAADP in IL-8-treated LAK cells. Moreover, NAADP increased intracellular Ca(2+) signaling as well as cell migration, which was completely blocked by bafilomycin A1, suggesting that NAADP is generated in lysosome-related organelles after cADPR production. IL-8 or exogenous cADPR, but not NAADP, increased intracellular cAMP levels. cGMP analog, 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate, increased both cADPR and NAADP production, whereas the cAMP analog, 8-(4-chlorophenylthio)-cAMP, increased only NAADP production, suggesting that cAMP is essential for IL-8-induced NAADP formation. Furthermore, activation of Rap1, a downstream molecule of Epac, was required for IL-8-induced NAADP formation in LAK cells. Taken together, our data suggest that IL-8-induced NAADP production is mediated by CD38 activation through the actions of cAMP/Epac/protein kinase A/Rap1 in LAK cells and that NAADP plays a key role in Ca(2+) signaling of IL-8-induced LAK cell migration.

CD38, a multifunctional enzyme that catalyzes the synthesis of intracellular Ca(2+) messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), is known to be expressed on platelets. However, the role of CD38 in platelets remains unclear. Our present results show that treatment of platelets with thrombin results in a rapid and sustained Ca(2+) signal, resulting from a coordinated interplay of Ca(2+)-mobilizing messengers, inositol 1,4,5-trisphosphate, cADPR, and NAADP. By dissecting the signaling pathway using various agents, we delineated that cADPR and NAADP are sequentially produced through CD38 internalization by protein kinase C via myosin heavy chain IIA following phospholipase C activation in thrombin-induced platelets. An inositol 1,4,5-trisphosphate receptor antagonist blocked the thrombin-induced formation of cADPR and NAADP as well as Ca(2+) signals. An indispensable response of platelets relying on cytosolic calcium is the surface exposure of phosphatidylserine (PS), which implicates platelet procoagulant activity. Scrutinizing this parameter reveals that CD38(+/+) platelets fully express PS on the surface when stimulated with thrombin, whereas this response was decreased on CD38(-/-) platelets. Similarly, PS exposure and Ca(2+) signals were attenuated when platelets were incubated with 8-bromo-cADPR, bafilomycin A1, and a PKC inhibitor. Furthermore, in vivo, CD38-deficient mice exhibited longer bleeding times and unstable formation of thrombus than wild type mice. These results demonstrate that CD38 plays an essential role in thrombin-induced procoagulant activity of platelets and hemostasis via Ca(2+) signaling mediated by its products, cADPR and NAADP.

BACKGROUND: The viscosity of a fluid is a measure of its resistance. It is the thickness and stickiness of blood, and a direct measure of the resistance of blood to flow through the vessels. Various factors in the blood have direct or indirect impact

Globally, acute respiratory illnesses are the most commonly manifesting illness in all age group. The disease mostly affects the upper respiratory tract (URT) and is self-limiting. However, a small percentage progresses to lower respiratory tract infections (LRTI). The most important causative agents of severe LRTIs are bacteria and viruses. Various viruses can cause respiratory tract infections, being the most essential belonging to the Orthomyxoviridae, Paramyxoviridae, Picornaviridae, coronaviruses, and adenoviruses. Quercetin is classified as a flavonoid compound and was previously known to have antiviral, antibacterial, antioxidant, and anti-inflammatory activities. Some preclinical studies highlight quercetin could also interfere with coronavirus infection and modulate the release of pro-inflammatory cytokines. Since there is no comprehensive compilation addressing the antiviral activities of quercetin and its derivatives, this narrative review provides a summary of the preclinical evidence of their antiviral activities on respiratory illnesses induced by viruses other than coronaviruses. The literature research was performed in PubMed, Scopus, and Google Scholar. The results explain that quercetin has a wide range of actions in viral-induced respiratory illnesses including, but not limited to suppressing pro-inflammatory cytokines and chemokines, promoting antioxidant-related genes expression, blocking viral entry and replication, accelerating viral clearance, reducing the accumulation of alveolar macrophages, and reducing goblet cells marker and mucin gene expression.

Quercetin (QUE) is a primary polyphenol in the flavonoid family. It is categorized as one of the six subclasses of flavonoid compounds. As an abundant form of flavonoid molecules, quercetins are ubiquitously distributed in various dietary plants, including apples, berries, onions, bananas, tomatoes, and grapes. Furthermore, it is affordably marketed in the form of dietary supplement tablets. QUE is relatively lipophilic with low solubility in the water. Withal, QUE glucoside is more water soluble than the aglycone, and its absorption is limited to sodium-dependent glucose transporter-1 (SGLT-1); however, glucose transporter-2 (GLUT-2)-dependent absorption is also a significant contributor. Following absorption, QUE undergoes extensive metabolism in the liver, generating numerous metabolites. Data on the bioavailability of QUE differ substantially depending on the methods used for measuring QUE level. Pharmacokinetic interactions of QUE and its metabolites on cytochrome P450 enzymes have been studied extensively, but the results among the studies were inconsistent, such as weak inhibition toward CYP3A4 and no inhibition of CYP2D6 activity. Additionally, inhibition affects ATP- (adenosine triphosphate) binding cassette (ABC). Based on the pharmacokinetics profile, QUE has variable bioavailability based on the polymorphism of intestinal enzymes and transporters.

Introduction: CD38 is a multifunctional enzyme with a potent Ca2+ mobilizing effect, cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). Here, we aimed to demonstrate the role of CD38 in platelets via protein kinase C (PKC)-mediated internalization and activation. Methods: Mouse platelets were used in this study. Thrombin, an agonist of platelet function, provoked a prompt and long-lasting increase in intracellular Ca2+ concentration ([Ca2+]i), resulting from an interplay of multifold Ca2+ mobilizing messengers.The signaling pathway was delineated using different inhibitors and techniques such as platelet aggregation assay, intracellular calcium measurements, immunoprecipitation, immunoblotting, and flow cytometry. Results: We observed a sequential formation of cADPR and NAADP through CD38 activation by PKC of non-muscle myosin heavy chain IIA (MHCIIA), resulting in phospholipase C (PLC) activation in the thrombin-stimulated platelets. These findings reveal that PKC is fundamental in activating CD38 and elicits a physiological response in the murine platelets. Conclusion: PKC is involved in many signaling pathways. Specifically, PKC is involved in the internalization of CD38 via MHCIIA in CD38+/+ wild-type (WT) and CD38-/- knockout mice (KO). CD38 generates calcium-mobilizing agents that act on specific receptors of the calcium stores. Calcium triggered platelet aggregation while serving as a secondary messenger.