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. A type II transmembrane protein, CD38, possesses ADP-ribosyl cyclase (ADPR cyclase) 3 and cyclic ADP-ribose hydrolase (cADPR hydrolase) activity (1, 2). These two enzyme activities are involved in the conversion of ␤-nicotinamide adenine dinucleotide (␤-NAD ϩ ) first to cADPR and then to ADPR (3-5). The metabolite cADPR is known to increase intracellular Ca 2ϩ concentration, [Ca 2ϩ ] i , by releasing Ca 2ϩ from intracellular stores or by Ca 2ϩ influx through plasma membrane Ca 2ϩ channels in a variety of cells (6 -10). It was shown that CD38 can also synthesize NAADP from NADP in the presence of nicotinic acid by a base exchange reaction in vitro (11). However, it still remains unclear whether the base exchange reaction occurs physiologically as intracellular nicotinic acid concentration is less than the millimolar concentration that is required for the enzymatic synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP) in vitro (12).NAADP is a potent Ca 2ϩ -releasing messenger in a variety of cell types, including mammalian cells (13-15). Although D-myo-inositol 1,4,5-trisphosphate (IP 3 ) and cADPR are firmly established as secondary Ca 2ϩ messengers, receptor-mediated formation of NAADP has been shown in a limited number of cellular systems (16 -18). It has been demonstrated that NAADP triggers Ca 2ϩ release from thapsigargin-insensitive Ca 2ϩ stores through the activation of channels distinct from those sensitive to ryanodine and IP 3 (19). In sea urchin eggs, NAADP releases Ca 2ϩ from acidic Ca 2ϩ stores, lysosome-related organelles (20). However, NAADP can also release Ca 2ϩ from the endoplasmic reticulum (21-23).Previously, we have reported that IL-8 stimulated cADPR formation by activation of CD38 via cGMP/protein kinase G and induced an increase of [Ca 2ϩ ] i and migration of LAK cells (24). In this study we investigated whether NAADP is involved in IL-8-induced Ca 2ϩ signaling and migration of LAK cells. We showed that NAADP plays a key role in IL-8-stimul...

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.

Hyperglycemia implicates the blood viscosity which in turn can have tedious effect on metabolic syndromes thus causing the serious effect in the tissue perfusion of an organs.

No abstract

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.