Essential role of CD38 in platelet aggregation through the PKC-mediated internalization and activation.

Introduction: CD38 is a multifunctional enzyme with a potent Ca 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.

CD38/ADP-ribose/TRPM2-mediated nuclear Ca signaling is essential for hepatic gluconeogenesis in fasting and diabetes.

Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments.

Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis.

Objective: Emerging evidence suggests that crosstalk between Kupffer cells (KCs) and hepatocytes protects against non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to the reduction of steatosis in NAFLD remain obscure.

Methods: Ttp and Ttp mice were fed with a high-fat diet.

Roles of cADPR and NAADP in pancreatic beta cell signaling.

Since the discovery of the pyridine nucleotide metabolites Ca mobilizing messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), they have been demonstrated to function as Ca signaling messengers in a wide range of cell types. In this review, I will briefly summarize the roles of cADPR and NAADP in the physiological process of stimulus-secretion coupling in pancreatic β cells. I am also going to outline the current breadth of knowledge regarding intracellular Ca stores and Ca channels targeted by cADPR and NAADP, as well as the biogenesis of these Ca signaling messengers.

PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway.

The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway.

Renin-angiotensin system at the interface of COVID-19 infection.

Angiotensin-converting enzyme 2 (ACE2) has been recognized as a potential entry receptor for SARS-CoV-2 infection. Binding of SARS-CoV-2 to ACE2 allows engagement with pulmonary epithelial cells and pulmonary infection with the virus. ACE2 is an essential component of renin-angiotensin system (RAS), and involved in promoting protective effects to counter-regulate angiotensin (Ang) II-induced pathogenesis.

Interleukin-8 drives CD38 to form NAADP from NADP and NAAD in the endolysosomes to mobilize Ca and effect cell migration.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca mobilizing second messenger whose formation has remained elusive. In vitro, CD38-mediated NAADP synthesis requires an acidic pH and a nonphysiological concentration of nicotinic acid (NA). We discovered that CD38 catalyzes synthesis of NAADP by exchanging the nicotinamide moiety of nicotinamide adenine dinucleotide phosphate (NADP ) for the NA group of nicotinic acid adenine dinucleotide (NAAD) inside endolysosomes of interleukin 8 (IL8)-treated lymphokine-activated killer (LAK) cells.

GSK-3β inhibition by curcumin mitigates amyloidogenesis via TFEB activation and anti-oxidative activity in human neuroblastoma cells.

The translocation of transcription factor EB (TFEB) to the nucleus plays a pivotal role in the regulation of basic cellular processes, such as lysosome biogenesis and autophagy. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, which is important in maintaining cellular homeostasis during environmental stress. Furthermore, oxidative stress is a critical cause for the progression of neurodegenerative diseases.

CO ameliorates cellular senescence and aging by modulating the miR-34a/Sirt1 pathway.

Oxidative stress is recognised as a key factor that can lead to cellular senescence and aging. Carbon monoxide (CO) is produced by haemoxygenase-1 (HO-1), which exerts cytoprotective effects in aging-related diseases, whereas the effect of CO on cellular senescence and aging has not been elucidated. In the current study, we clearly demonstrated that CO delays the process of cellular senescence and aging through regulation of miR-34a and Sirt1 expression.

Cross-talk between CD38 and TTP Is Essential for Resolution of Inflammation during Microbial Sepsis.

The resolution phase of acute inflammation is essential for tissue homeostasis, yet the underlying mechanisms remain unclear. We demonstrate that resolution of inflammation involves interactions between CD38 and tristetraprolin (TTP). During the onset of acute inflammation, CD38 levels are increased, leading to the production of Ca-signaling messengers, nicotinic acid adenine dinucleotide phosphate (NAADP), ADP ribose (ADPR), and cyclic ADPR (cADPR) from NAD(P).

Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.

Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP-induced liver damage remain incompletely understood. Carbon monoxide (CO), an end-product of heme oxygenase (HO)-1 activity, can confer anti-inflammatory and antiapoptotic properties in cellular models of toxicity regulation of mitochondrial function.

Carbon monoxide induces the assembly of stress granule through the integrated stress response.

Stress granules (SGs) are membraneless and phase-dense organelles that form transiently in response to a variety of harmful stimuli, including oxidative, heat, osmotic, ultraviolet light and chemotoxic stresses, and thus providing protective effects, allowing survivals. Carbon monoxide (CO), a gaseous second messenger, is synthesized by heme-oxygenases, and exerts anti-inflammatory, anti-proliferative and anti-apoptotic effects in a variety of cellular- and tissue-injury models. Several reports indicate that low levels of mitochondrial reactive oxygen species (mtROS) generated by CO can selectively activate PERK-eIF2α integrated stress response (ISR) to preserve the cellular homeostasis.

The Essential Role of Ca Signals in UVB-Induced IL-1β Secretion in Keratinocytes.

UVB-induced skin damage is attributable to reactive oxygen species, which are triggered by intracellular Ca signals. However, exactly how the reactive oxygen species are triggered by intracellular Ca upon UVB irradiation remains obscure. Here, we show that UVB induces Ca signals via sequential generation of the following Ca messengers: inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate, and cyclic ADP-ribose.

Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca signaling.

Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) has been shown to activate ADP-ribosyl cyclase (ARC), which produces the Ca mobilizing second messenger, cyclic ADP-ribose (cADPR). In the present study, we examined how ROS activates cluster of differentiation (CD)38, a mammalian prototype of ARC. CD38 exists in type II and III forms with opposing membrane orientation.

Pterostilbene 4'--Glucoside Attenuates LPS-Induced Acute Lung Injury via Induction of Heme Oxygenase-1.

Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4'--glucoside (4-PG), the glycosylated form of the antioxidant pterostilbene (PTER), can protect against lipopolysaccharide- (LPS-) or -) induced ALI when applied as a pretreatment or therapeutic post-treatment, via the induction of HO-1.

Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-κB-mediated BACE1 gene expression.

Amyloid-β (Aβ) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β-secretase (BACE1) and the γ-secretase complex. It has been proposed that the abnormal secretion and accumulation of Aβ are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment.

Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury.

Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increased the nuclear translocation of transcription factor EB (TFEB). PERK activation by CO increased intracellular Ca concentration and the phosphatase activity of calcineurin against TFEB.

Trpm2 Ablation Accelerates Protein Aggregation by Impaired ADPR and Autophagic Clearance in the Brain.

TRPM2 a cation channel is also known to work as an enzyme that hydrolyzes highly reactive, neurotoxic ADP-ribose (ADPR). Although ADPR is hydrolyzed by NUT9 pyrophosphatase in major organs, the enzyme is defective in the brain. The present study questions the role of TRPM2 in the catabolism of ADPR in the brain.

Disassembly of Subplasmalemmal Actin Filaments Induces Cytosolic Ca2+ Increases in Astropecten aranciacus Eggs.

Background/aims: Eggs of all animal species display intense cytoplasmic Ca2+ increases at fertilization. Previously, we reported that unfertilized eggs of Astropecten aranciacus exposed to an actin drug latrunculin A (LAT-A) exhibit similar Ca2+ waves and cortical flashes after 5-10 min time lag. Here, we have explored the molecular mechanisms underlying this unique phenomenon.

Hyperglycemia associated blood viscosity can be a nexus stimuli.

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 on blood viscosity.

CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation.

Background/aims: Cyclic ADP-ribose (cADPR) is a Ca2+ -mobilization messenger that acts on ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum (SR) Ca2+ stores. Moreover, it has been proposed that cADPR serves an additional role in activating the sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) pump. The aim of this study was to determine the exact mechanism by which cADPR regulates SR Ca2+ stores in physiologically relevant systems.

Critical Roles of Carbon Monoxide and Nitric Oxide in Ca Signaling for Insulin Secretion in Pancreatic Islets.

Aims: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca concentrations, resulting in insulin secretion from pancreatic β-cells through the sequential production of Ca mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca signals and gasotransmitters formation in insulin secretion in β-cells upon GLP-1 stimulation.

FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.

The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro.

Exercise induces muscle fiber type switching via transient receptor potential melastatin 2-dependent Ca signaling.

The aim of the present study was to examine whether transient receptor potential melastatin 2 (TRPM2) plays a role in muscle fiber-type transition during exercise. Mice were trained at a speed of 12 m/min at a slope of 0° for 60 min for 5 consecutive days/wk for 4 wk. Exhaustion tests were performed on the treadmill (the speed was set at 6 m/min at a slope of 0° and increased at a rate of 1 m/min every 6 min).

The critical role of uterine CD31 as a post-progesterone signal in early pregnancy.

CD31 has been shown to play a role in endothelial cell migration and angiogenesis, which are critical to the formation and function of the endometrium and myometrium in uterine development during early pregnancy. However, the role of CD31 in uterine receptivity during blastocyst implantation is poorly understood. The pregnancy rate in female mice mated with male mice was higher than that observed in female mice mated with male mice.