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Frontiers in Plant Science 2016In plants, nitric oxide (NO)-mediated 3', 5'-cyclic guanosine monophosphate (cGMP) synthesis plays an important role during pathogenic stress response, stomata closure... (Review)
Review
In plants, nitric oxide (NO)-mediated 3', 5'-cyclic guanosine monophosphate (cGMP) synthesis plays an important role during pathogenic stress response, stomata closure upon osmotic stress, the development of adventitious roots and transcript regulation. The NO-cGMP dependent pathway is well characterized in mammals. The binding of NO to soluble guanylate cyclase enzymes (GCs) initiates the synthesis of cGMP from guanosine triphosphate. The produced cGMP alters various cellular responses, such as the function of protein kinase activity, cyclic nucleotide gated ion channels and cGMP-regulated phosphodiesterases. The signal generated by the second messenger is terminated by 3', 5'-cyclic nucleotide phosphodiesterase (PDEs) enzymes that hydrolyze cGMP to a non-cyclic 5'-guanosine monophosphate. To date, no homologues of mammalian cGMP-synthesizing and degrading enzymes have been found in higher plants. In the last decade, six receptor proteins from Arabidopsis thaliana have been reported to have guanylate cyclase activity in vitro. Of the six receptors, one was shown to be a NO dependent guanylate cyclase enzyme (NOGC1). However, the role of these proteins in planta remains to be elucidated. Enzymes involved in the degradation of cGMP remain elusive, albeit, PDE activity has been detected in crude protein extracts from various plants. Additionally, several research groups have partially purified and characterized PDE enzymatic activity from crude protein extracts. In this review, we focus on presenting advances toward the identification of enzymes involved in the cGMP metabolism pathway in higher plants.
PubMed: 27200049
DOI: 10.3389/fpls.2016.00576 -
Journal of Veterinary Science Sep 2017We evaluated the effects of guanosine 5'-monophosphate (GMP)-chelated calcium and iron (CaFe-GMP) on health and egg quality in layers experimentally infected with...
We evaluated the effects of guanosine 5'-monophosphate (GMP)-chelated calcium and iron (CaFe-GMP) on health and egg quality in layers experimentally infected with Gallinarum. In this study, a CaFe-GMP feed additive was added to a commercial layer feed and fed to layers over a four-week period. All were inoculated with Gallinarum. Body weight, mortality, clinical symptoms, and poultry production including feed intake, egg production, egg loss, and feed conversion rate were observed, and Gallinarum was re-isolated from the liver, spleen, and cecum of the layers. All tested internal organs for the CaFe-GMP additive group exhibited significantly lower re-isolation numbers of Gallinarum and less severe pathological changes than those in the control group, indicating that the CaFe-GMP feed supplement induced bacterial clearance and increased resistance to Gallinarum. Additionally, due to the inhibitory action of CaFe-GMP on the growth of Gallinarum, the CaFe-GMP additive group exhibited better egg production, including a higher laying rate and fewer broken eggs. The results suggest that a 0.16% CaFe-GMP additive may help prevent salmonellosis in the poultry industry.
Topics: Animal Feed; Animals; Calcium; Calcium Chelating Agents; Chickens; Dietary Supplements; Female; Guanosine Monophosphate; Iron; Iron Chelating Agents; Oviposition; Poultry Diseases; Salmonella; Salmonella Infections, Animal
PubMed: 28057911
DOI: 10.4142/jvs.2017.18.3.291 -
American Journal of Respiratory Cell... Nov 2021Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric...
Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) amounts in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cyclic guanosine monophosphate (cGMP)-PKG (protein kinase G) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN. PPHN was induced by ductus arteriosus constriction from 128-136 days' gestation in fetal lambs. Control animals were gestation-matched lambs that did not undergo ductal constriction. PAEC isolated from PPHN lambs were treated with the sGC (soluble guanylate cyclase) activator cinaciguat, the PKG activator 8-bromo-cGMP, or the PDE-V (PDE type V) inhibitor sildenafil. Lysates were immunoblotted for mitochondrial transcription factors and electron transport chain C-I (complex I), C-II, C-III, C-IV, and C-V proteins. The angiogenesis of PAEC was evaluated by using tube-formation and scratch-recovery assays. cGMP concentrations were measured by using an enzyme immunoassay. Fetal lambs with ductal constriction were given sildenafil or control saline through continuous infusion , and the lung histology, capillary counts, vessel density, and right ventricular pressure were assessed at birth. PPHN PAEC showed decreased mitochondrial transcription factor levels, electron transport chain protein levels, and tube formation and cell migration; these were restored by cinaciguat, 8-bromo-cGMP, and sildenafil. Cinaciguat and sildenafil increased cGMP concentrations in PPHN PAEC. Radial alveolar and capillary counts and vessel density were lower in PPHN lungs, and the right ventricular pressure and Fulton Index were higher in PPHN lungs; these were improved by sildenafil infusion. cGMP-PKG signaling is a potential therapeutic target to restore decreased mitochondrial biogenesis and angiogenesis in PPHN.
Topics: Animals; Animals, Newborn; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelial Cells; Female; Guanosine Monophosphate; Humans; Hypertension, Pulmonary; Infant, Newborn; Mitochondria; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pregnancy; Pulmonary Artery; Sheep; Signal Transduction; Sildenafil Citrate
PubMed: 34185619
DOI: 10.1165/rcmb.2020-0434OC -
Frontiers in Microbiology 2021Type I interferons (IFN), a family of cytokines widely expressed in various tissues, play important roles in anti-infection immunity. Nevertheless, it is not known...
Type I interferons (IFN), a family of cytokines widely expressed in various tissues, play important roles in anti-infection immunity. Nevertheless, it is not known whether spp. could interfere with IFN-I production induced by other pathogens. This study investigated the regulatory roles of outer membrane protein (Omp)25 on the IFN-I signaling pathway and found that Omp25 inhibited the production of IFN-β and its downstream IFN-stimulated genes induced by various DNA viruses or IFN-stimulatory DNA in human, murine, porcine, bovine, and ovine monocyte/macrophages or peripheral blood mononuclear cells. Omp25 suppressed the phosphorylation of stimulator of IFN genes (STINGs) and IFN regulatory factor 3 and nuclear translocation of phosphorylated IFN regulatory factor 3 in pseudorabies virus- or herpes simplex virus-1-infected murine, human, or porcine macrophages. Furthermore, we found that Omp25 promoted cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) degradation the proteasome-dependent pathway, resulting in a decreased cyclic guanosine monophosphate-adenosine monophosphate production and downstream signaling activation upon DNA virus infection or IFN-stimulatory DNA stimulation. Mapping the predominant function domain of Omp25 showed that the amino acids 161 to 184 of Omp25 were required for Omp25-induced cGAS degradation, among which five amino acid residues (R176, Y179, R180, Y181, and Y184) were required for the inhibitory effect of Omp25 on IFN-β induction. Altogether, our results demonstrated that Omp25 inhibits cGAS STING signaling pathway-induced IFN-β facilitating the ubiquitin-proteasome-dependent degradation of cGAS in various mammalian monocyte/macrophages.
PubMed: 34394047
DOI: 10.3389/fmicb.2021.702881 -
Purinergic Signalling Dec 2019The guanine-based purines (GBPs) have essential extracellular functions such as modulation of glutamatergic transmission and trophic effects on neurons and astrocytes....
The guanine-based purines (GBPs) have essential extracellular functions such as modulation of glutamatergic transmission and trophic effects on neurons and astrocytes. We previously showed that GBPs, such as guanosine-5'-monophosphate (GMP) or guanosine (GUO), promote the reorganization of extracellular matrix proteins in astrocytes, and increase the number of neurons in a neuron-astrocyte co-culture protocol. To delineate the molecular basis underlying these effects, we isolated cerebellar neurons in culture and treated them with a conditioned medium derived from astrocytes previously exposed to GUO or GMP (GBPs-ACM) or, directly, with GUO or GMP. Agreeing with the previous studies, there was an increase in the number of β-tubulin III-positive neurons in both conditions, compared with controls. Interestingly, the increase in the number of neurons in the neuronal cultures treated directly with GUO or GMP was more prominent, suggesting a direct interaction of GBPs on cerebellar neurons. To investigate this issue, we assessed the role of adenosine and glutamate receptors and related intracellular signaling pathways after GUO or GMP treatment. We found an involvement of A adenosine receptors, ionotropic glutamate N-methyl-D-aspartate (NMDA), and non-NMDA receptors in the increased number of cerebellar neurons. The signaling pathways extracellular-regulated kinase (ERK), calcium-calmodulin-dependent kinase-II (CaMKII), protein kinase C (PKC), phosphatidilinositol-3'-kinase (PI3-K), and protein kinase A (PKA) are also potentially involved with GMP and GUO effect. Such results suggest that GMP and GUO, and molecules released in GBPs-ACM promote the survival or maturation of primary cerebellar neurons or both via interaction with adenosine and glutamate receptors.
Topics: Adenosine; Animals; Astrocytes; Central Nervous System; Glutamic Acid; Guanosine; Guanosine Monophosphate; Neurons; Receptors, Glutamate; Receptors, Purinergic P1
PubMed: 31478180
DOI: 10.1007/s11302-019-09677-y -
Biomedicine & Pharmacotherapy =... Apr 2022Hepatic inflammation is prevalent in several metabolic liver diseases. Recent scientific advances about the pathogenesis of metabolic liver diseases showed an emerging... (Review)
Review
Hepatic inflammation is prevalent in several metabolic liver diseases. Recent scientific advances about the pathogenesis of metabolic liver diseases showed an emerging role of several damage-associated molecular patterns (DAMPs), including DNA, high-mobility group box 1 (HMGB1), ATP and uric acid. For these DAMPs to induce inflammation, they should stimulate pattern recognition receptors (PRRs), which are located in the hepatic immune cells like resident Kupffer cells, infiltrated neutrophils, monocytes or dendritic cells. As a consequence, proinflammatory cytokines like interleukins (ILs)-1β and 18 alongside tumor necrosis factor (TNF)-α are overproduced and released, leading to pronounced hepatic inflammation and cellular death. This review highlights the contribution of these DAMPs and PRRs in the settings of alcoholic and nonalcoholic steatohepatitis. The review also summarizes the therapeutic usefulness of targeting NLR family pyrin domain containing 3 (NLRP3)-inflammasome, Toll-like receptors (TLRs) 4 and 9, IL-1 receptor (IL-1R), caspase 1, uric acid and GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) in these hepatic inflammatory disorders.
Topics: Adenosine Monophosphate; Alarmins; Caspase 1; Guanosine Monophosphate; Humans; Inflammation; Inflammation Mediators; Interleukin-18; Interleukin-1beta; Liver Diseases, Alcoholic; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition; Receptors, Purinergic P2X7; Signal Transduction; Toll-Like Receptor 4; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha; Uric Acid
PubMed: 35272137
DOI: 10.1016/j.biopha.2022.112789 -
Communications Biology Oct 2022Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on...
Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1 granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.
Topics: Acute Disease; Animals; Diabetes Mellitus, Type 2; Guanosine Monophosphate; Inosine Monophosphate; Mice; Myelopoiesis; Pancreatitis; Purines
PubMed: 36224248
DOI: 10.1038/s42003-022-04041-0 -
Journal of the American College of... Aug 2019Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF).
BACKGROUND
Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF).
OBJECTIVES
This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I).
METHODS
A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals).
RESULTS
PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p < 0.05) while concurrently reducing circulating atrial natriuretic peptide levels (p < 0.01). Similar trends were evident in HF, resulting in significant elevations in the cGMP/NP ratio in both states (p < 0.001 and p < 0.05, respectively). PDE9-I also produced progressive falls in arterial pressure (HF: p < 0.001), atrial pressure (Normal: p < 0.001; HF: p < 0.001), and peripheral resistance (HF: p < 0.001), and transiently increased cardiac output at the top dose (Normal: p < 0.05; HF: p < 0.001). Inhibition of PDE9 had a negligible effect on circulating hormones at the lower doses, but post-high dose, acutely increased renin activity (Normal: p < 0.001; HF: p < 0.05), vasopressin (Normal: p < 0.001; HF: p < 0.01), and cyclic adenosine monophosphate (HF: p < 0.001). Plasma aldosterone increased briefly after high-dose PDE9-I in normal sheep, and fell following the top dose in HF. PDE9-I dose-dependently increased urinary cGMP in both states (both p < 0.001). In HF, this was associated with increases in urine volume (p < 0.01), sodium excretion (p < 0.01), and creatinine clearance (p < 0.001).
CONCLUSIONS
PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenosine Monophosphate; Aldosterone; Animals; Atrial Natriuretic Factor; Atrial Pressure; Blood Pressure; Cardiac Output; Creatinine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Guanosine Monophosphate; Heart Failure; Phosphodiesterase Inhibitors; Renin; Sheep; Sodium; Urine; Vascular Resistance; Vasopressins
PubMed: 31416533
DOI: 10.1016/j.jacc.2019.05.067 -
JACC. Basic To Translational Science Aug 2023Reduced nitric oxide (NO) bioactivity in red blood cells (RBCs) is critical for augmented myocardial ischemia-reperfusion injury in type 2 diabetes. This study...
Reduced nitric oxide (NO) bioactivity in red blood cells (RBCs) is critical for augmented myocardial ischemia-reperfusion injury in type 2 diabetes. This study identified the nature of "NO bioactivity" by stimulating the intracellular NO receptor soluble guanylyl cyclase (sGC) in RBCs. sGC stimulation in RBCs from patients with type 2 diabetes increased export of cyclic guanosine monophosphate from RBCs and activated cardiac protein kinase G, thereby attenuating ischemia-reperfusion injury. These results provide novel insight into RBC signaling by identifying cyclic guanosine monophosphate from RBC as a mediator of protection against cardiac ischemia-reperfusion injury induced by sGC stimulation in RBCs.
PubMed: 37719424
DOI: 10.1016/j.jacbts.2023.02.017 -
Experimental and Therapeutic Medicine Sep 2018Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the...
Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the contractility of GI smooth muscle. Although increased plasma estrogen levels have been implicated in GI disorders, the role of gastric estrogen receptor (ER) in these sex-specific differences remains to be fully elucidated. The present study was designed to investigate the sex-associated differences in the expression of the two ER isoforms, ERα and ERβ, and the effect of estrogen on gastric muscle contraction via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Experiments were performed on single gastric smooth muscle cells (GSMCs) isolated from male and female Sprague Dawley rats. The effect of acetylcholine (ACh), a muscarinic agonist, on the contraction of GSMCs was measured via scanning micrometry in the presence or absence of 1 µM 17β-estradiol (E2), an agonist to the majority of ERs, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), an ERα agonist, or diarylpropionitrile (DPN), an ERβ agonist. The protein expression levels of ER subtypes in GSMCs were measured using a specifically designed ELISA. GSMCs from female rats had a higher expression of ERα and ERβ protein compared with GSMCs from males. ACh induced less contraction in female that in male GSMCs. Pre-treatment of GSMCs with E2 reduced the contraction of GSMCs from both sexes, but to a greater extent in those from females. PPT and DPN inhibited ACh-induced contraction in GSMCs from females. Furthermore, E2 increased NO and cGMP levels in GSMCs from males and females; however, higher levels were measured in females. Of note, pre-incubation of female GSMCs with Nω-nitro-L-arginine, a NO synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylyl cyclase inhibitor, reduced the inhibitory effect of estrogen on GSMC contraction. In conclusion, estrogen relaxes GSMCs via an NO/cGMP-dependent mechanism, and the reduced contraction in GSMCs from females by estrogen may be associated with the sex-associated increased expression of ERα and ERβ, and greater production of NO and cGMP, compared with that in GSMCs from males.
PubMed: 30186388
DOI: 10.3892/etm.2018.6406