As a DNA receptor in the cytoplasm,cyclic GMP-AMP synthase (cGAS) can recognize abnormal DNA in the cytoplasm and activate stimulator of interferon genes (STING) to regulate the immune response. The recent studies have demonstrated that this pathway plays a role in non-infectious inflammatory diseases by promoting the expression of type Ⅰ interferon and interferon-stimulated gene.This article reviews the activation and regulation of cGAS-STING pathway in multiple systems and the effect of this pathway on the occurrence and progression of non-infectious inflammatory diseases,providing theoretical reference for future application of cGAS-STING pathway-related drugs in non-infectious inflammatory diseases.
Humans ; Interferons ; Membrane Proteins/metabolism* ; Noncommunicable Diseases ; Nucleotides, Cyclic ; Nucleotidyltransferases/metabolism* ; Signal Transduction

The aim of this paper was to study the effect of Lepidium meyenii(Maca) on cyclic nucleotides, neurotransmitter levels and hypothalamic-pituitary-adrenal axis and immunization of deficiency-cold and deficiency-heat syndrome rats, in order to explore the cold and hot medicinal properties of Maca. SD rats were divided into blank group, deficiency-cold syndrome group, Cinnamomi Cortex of deficiency-cold syndrome(30 g·kg~(-1)) group, high and low-dose Maca groups(2.4, 1.2 g·kg~(-1)), deficiency-heat syndrome group, Phellodendri Chinensis Cortex(PCC) of deficiency-heat syndrome(5 g·kg~(-1)), and high and low-dose Maca groups(2.4, 1.2 g·kg~(-1)). The rats were treated with intramuscular injection of hydrocortisone(20 mg·kg~(-1)) or dexamethasone sodium phosphate(0.35 mg·kg~(-1)) for 21 days to set up the deficiency-cold and deficiency-heat model. The levels of cAMP, cGMP, NE, DA, 5-HT, CRH, ACTH, CORT and IgM, IgG, C3, C4 were detected by radio immunoassay. Both the high-dose Maca group and the low-dose Maca group can significantly improve the overall state and body weight of rats with deficiency-cold syndrome(P<0.01, P<0.05), significantly increasing cAMP, cAMP/cGMP, NE, DA, ACTH(P<0.01, P<0.001), and significantly decreasing 5-HT(P<0.01, P<0.001). However, high-dose and low-dose Maca groups could not improve the deficiency-heat syndrome, and the levels of cAMP, cGMP, cAMP/cGMP, NE, DA, 5-HT and ACTH were not statistically significant. Maca had a significant regulatory effect on CORT, IgM, IgG and C3 content of rats with deficiency-cold and deficiency-heat syndrome(P<0.01, P<0.05, P<0.001). Maca showed the same effect with Cinnamomi Cortex in adjusting the levels of deficiency-cold rats, but in opposition to Phellodendri Chinese Cortex. This paper confirmed that Maca was slightly warm based on its effect on cyclic nucleotide levels and neuro-endocrine-immune networks by the pharmacological experimental method.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Endocrine System/drug effects* ; Hypothalamo-Hypophyseal System ; Immune System/drug effects* ; Lepidium/chemistry* ; Medicine, Chinese Traditional ; Nervous System/drug effects* ; Neurotransmitter Agents ; Nucleotides, Cyclic ; Pituitary-Adrenal System ; Plant Extracts/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Temperature

OBJECTIVEThis work aims to determine the effect of cytosolic bacteria on the expression of cyclic GMP-AMP synthase (cGAS) in human periodontal ligament cells (hPDLCs) and gingival tissues.

METHODSThe ability of Porphyromonas gingivalis (P. gingivalis) to invade hPDLCs was detected using laser scanning confocal microscope assay at a multiplicity of infection of 10. P. gingivalis-infected cells were sorted by fluorescence-activated cell sorting (FACS). Then, quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect cGAS expression in infected cells. Finally, the location and expression of cGAS in inflammatory and normal gingival tissues were investigated by immunohistochemistry.

RESULTSP. gingivalis actively invaded hPDLCs. Moreover, cGAS expression significantly increased in P. gingivalis-infected cells. Although cGAS was expressed in the epithelial and subepithelial cells of both inflamed and normal gingival tissues, cGAS expression significantly increased in inflamed gingival tissues.

CONCLUSIONSCytosolic bacteria can upregulate cGAS expression in infected cells. These data suggest that cGAS may act as pattern-recognition receptors and participate in recognizing cytosolic nucleic acid pathogen-associated molecular patterns.
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PURPOSE: The objective of this study was to evaluate the relaxant effect of scoparone from Artemisia capillaris on rabbit penile corpus cavernosum smooth muscle (PCCSM) and to elucidate the mechanism of action of scoparone for the treatment of erectile dysfunction (ED). MATERIALS AND METHODS: PCCSM that had been precontracted with phenylephrine was treated with 3 Artemisia herbs (A. princeps, A. capillaris, and A. iwayomogi) and 3 fractions (n-hexane, ethyl acetate, and n-butanol) with different concentrations (0.1, 0.5, 1.0, and 2.0 mg/mL). Four components (esculetin, scopoletin, capillarisin, and scoparone) isolated from A. capillaris were also evaluated. The PCCSM was preincubated with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ). Cyclic nucleotides in the perfusate were measured by a radioimmunoassay. The interactions of scoparone with udenafil and rolipram were also evaluated. RESULTS: A. capillaris extract relaxed PCCSM in a concentration-dependent manner. Scoparone had the highest relaxant effect on PCCSM among the 4 components (esculetin, scopoletin, capillarisin, and scoparone) isolated from the ethyl acetate fraction. The application of scoparone on PCCSM pretreated with L-NAME and ODQ led to significantly less relaxation. Scoparone also increased the cyclic guanosine monophosphate (cGMP) levels in the perfusate in a concentration-dependent manner. Furthermore, scoparone enhanced udenafil- and rolipram-induced relaxation of the PCCSM. CONCLUSIONS: Scoparone relaxed the PCCSM mainly by activating the nitric oxide-cGMP signaling pathway, and it may be a new promising treatment for ED patients who do not completely respond to udenafil.
Artemisia* ; Coumarins ; Erectile Dysfunction ; Guanosine Monophosphate* ; Guanosine* ; Humans ; Male ; Muscle, Smooth ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; Nucleotides, Cyclic ; Penile Erection* ; Phenylephrine ; Phosphodiesterase 5 Inhibitors ; Radioimmunoassay ; Relaxation ; Rolipram ; Scopoletin

The aim of this study was to investigate the effect and action mechanism of quercetin on penile corpus cavernosum smooth muscle (PCCSM). PCCSM precontracted with phenylephrine (Phe) was treated with four different concentrations of quercetin (10−7, 10−6, 10−5 and 10−4 M). PCCSM were preincubated with N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to block nitric oxide synthase and guanylate cyclase, respectively. The changes in PCCSM tension were recorded, and cyclic nucleotides in the perfusate were measured by radioimmunoassay. The interactions of quercetin with phosphodiesterase type 5 inhibitors (PDE5-Is) such as sildenafil, udenafil and mirodenafil, were also evaluated. PCCSM relaxation induced by quercetin occurred in a concentrationdependent manner. The application of quercetin to PCCSM pre-treated with L-NAME and ODQ significantly inhibited the relaxation. Quercetin significantly increased cGMP in the perfusate. Furthermore, quercetin enhanced PDE5-Is-induced relaxation of PCCSM. Quercetin relaxed the PCCSM by activating the NO-cGMP signaling pathway, and it may be a therapeutic candidate or an alternative treatment for patients with erectile dysfunction who do not completely respond to PDE5-Is.
Erectile Dysfunction ; Guanylate Cyclase ; Humans ; Male ; Muscle, Smooth* ; NG-Nitroarginine Methyl Ester ; Nitric Oxide Synthase ; Nucleotides, Cyclic ; Phenylephrine ; Phosphodiesterase 5 Inhibitors ; Quercetin* ; Radioimmunoassay ; Relaxation ; Sildenafil Citrate

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.
DNA, Bacterial ; immunology ; metabolism ; DNA, Viral ; immunology ; metabolism ; Gene Expression Regulation ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3 ; genetics ; immunology ; Interferon Type I ; biosynthesis ; immunology ; Membrane Proteins ; genetics ; immunology ; Models, Molecular ; NF-kappa B ; genetics ; immunology ; Nucleotides, Cyclic ; biosynthesis ; immunology ; Nucleotidyltransferases ; genetics ; immunology ; Protein Binding ; Protein-Serine-Threonine Kinases ; genetics ; immunology ; Signal Transduction

This study was designed to investigate the effects an 8-Br-cGMP on the neuronal activity of rat vestibular nuclear cells. Sprague-Dawley rats aged 14 to 16 days were decapitated under ether anesthesia. After treatment with pronase and thermolysin, the dissociated vestibular nuclear cells were transferred into a chamber on an inverted microscope. Spontaneous action potentials and potassium currents were recorded by standard patch-clamp techniques under current and voltage-clamp modes. Twelve vestibular nuclear cells revealed excitatory responses to 1-5 microM of 8-Br-cGMP, and 3 neurons did not respond to 8-Br-cGMP. Whole potassium currents of vestibular nuclear cells were decreased by 8-Br-cGMP (n=12). After calcium-dependent potassium currents were blocked by tetraethylammonium, the potassium currents were not decreased by 8-Br-cGMP. These experimental results suggest that 8-Br-cGMP changes the neuronal activity of vestibular nuclear cells by blocking the calcium-dependent potassium currents that underlie the afterhyperpolarization.
Action Potentials ; Aged ; Anesthesia ; Animals ; Ether, Ethyl ; Humans ; Neurons ; Nucleotides, Cyclic ; Patch-Clamp Techniques ; Potassium ; Pronase ; Rats ; Rats, Sprague-Dawley ; Tetraethylammonium ; Thermolysin

We cultured canine kidney (MDCK) cells stably expressing aquaporin-2 (AQP2) on collagen-coated permeable membrane filters and examined the effect of extracellular ATP on arginine vasopressin (AVP)-stimulated fluid transport and cAMP production. Exposure of cell monolayers to basolateral AVP resulted in stimulation of apical to basolateral net fluid transport driven by osmotic gradient which was formed by addition of 500 mM mannitol to basolateral bathing solution. Pre-exposure of the basolateral surface of cell monolayers to ATP (100 ?M) for 30 min significantly inhibited the AVP-stimulated net fluid transport. In these cells, AVP-stimulated cAMP production was suppressed as well. Profile of the effects of different nucleotides suggested that the P2Y2 receptor is involved in the action of ATP. ATP inhibited the effect of isoproterenol as well, but not that of forskolin to stimulate cAMP production. The inhibitory effect of ATP on AVP-stimulated fluid movement was attenuated by a protein kinase C inhibitor, calphostin C or pertussis toxin. These results suggest that prolonged activation of the P2 receptors inhibits AVP-stimulated fluid transport and cAMP responses in AQP2 transfected MDCK cells. Depressed responsiveness of the adenylyl cyclase by PKC-mediated modification of the pertussis-toxin sensitive Gi protein seems to be the underlyihng mechanism.
Adenosine Triphosphate ; Adenylyl Cyclases ; Aquaporin 2 ; Arginine Vasopressin ; Baths ; Cyclic AMP ; Forskolin ; Isoproterenol ; Kidney ; Madin Darby Canine Kidney Cells ; Mannitol ; Membranes ; Naphthalenes ; Nucleotides ; Pertussis Toxin ; Protein Kinase C ; Vasopressins

To elucidate the mechanism of cyclic nucleotides, such as adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5' -cyclic monophosphate (cGMP), in the regulation of human gastric motility, we examined the effects of forskolin (FSK), isoproterenol (ISO) and sodium nitroprusside (SNP) on the spontaneous, high K+ and acetylcholine (ACh)-induced contractions of corporal circular smooth muscle in human stomach. Gastric circular smooth muscle showed regular spontaneous contraction, and FSK, ISO and SNP inhibited its phasic contraction and basal tone in a concentration-dependent manner. High K+ (50 mM) produced sustained tonic contraction, and ACh (10 micrometer) produced initial transient contraction followed by later sustained tonic contraction with superimposed phasic contractions. FSK, ISO and SNP inhibited high K+-induced tonic contraction and also ACh-induced phasic and tonic contraction in a reversible manner. Nifedipine (1 micrometer), inhibitor of voltage-dependent L-type calcium current (VDCC(L)), almost abolished ACh-induced phasic contractions. These findings suggest that FSK, ISO and SNP, which are known cyclic nucleotide stimulators, inhibit smooth muscle contraction in human stomach partly via inhibition of VDCCL.
Acetylcholine ; Adenosine ; Calcium ; Contracts ; Forskolin ; Guanosine ; Humans ; Isoproterenol ; Muscle, Smooth ; Nifedipine ; Nitroprusside ; Nucleotides, Cyclic ; Relaxation ; Stomach

Members of prostaglandin (PG) E-series elicit cellular effects mainly through adenylyl cyclase-cAMP signaling. The role of PGE2-induced increase in cAMP has been shown to be compartmentalized in the cardiac myocytes: PGE2-induced increase of cAMP is not involved in the control of cardiomyocytic contraction. The purpose of the present study was to define the effect of PGE1 on the cGMP levels and the role of PGE1 in the atrial secretory function. Experiments were performed in perfused beating rabbit atria and atrial contractile responses, cGMP and cAMP efflux, and atrial natriuretic peptide (ANP) secretion were measured. PGE1 increased cGMP as well as cAMP efflux concentration in a concentration-dependent manner, however, no significant changes in atrial secretory responses were observed (with 1.0microM PGE1; for cGMP, 144.76+/-37.5%, n=11 versus -16.81+/-4.76%, n=6, control, p<0.01; for cAMP, 187.60+/-41.52%, n=11 versus 7.38+/-19.44%, n=6, control, p<0.01). PGE1 decreased atrial dynamics slightly but transiently, whereas PGE2 showed similar effects but with lower potency. Isoproterenol increased atrial cAMP efflux (with 2.0 nM; 145.71+/-41.89, n=5 versus 7.38+/-19.44%, n=6, control, p<0.05) and mechanical dynamics and decreased ANP secretion. The PGE1-induced increase in cGMP efflux showed a bell-shaped concentration-response curve. PGE1-induced increase of cGMP efflux was not observed in the presence of L-NAME, an inhibitor of nitric oxide (NO) synthase, or ODQ, an inhibitor of NO-sensitive guanylyl cyclase. L-NAME and ODQ showed no significant effect on the PGE1-induced transient decrease of atrial dynamics. These data indicate that PGE1 increases cGMP levels via NO-soluble GC signaling in the cardiac atrium and also show that PGE1-induced increases in cGMP and cAMP levels are not involved in the regulation of atrial secretory and contractile functions.
Alprostadil* ; Atrial Function ; Atrial Natriuretic Factor ; Dinoprostone ; Guanylate Cyclase ; Isoproterenol ; Myocytes, Cardiac ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; Nucleotides, Cyclic*