Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.

On the Impairment of Stress-Induced Changes in Triglyceride Levels via a Sub-Toxic Dose of Unmethylated Cytidine Phosphate Guanosine Oligodinucleotide (a Toll-Like Receptor 9 Ligand)

Changes in lipid metabolism have been implicated in protection against infectious diseases. In the first experiment of this study, we measured clinical lipid parameters in a murine model where the unmethylated cytidine phosphate guanosine (CpG) oligodinucleotide (ODN1826), a Toll-like receptor 9 (TLR9) agonist was administered in combination with D-galactosamine (GalN) that caused relatively liver-specific inflammation and toxicity. In the control mice group injected with phosphate-buffered saline (PBS) (acute psychological stress model associated with blood sampling), the serum triglyceride (TG) levels showed a rapid decrease followed by a rebound at 24 h as we have recently reported. However, such a TG rebound was impaired in the CpG/GalN- and solely CpG-treated groups of mice despite an absence of liver injury based on serum alanine aminotransferase levels in the latter group. Thus, the stress-associated serum TG rebound was abrogated by the injection of a sub-hepatotoxic CpG dose. In the second experiment, we simply measured the hepatic CD36 and SACRB1 (the gene for scavenger receptor B1 (SR-B1)) transcripts after the i.p. administration of PBS, CpG or CpG/GalN. There was a remarkable elevation of hepatic CD36 transcript expression in both the CpG- and CpG/GalN-treated mice at 8 h post-CpG injection whereas the increase in the PBS-treated mice was slower than the former two groups, suggesting that hepatic CD36 transcript expression is more pronounced in the combined stress models than under psychological stress alone. The individual mice data showed that the increase in CD36 expression was accompanied by a reduction in SCARB1 mRNA, showing reciprocal regulation between these two genes. Together with our previously reported findings, these data suggest that, in a murine model combining psychological stress with TLR-triggered hepatic inflammation, the psychological stress facilitates liver uptake of plasma TG (and its components fatty acids), but the subsequent re-esterification and/or release of TG-rich lipoproteins from the liver is impaired due to the concomitant TLR-signaling. We hypothesize that lipid metabolism during acute stress shifts toward an elevated hepatic uptake of lipids due to concomitant TLR signaling, facilitating the clearance of bacterial lipids by the liver.

Guanosine的酰化与酯解——均匀设计用作有机合成中的新颖计量化学技术(英文)

均匀设计可用作新颖的计量化学和计量合成工具 ,特别是用于有机合成试验设计和优化 从Guanosine分别经酰化和酯解可制务出NAG和TAR 为寻找最优合成反应条件 ,采用计量合成化学中均匀设计方法和逐步回归技术 ,使两者合成产率分别从 72 2 %和 35 6 %提高至 90 3%和 59 8% 。

N^2-(1-Methoxycarbonylethyl)guanosine,a new nucleoside coupled with an amino acid derivative from Amanita exitialis

A new purine nucleoside coupled with an amino acid derivative, N^2-（l-methoxycarbonylethyl）guanosine 1, along with β- carboline and russulaceramide was isolated from the fruiting bodies of Amanita exitialis, a newly described poisonous mushroom. Its structure was elucidated by spectroscopic methods. This is the first report of naturally occurring nucleosides in which an a-amino acid derivative is bonded through its a-amino nitrogen to a nucleobase aglycone by a C-N bond. The new compound was found to be toxic in brine shrimp lethality test （BST）. C 2009 Published by Elsevier B.V. on behalf of Chinese Chemical Society.

Study on disulfur-backboned nucleic acids:Part Ⅳ.Efficient synthesis of 3',5'-dithio-2'-deoxyguanosine

An efficient and novel method for synthesizing 3′,5′-dithio-2′-deoxyguanosine was described.In this method normal guanosine was used as the starting material.A very efficient procedure was used to synthesize 2-O-tosylguanosine 1,which used 0.1 eq.DBTO instead of 2 eq.1 was treated with LTBH to give 9-(2-deoxy-β-D-threo-pentofuranosyl)guanine 2.2 could be easily turned to the target compound.

Effects of plant extract neferine on cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in rabbit corpus cavernosum in vitro

Aim： To further investigate the relaxation mechanism of neferine （NED, a bis-benzylisoquinoline alkaloid extracted （isolated） from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavernosum tissue in vitro. Methods： The effects of Nef on the concentrations of cyclic adenosine monophosphate （cAMP） and cyclic guanosine monophosphate （cGMP） in isolated and incubated rabbit corpus cavernosum tissue were recorded using ^125I radioimmunoassay. Results： The basal concentration of cAMP in corpus cavernosum tissue was 5.67 ± 0.97 pmol/mg. Nef increased the cAMP concentration in a dose-dependent manner （P 〈 0.05）, but this effect was not inhibited by an adenylate cyclase inhibitor （cis-N-[2-phenylcyclopentyl]azacyclotridec-1-en-2-amine, MDL-12, 330A） （P 〉 0.05）. The accumulation of cAMP induced by prostaglandin Et （PGEt, a stimulator of cAMP production） was also augmented by Nef in a dose-dependent manner （P 〈 0.05）. The basal concentration of cGMP in corpus cavernosum tissue is 0.44 ± 0.09 pmol/mg. Nef did not affect this concentration of cGMP, either in the presence or in the absence of a guanyl cyclase inhibitor （1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ） （P 〉 0.05）. Also, sodium nitroprusside （SNP, a stimulator of cGMP production）-induced cGMP production was not enhanced by Nef （P 〉 0.05）. Conclusion： Nef, with its relaxation mechanism, can enhance the concentration of cAMP in rabbit corpus cavernosum tissue, probably by inhibiting phosphodiesterase activity. （Asian JAndro12008 Mar; 10： 307-312）

Chelerythrine chloride binding of guanosine in aqueous solution

In this work, the interaction between chelerythrine （CHE） and guanosine is studied using UV-vis and fluorescence measurements at various temperatures. The UV-vis spectra show that the increasing guanosine concentrations result in the decreasing absorption intensity and red shift of CHE E absorption band （267 nm）. The fluorescence spectra are fitted to linear analysis, yielding a binding constant of 1.04×10^4 L/tool at 298.15 K of CHE with guanosine. Besides, with △rHm^θ = - 8.26 kJ/mol, △rGm^θ = -22.90 kJ/mol, and △rSm^θ = 49.38 J/（mol K） the interaction should be entropy-driven and exterothermic.

Existence of Heme Oxygenase-carbon Monoxide-cyclic Guanosine Monophosphate Pathway in Human Trabecular Meshwork Cells In Vitro

To confirm the existence of heme oxygenase (HO)-carbon monoxide (CO)- cyclic guanosine monophosphate (cGMP) pathway in the cultured human trabecular meshwork cells (HTMCs) in vitro, and to evaluate the inductive role of hemin on this pathway, HTMCs of the third to fourth generation were cultured in vitro. Reverse transcripase-polymerase chain reaction (RT-PCR) was employed for detection of HO-1 and HO-2 mRNA. Immunohistochemical staining was used to detect HO-1 and HO-2 proteins. Hemin was added into the culture solution. The HO-1 mRNA levels were quantified by RT-PCR. The relative amount of carbon monoxide released into the media was measured with the quantifying carbon monoxide hemoglobin (HbCO) by spectrophotometry. Radioimmunoassay was used to determine changes of cGMP in HTMCs. The results showed that cultured cells had the specific characteristics of HTMCs. Both HO-1 and HO-2 genes were expressed in HTMCs, as well as HO-1 and HO-2 proteins in HTMCs. Hemin induced HO-1 mRNA, HbCO and cGMP in a dose-dependent manner. In conclusion, HO-CO-cGMP pathway exists in the cultured HTMCs and can be induced by hemin. Pharmacological stimulation of HO-CO-cGMP pathway may constitute a novel therapeutic approach to rescuing glaucoma.

Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension

AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.

Transformation of microstructure and phase of disodium guanosine 5′-monophosphate: Thermodynamic perspectives

Microstructure and phase transformation of disodium guanosine 5′-monophosphate(5′-GMPNa_2) are extremely important for controlling the process and understanding the mechanism of crystallization. In this work, the thermodynamic properties of polymorphous 5′-GMPNa_2 especially the solubility were studied, the solubility results show that 5′-GMPNa_2 is more soluble in ethanol–water(E–W) than in isopropanol–water(I–W). The amorphous form of 5′-GMPNa_2 is more soluble than the crystalline form at the same mole fraction and temperature. Meanwhile, the crystalline forms and morphologies of the residual solids were characterized by PXRD and SEM. The results indicate that solid forms of 5′-GMPNa_2 transformed spontaneously from amorphous to crystalline when the ethanol proportion is ≥20%. In addition, increasing the pH facilitates the dissolution of 5′-GMPNa_2 and helps to maintain the crystalline form. The associated Gibbs free energy values were calculated to verify the trend of transformation from amorphous to crystalline 5′-GMPNa_2. These results should help to guide the industrial crystallization process and to obtain the crystalline form of 5′-GMPNa_2.

Spectral studies of the interaction between sanguinarine and guanosine

The interaction between sanguinarine and guanosine was investigated by using UV-vis and fluorescence spectra at pH 7.2. The binding of sanguinarine to guanosine was substantiated by the hypochromism and bathochromism in the absorption spectra and the emission quenching in fluorescence spectra. The fluorescence lifetime results, the varieties of the fluorophore absorption spectra and the decrease of the binding constant with the increasing temperature all indicate that the fluorescence quenching is static. The ratio and constant of the binding cytidine to sanguinarine are 2 and 6.44 × 10^7, respectively. The result shows that the binding of sanguinarine to guanosine is not only exothermic but also entropy-driven with △H=-8.53kJ/mol, AS = 0.12 kJ/（molK）, and AG =-44.57 kJ/mol at 298.15 K.

Current perspectives on the antidepressant-like effects of guanosine

Purines have a recognized importance as intercellular mes- sengers. These molecules play an important role in the de- velopment and maintenance of the central nervous system （CNS）, as well as in its response to pathological conditions. Both adenine and guanine-based purines can be released from astrocytes, where they play a relevant role as extracel- lular signaling molecules. Particularly, the nucleoside gua- nosine has been proposed as an extracellular molecule that regulates the response of CNS to damage. Following injury, this nucleoside attains high concentrations in the extracel- lular space, where it activates multiple signaling pathways.

Studies on Relationship between Serum Nitric Oxide and Plasma Cyclic Guanosine Monophosphate and Prolonged Bleeding after Medical Abortion as well as Prophylaxis and Treatment of Bleeding with Traditional Chinese Medicine

Objectives To study the relationship between serum nitric oxide (NO and plasma cyclic guanosine monophosphate (cGMP) and prolonged bleeding after medical abortion. Methods A total of 120 women having received medical abortions at random were recruited and divided into two groups: the one (Group A,n=60) taking 'Gong Fu Mixture(Uterus Recovering Mixture)' and the other (Group B,n=60) not taking it after abortion. On d 10, 20 and 30 after medical abortion, serum NO and plasma cGMP were tested before and after mifepristone administration and 10 d later by Gresis reaction method and radioimmunoassay respectively. Results NO concentration in serum and cGMP concentration in plasma decreased significantly after taking mifepristone given (P<0.05). Ten days later, the number of those with bleeding discontinuation in the group A was significantly greater than that in the group B (P<0.05). Serum NO level and plasma cGMP level in the group A decreased more significantly than those in the group B (P<0.05). Conclusion The slow decrease of serum NO and plasma cGMP is closely related to prolonged bleeding after medical abortion. “Gong Fu Mixture (uterus recovering mixture)” is effective in prevention and treatment of prolonged bleeding.

X-ray Examination of the Complex Adenosine, Guanosine and Cytidine with UO2^2＋ Ions

Interaction of dioxouranitm （VI） UO2^2＋ ion with Adenosine-5＇-triphosphate, Guanosine-5＇-triphosphate and 3ytidine-5＇-triphosphate were obtained a complexs of Adenosine, Guanosine and Cytidine with uranium UO2^2＋ ions and X-ray nethod to explore these complexes.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

The mechanistic study on Wa medicine Niang-Mu-Liang medicinal liquor mitigating diabetes mellitus erectile dysfunction in rats by inhibiting ferroptosis

Background:This study aims to investigate the therapeutic effect of Wa medicine Niang-Mu-Liang medicinal liquor(NML)on rats with diabetes mellitus erectile dysfunction(DMED)and its impact on the ferroptosis signaling pathway.Methods:Thirty Sprague-Dawley rats were randomly divided into three groups:Control,DMED,and NML.After establishing the DMED model,treatments were administered for 8 weeks.After the administration,apomorphine hydrochloride tests were conducted to measure the mass and organ index of testes and epididymides,sperm concentration and viability in each group.Penile corpus cavernosum tissues were stained with hematoxylin and eosin.Nitric oxide and cyclic guanosine monophosphate levels in the penile corpus cavernosum tissues were determined using biochemical kits and enzyme-linked immunosorbent assay,while the expression of proteins related to the ferroptosis signaling pathway was measured by Western blot.Results:Compared to the DMED group,the DMED rats treated with NML showed significantly increased erection frequency,testicular and epididymal mass and index,sperm count and viability,along with noticeable improvement in the pathological morphology of penile corpus cavernosum.The content of nitric oxide and cyclic guanosine monophosphate,and the expression of ferritin heavy chain,ferritin light chain,and glutathione peroxidase 4 proteins in penile corpus cavernosum tissue were elevated,while the expression of transferrin and STEAP3 proteins was reduced.Conclusion:NML can improve erectile function in DMED rats by inhibiting the ferroptosis signaling pathway.

Diversification of the RAB Guanosine Triphosphatase Family in Dicots and Monocots

RAB guanosine triphosphatases （GTPases） are key regulators of vesicle trafficking and are essential to the growth and development of all eukaryotic cells. During evolution, the RAB family has expanded in different patterns to facilitate distinct cellular, developmental and physiological adaptations. Yeast has only 11 family members, whereas mammalian RABs have expanded to 18 RAB subfamilies. Plant RABs have diversified primarily by duplicating members within a single subfamily. Plant RABs are divided into eight subfamilies, corresponding to mammalian RAB1, RAB2, RAB5, RAB6, RAB7, RAB8, RAB11 and RAB18. Functional diversification of these is exemplified by the RAB1 ls, orthologs of which are partitioned into unique cell compartments in plants where they function to transport vesicles during localized tip growth. Similarly, the RAB2 family in grasses is likely involved in vesicle secretion associated with wall expansion, as determined by analysis of over-expression mutants. We propose that dicots and monocots have also diverged in their RAB profiles to accommodate unique cellular functions between the two groups. Here we present a bioinformatics analysis comparing the RAB sub-families of rice, maize and Arabidopsis. These results will guide future functional studies to test for the role of diversification of subfamilies unique to monocots compared to dicots.

Fluorescence quenching of TMR by guanosine in oligonucleotides

Nucleotide-specific fluorescence quenching in fluorescently labeled DNA has many applications in biotechnology. We have studied the inter-and intra-molecular quenching of tetramethylrhodamine (TMR) by nucleotides to better understand their quenching mechanism and influencing factors. In agreement with previous work, dGMP can effectively quench TMR, while the quenching of TMR by other nucleotides is negligible. The Stern-Volmer plot between TMR and dGMP delivers a bimolecular quenching constant of Ks=52.3 M-1. The fluorescence of TMR in labeled oligonucleotides decreases efficiently through photoinduced electron transfer by guanosine. The quenching rate constant between TMR and guanosine was measured using fluorescence correlation spectroscopy (FCS). In addition, our data show that the steric hindrance by bases around guanosine has significant effect on the G-quenching. The availability of these data should be useful in designing fluorescent oligonucleotides and understanding the G-quenching process.

^(13)C NMR STUDIES ON BASE-PAIRING BETWEEN GUANOSINE, COORDINATED GUANOSINE AND CYTIDINE

The study on the interaction of cisplatin with guanosine in neutral solution by 13C NMR spectroscopy has shown that besides the formation of [Pt（NH3）2（N7-Guo）2]2+, a new 1:1 complex [Pt（NH3）2(N7.N1-GuoH-1)]nn+, in which deprotonated guanosine was bonded to platium by N1 and N7 atoms, was also formed. Recently we have succeed-

Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design

Deamination is a crucial step in the transformation of 6-cyclopropylamino guanosine prodrug to its active form. A convenient method using capillary electrophoresis （CE） without sample labeling was developed to analyze the deamination of a series of D-/L-6-cyclopropylamino guanosine analogs by mouse liver homogenate, mouse liver microsome, and adenosine deaminase （ADA）. A two-step process involving a 6-amino guanosine intermediate formed by oxidative N-dealkylation was demonstrated in the metabolism of 6-cyclopropylamino guanosine to 6-hydroxy guanosine. The results indicated that the transformation rates of different prodrugs to the active form varied greatly, which were closely correlated with the configuration of nucleosides and the structure of glycosyl groups. Most importantly, D-form analogs were metabolized much faster than their L-counterparts, thus clearly pointed out that compared to guanine, modification of glycosyl part might be a better choice for the development of L-Kuanosine analogs for the treatment of HIV,