Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing an...Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing and treating cardiovascular diseases.However,its poor metabolic stability and high permeability across the blood-brain barrier(BBB)make it unsuitable for preventing and treating peripheral cardiovascular diseases.Herein,the hit-to-lead optimization was performed to discover novel 3-trifiuoromethylsubstituted pyrazole derivatives as potent and selective PDE10A inhibitors.The structure-activity relationships,biological characterization,molecular mechanism,and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A(half maximal inhibitory concentration,IC_(50)=11.9 nmol/L),more than 840-fold selectivity over other PDE subtypes,enhanced liver microsomes stability(T_(1/2)=239 min)compared to MP-10 and low BBB permeability.Importantly,oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline(ISO)-induced pathological cardiac hypertrophy in mice,particularly suppressing increase of cardiac weight,atrial natriuretic peptide(ANP)andβ-myosin heavy chain(β-MHC)hypertrophic markers along with cardiac fibrosis.These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.展开更多
Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity ...Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity and mortality worldwide(Xia and Liang,2019).According to the World Health Organization(WHO),an estimated 296 million people live with chronic HBV infection,contributing to around 820,000 deaths annually due to complications such as liver cirrhosis and hepatocellular carcinoma(HCC)(Easterbrook et al.,2021).展开更多
Objective Cyclic nucleotide phosphodiesterase（PDE）is a critical component of the nitric oxide（NO）signaling pathway and plays critical roles in cognition and learning,Parkinson’s disease,attention deficit hyperact...Objective Cyclic nucleotide phosphodiesterase（PDE）is a critical component of the nitric oxide（NO）signaling pathway and plays critical roles in cognition and learning,Parkinson’s disease,attention deficit hyperactivity disorder, psychosis and depression.The PDEs in the brain of guinea pig have not yet been reported.The present study aimed to detect the unknown Pde cDNAs in the brain of guinea pig.Methods Reverse transcription polymerase chain reaction（RT-PCR）and sequence comparison analysis were performed to detect the expression of Pde cDNAs and to assess the identity rates of cDNA and amino acid sequences between guinea pig and human or mouse,respectvely.The RT-PCR primers were located on the conserved region of human PDE and mouse Pde cDNAs.Results Eleven novel Pde cDNAs were detected in the brain of guinea pig（Cavia porcellus）,including CpPde1a,CpPde1b,CpPde2a,CpPde4a,CpPde4d,CpPde5a,CpPde6c,CpPde7b, CpPde8a,CpPde9a,and CpPde10a.The identity rates of the Pde cDNA sequences between guinea pig and human ranged from 83.8%to 94.3%,and those of the amino acid sequences ranged from 91.9%to 100%.The identity rates of Pde cDNA sequences between guinea pig and mouse ranged from 84.6%to 92.1%,and those of amino acid sequences ranged from 91.2% to 99.2%.The average identity rate of the 11 Pde cDNA sequences between guinea pig and human was significantly higher（P 0.01）than that between guinea pig and mouse.The putative partial amino acid sequences of guinea pig contained at least one of the conserved domains of human and mouse PDE proteins.Conclusion These results indicate that the brainexpressed Pde genes are identified in guinea pig,which lays the foundation for further investigating the physiological roles of PDE proteins in the brain.展开更多
Parkinson disease(PD) is a chronic neurodegenerative disorder caused by progressive dopaminergic neuronal death in the substantia nigra pars compacta within the midbrain.There still is no cure,effective treatments for...Parkinson disease(PD) is a chronic neurodegenerative disorder caused by progressive dopaminergic neuronal death in the substantia nigra pars compacta within the midbrain.There still is no cure,effective treatments for PD,available therapies are only capable of offering temporary and symptomatic relief to the patients.There are certain patents that claim phosphodiesterase(PDE) inhibitors as possible anti-PD drugs,PDE4 is a promising target for the treatment of PD and the underlying mechanism has not yet been well elucidated.PDE4 is an enzyme that specifically hydrolyzes intracellular cyclic adenosine monophosphate(cAMP)throughout the body,including the brain.Most of the available PDE4 inhibitors exert unpleasant and serious side effects,such as emesis and nausea,which hinder its clinical application.Therefore,more efforts are needed before PDE4 inhibitors with high therapeutic indices are available for treatment of PD.FCPR16 is a novel PDE4 inhibitor with little emetic potential,which exhibits excellent enzyme inhibition activity(IC50=90 nmol·L^(-1)).METHODS SH-SY5 Y cell was induced with 1-methyl-4-phenylpyridinium(MPP+)to mimic PD cell injury in vitro,and CCK-8 assay was used to investigate the viability effects of different concentration of FCPR16(3.1-50 μmol·L^(-1)) on MPP+-injured SH-SY5 Y cells.Detection of apoptosis was performed by flow cytometry.The level of ntracellular reactive oxygen species was detected with the fluorescent probe DCFH-DA,and the mitochondrial membrane potential of cells in different experimental groups was detected with the JC-1 fluorescent probe.AO staining and Lysotracker Red staining were used to detect the intracellular antophagy changes.The expression of apoptosis related proteins,autophagy and other related signal molecules were demonstrated by Western blotting.Different cellular signaling pathway inhibitors were used to invesitigate the specific cellular mechanisms of FCPR16 protecting MPP+-induced cell injury.RESULTS FCPR16(12.5-50 μmol·L^(-1)) dose-dependently reduced MPP+-induced decline of cell viability,accompanied by reductions in nuclear condensation and lactate dehydrogenase release.The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells.Furthermore,FCPR16(25 μmol·L^(-1)) significantly suppressed the accumulation of reactive oxygen species(ROS),prevented the decline of mitochondrial membrane potential(Δψm) and attenuated the expression of malonaldehyde level.Further studies disclosed that FCPR16 enhanced the levels of cA MP and the exchange protein directly activated by cA MP(Epac) in SHSY5 Y cel s.Western blotting analysis revealed that FCPR16 increased the phosphorylation of c AMP response element-binding protein(CREB) and protein kinase B(Akt)down-regulated by MPP+in SHSY5 Y cells.Moreover,the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401.CONCLUSION The novel PDE4 inhibitor FCPR16 can protect against damaging pathways including oxidative stress,mitochondrial dysfunction and apoptosis in SH-SY5 Y cells.FCPR16 preventes MPP+-induced neurotoxicity through activation of cAMP/PKA/CREB and Epac/Akt signaling pathways.These may lead to develop mechanism based therapeutics and improved pharmacotherapy for PD.It is reasonable to assume that FCPR16 is a potential candidate for the prevention and treatment of PD.展开更多
The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger ...The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology （ART） programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.展开更多
Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effec...Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effects of anti-inflammation, anti-anaphylaxis, antitumor, antioxidant, protection of nervous system and so on, and has mainly been used for the treatment of respiratory inflammatory diseases, cancer and cardiovascular disease in clinic. PDE4, specific to hydrolyze cyclic AMP （cAMP）, is considered to be a new anti-inflammatory target due to the decisive role on cAMP signal in inflammatory cells such as neutrophils. In order to explore the anti-inflammatory mechanism, we further studied the effects of luteolin on the activity and expression of PDE4, the expression of lymphocyte function-associated antigen-1 （LFA-1） and macrophage-1 （MAC-l） in neutrophils, and the adhesion of neutrophils and endothelial cells. The results showed that luteolin had a dose-dependent inhibition on both bare PDE4 activity and PDE4 in cultured neutrophils, and had an obviously promotive effect on gene expressions of PDE4A, 4B and 4D in later period. Luteolin had a significant inhibitory effect on neutrophils adhesion and LFA-1 expression in early stage, and had no obvious effect on MAC-1 expression. Therefore, luteolin can inhibit LFA-1 expression of neutrophils, then inhibit the adhesion of neutrophils and endothelial cells, and the mechanism is at least related with the inhibition of PDE4 activity.展开更多
Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inh...Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on c AMP-phosphodiesterase（PDE）. To explore the anti-inflammatory effect and mechanism, the influence of gallic acid on neutrophils PDE4 activity and expression, TNF-α and IL-6 content and rat arthritis model were further studied. PDE4 activity and gene express were calculated respectively by substrate c AMP change examined with HPLC and real-time RT-PCR. The concentration of IL-6 and TNF-α in supernatant were assayed by ELISA method. Model of rat arthritis was caused by complete Freund＇s adjuvant. Results showed that gallic acid had a dose-dependent restraint on PDE4 activity of neutrophils in vitro, promoted significantly PDE4 A expression（P〈0.01）, and had no influence on the expressions of PDE4 B and 4D. However, PDE4 C expression was not detected. Gallic acid could promote IL-6 release（P〈0.05）, and inhibit TNF-α release of neutrophils（P〈0.05）. The experiment in vivo showed that gallic acid had obvious restraint on local inflammation of animal model（P〈0.05）. Therefore, the anti-inflammatory effect of gallic acid may be mediated in part through an inhibition on PDE4 activity and further an increase of IL-6 and a decrease of TNF-α of neutrophils, and this effect seemed to have no relationship with PDE4 expression.展开更多
The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate （sildenafil） and tadalafil for treating erectile dysfunction （ED） in Chinese men na＇ive to phosphodiesterase 5 （PDE...The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate （sildenafil） and tadalafil for treating erectile dysfunction （ED） in Chinese men na＇ive to phosphodiesterase 5 （PDE5） inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire （PITPQ）. Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function （IIEF） erectile function （EF） domain, sexual encounter profile （SEP） Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men （91%） completed the randomized treatment phase. Two hundred and forty-two per 350 （69.1%） patients preferred 20-mg tadalafil, and 108/350 （30.9%） preferred lO0-mg sildenafil （P 〈 0.001） as their treatment in the 8 weeks extension. Ninety-two per 242 （38%） patients strongly preferred tadalafil and 37/108 （34.3%） strongly the preferred sildenafil. The SEP2 （penetration）, SEP3 （successful intercourse）, and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by 〉 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED na＇ive to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.展开更多
The importance of nitric oxide(NO) in vascular physiology is irrefutable;it stimulates the intracellular production of cyclic guanosine monophosphate(cGMP),initiating vascular smooth muscle relaxation.This biochemical...The importance of nitric oxide(NO) in vascular physiology is irrefutable;it stimulates the intracellular production of cyclic guanosine monophosphate(cGMP),initiating vascular smooth muscle relaxation.This biochemical process increases the diameter of small arteries,regulating blood flow distribution between arterioles and the microvasculature.The kidney is no exception,since NO predominantly dilates the glomerular afferent arterioles.It is now evident that the vascular production of cGMP can be augmented by inhibitors of phosphodiesterase type 5(PDE 5),the enzyme which breakdowns this cyclic nucleotide.This has clinical relevance,since diabetic nephropathy(DN) a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease,increases intraglomerular capillary pressure,leading to glomerular hypertension.PDE 5 inhibitors may have,therefore,the potential to reduce glomerular hypertension.This review describes the use of PDE 5 inhibitors to improve the metabolic,haemodynamic and inflammatory pathways/responses,all of which are dysfunctional in DN.展开更多
Summary： To further investigate the mechanisms of action of icariin （ICA）, we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit...Summary： To further investigate the mechanisms of action of icariin （ICA）, we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of ^125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil （Sild）. Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type Ⅴ （PDE5） in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction （RT-PCR）. The results showed that ICA increased cGMP concentrations directly （P〈0.05）, but there was no significant effect on cAMP concentrations （P〉0.05）. In the presence of sodium nitroprusside （SNP）, a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose （P〈0.01）. Their EC50 was 4.62 （ICA） and 0.42 （Sild） μmol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly （P〉0.05）. There were PDE5A 1 and PDE5A2 mRNA expressions in rat cor- pus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly （P〈 0.01）. The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.展开更多
Phosphodiesterase isoenzymes 5 inhibitors （PDE5-1s） are the first-line therapy for erectile dysfunction （ED）. The constant discoveries of nitric oxide （NO）/cyclic guanosine monophosphate （cGMP） cell-signaling ...Phosphodiesterase isoenzymes 5 inhibitors （PDE5-1s） are the first-line therapy for erectile dysfunction （ED）. The constant discoveries of nitric oxide （NO）/cyclic guanosine monophosphate （cGMP） cell-signaling pathway for smooth muscle （SM） control in other urogenital tracts （UGTs） make PDE5-1s promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-1s have been widely recognized. On-demand PDE5-1s are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase （sGC） stimulators also have promising role in the management of severe ED conditions. PDE5-1s are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-1s, especially combined with （z-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia （BPH） except on maximum urinary flow rate （Qmax） with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-1s are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie＇s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-1s in disorders of UGTs are required.展开更多
The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors(PDE5-1s)and(x-blockers used alone or combined for the treatment of lower urinary tract sympt...The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors(PDE5-1s)and(x-blockers used alone or combined for the treatment of lower urinary tract symptoms(LUTS)due to benign prostatic hyperplasia(BPH).An electronic search of PubMed,Cochrane Library and Embase up to January 2014 was performed to identify randomized controlled trials comparing the efficacy and safety of PDE5-Is and(x-blockers for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia,which assessed IPSS score,maximum flow rate,postvoided residual urine,quality of life and Erectile Function(IIEF)score as outcomes.Data were analyzed by fixed or random effect models using Cochrane Collaboration review manager software.A total of 12 studies were included,Our novel data demonstrated that there was a trend that(x-blockers were more efficacious than PDE5-Is on decreasing IPSS score and increasing maximum flow rate.(x-blockers were significantly more effective than PDE5-Is on reduction of postvoided residual urine with a mean difference of 3.67(95%CI 1.56 to 5.77,P=0.0006)and PDE5-Is showed greater effect than(x-blockers on increasing IIEF score with a mean difference of 9.82(95%CI 3.80 to 15.85,P=0.001).In conclusion,our novel data demonstrated that PDE5-Is plus ABs ranked the highest on the improvement of LUTS/BPH.PDE5-Is monotherapy was also effective in this kind of disorder except less reduction of PVR than ABs,In addition,both combined-or mono-therapy were safe.展开更多
Aim： To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 （PDE5） inhibitor, on penile erection in obese rats. Meth...Aim： To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 （PDE5） inhibitor, on penile erection in obese rats. Methods： The rats were fed a high-energy diet for 12 weeks and divided into three groups： an obesity-resistant （OR） control group, an obesity-prone （OP） control group, and an OP-DA-8159 treatment （DA-8159） group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. Results： In the OP control group, the maximum intracavernous pressure （ICP） and ICP/blood pressure （ICP/BP） ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve （AUC） of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. Conclusion： These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction （ED） can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.展开更多
The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction （ED） treated with phosphodiesterase type 5 inhibitors （PDE-5i） over a 7-year period vs. men with...The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction （ED） treated with phosphodiesterase type 5 inhibitors （PDE-5i） over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate cancer prior to 2000 were identified. These individuals were divided into two groups： 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 （4.1%） men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 （9.9%） men with ED in the non-treated group （P〈00001）. A higher percentage of African Americans were treated with PDE-5i vs. those who were not （10.5% vs. 7.1%; P〈O.O001）. The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen （10.0% vs. 13.1%; P=-0.0008） and higher percentage of benign prostatic hyperplasia （38.4% vs. 35.1%; P=0.0149）. Men with ED treated with PDE-5i tended to have less chance （adjusted odds ratio： 0.4; 95% confidence intervals： 0.3-0.5; P〈0.0001） of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of beine diaenosed with orostate cancer. Further research is warranted.展开更多
Phosphate deficiency is one of the leading causes of crop productivity loss.Phospholipid degradation liberates phosphate to cope with phosphate deficiency.Glycerophosphodiester phosphodiesterases(GPX-PDEs)hydrolyse th...Phosphate deficiency is one of the leading causes of crop productivity loss.Phospholipid degradation liberates phosphate to cope with phosphate deficiency.Glycerophosphodiester phosphodiesterases(GPX-PDEs)hydrolyse the intermediate products of phospholipid catabolism glycerophosphodiesters into glycerol-3-phosphate,a precursor of phosphate.However,the function of GPX-PDEs in phosphate remobilization in maize remains unclear.In the present study,we characterized two phosphate deficiency-inducible GPX-PDE genes,ZmGPX-PDE1 and ZmGPX-PDE5,in maize leaves.ZmGPX-PDE1 and ZmGPX-PDE5 were transcriptionally regulated by ZmPHR1,a well-described phosphate starvation-responsive transcription factor of the MYB family.Complementation of the yeast GPX-PDE mutant gde1Δindicated that ZmGPX-PDE1 and ZmGPX-PDE5 functioned as GPX-PDEs,suggesting their roles in phosphate recycling from glycerophosphodiesters.In vitro enzyme assays showed that ZmGPX-PDE1 and ZmGPX-PDE5 catalysed glycerophosphodiester degradation with different substrate preferences for glycerophosphoinositol and glycerophosphocholine,respectively.ZmGPX-PDE1 was upregulated during leaf senescence,and more remarkably,loss of ZmGPXPDE1 inmaize compromised the remobilization of phosphorus fromsenescing leaves to young leaves,resulting in a stay-green phenotype under phosphate starvation.These results suggest that ZmGPX-PDE1 catalyses the degradation of glycerophosphodiesters in maize,promoting phosphate recycling from senescing leaves to new leaves.This mechanism is crucial for improving phosphorus utilization efficiency in crops.展开更多
Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target speci...Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.展开更多
We aimed to determine whether combination of LIM-kinase 2 inhibitor(LIMK2i)and phosphodiesterase type-5 inhibitor(PDE5i)could restore erectile function through suppressing cavernous fibrosis and improving caver nous a...We aimed to determine whether combination of LIM-kinase 2 inhibitor(LIMK2i)and phosphodiesterase type-5 inhibitor(PDE5i)could restore erectile function through suppressing cavernous fibrosis and improving caver nous apoptosis in a rat model of cavernous nerve crush injury(CNCI).Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows:(1)sham surgery(Group S),(2)CNCI(Group I),(3)CNCI treated with daily intraperitoneal administration of 10.0 mg kg^-1 LIMK2i(Group I+L),(4)daily oral administration of 20.0 mg kg-1 udenafil,PDE5i(Group I+U),and(5)combined administration of 10.0 mg kg^-1 LIMK2i and 20.0 mg kg^-1 udenafil(Group I+L+U).Rats in Groups I+L,I+U,and I+L+U were treated with respective regimens for 2 weeks after CNCI.At 2 weeks after surgery,erectile response was assessed using electrostimulation.Penile tissues were processed for histological studies and western blot.Group I showed lower intracavernous pressure(ICP)/mean arterial pressure(MAP),lower area under the curve(AUC)/MAP,decreased immunohistochemical staining for alpha-smooth muscle(SM)actin,higher apoptotic index,lower SM/collagen ratio,increased phospho-LIMK2-positive fibroblasts,decreased protein kinase B/endothelial nitric oxide synthase(Akt/eNOS)phosphorylation,increased LIMK2/cofilin phosphorylation,and increased protein expression of fibronectin,compared to Group S.In all three treatment groups,erectile responses,protein expression of fibronectin,and SM/collagen ratio were improved.Group I+L+U showed greater improvement in erectile response than Group I+L.SM content and apoptotic index in Groups I+U and I+L+U were improved compared to those in Group I.However,Group I+L did not show a significant improvement in SM content or apoptotic index.The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I+L and I+L+U,but not in Group I+U.Akt/eNOS phosphorylation was improved in Groups I+U and I+L+U,but not in Group I+L.LIMK2/cofilin phosphorylation was improved in Groups I+L and I+L+U,but not in Group I+U.Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis.Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.展开更多
OBJECTIVE Alcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world. However,there are no ideal treatments for this disease in clinic.Phosphodiesterases(PD...OBJECTIVE Alcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world. However,there are no ideal treatments for this disease in clinic.Phosphodiesterases(PDEs) are a superfamily of enzymes consisting of 11 PDE families that hydrolyze cyclicAMP(cA MP) and/or cyclicGMP(cGMP). Among them,PDE4 is critical in the control of intracellular cAMP levels and has been shown to play an important role in the regulation of ethanol consumption.However,the functional role of PDE4 in mediating alcoholism remains unclear. METHODS Ethanol drinking and preference were examined using the two-bottle choice and/or drinking-in-dark(DID) test in high alcohol preferring(HAP) animals,including C57,HAP,and PDE4-subtype knockout mice,and Fawn-Hooded(FH/Wjd) rats,treated with or without the PDE4 inhibitor rolipram or roflumilast. Ethanol withdrawal-induced anxiety-and depressive-like behaviors were examined using the elevated plusmaze,holeboard,forced-swim,and tail-suspension tests in C57 mice or FH rats in the presence of PDE4 inhibition. Levels of cAMP,CREB were determined in brain regions. RESULTS Treatment with rolipram or roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in C57 and HAP mice as well as FH rats. Mice deficient in PDE4 B,but not PDE4 D,displayed similar effects to general PDE4 inhibition. In addition,rolipram reversed ethanol withdrawal-induced anxietyand depressive-like behaviors 1 d and 14 d,respectively,following withdrawal from ethanol drinking in the two-bottle choice in C57 mice or FH rats. Locomotor activity was not changed in either mice or rats treated with the PDE4 inhibitors. Levels of cAMP,p CREB in the brain were increased by rolipram.CONCLUSION The results provide solid evidence for the important role of PDE4 in ethanol consumptionand ethanol withdrawal-induced symptoms. Inhibitors of PDE4,in particular the PDE4 B isoform,can be a novel class of treatment for alcoholism.展开更多
The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might req...The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.展开更多
基金supported by the National Natural Science Foundation of China(Nos.22277154,82003576,82273856,22277019,22077143,22377023,82273925)Natural Science Foundation of Guangdong Province(No.2021A1515012499)+1 种基金Fundamental Research Funds for Hainan University(Nos.KYQD(ZR)-21031,KYQD(ZR)-21108,KYQD(ZR)-23003,XTCX2022JKA01)Natural Science Foundation of Hainan Province(Nos.KJRC2023B10,822MS051,824YXQN420,324MS018)。
文摘Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing and treating cardiovascular diseases.However,its poor metabolic stability and high permeability across the blood-brain barrier(BBB)make it unsuitable for preventing and treating peripheral cardiovascular diseases.Herein,the hit-to-lead optimization was performed to discover novel 3-trifiuoromethylsubstituted pyrazole derivatives as potent and selective PDE10A inhibitors.The structure-activity relationships,biological characterization,molecular mechanism,and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A(half maximal inhibitory concentration,IC_(50)=11.9 nmol/L),more than 840-fold selectivity over other PDE subtypes,enhanced liver microsomes stability(T_(1/2)=239 min)compared to MP-10 and low BBB permeability.Importantly,oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline(ISO)-induced pathological cardiac hypertrophy in mice,particularly suppressing increase of cardiac weight,atrial natriuretic peptide(ANP)andβ-myosin heavy chain(β-MHC)hypertrophic markers along with cardiac fibrosis.These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.
基金supported by the National Key Research and Development Program of China(No.2023YFC2308500)the Fundamental Research Funds for the Central Universities(project no.2042024kf0026),the Open Grant from the Pingyuan Laboratory(2023PY-OP-0101)+3 种基金the National Natural Science Foundation of China(project no.81971936,32100125 and 32300131)Hubei Province's Outstanding Medical Academic Leader Program,East Lake Hi-tech Development Zone Unveiling and Commanding Project(No.2023KJB219)Science and Technology Talent Service Enterprise Project(No.2024DJC064)Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital,Wuhan University.
文摘Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity and mortality worldwide(Xia and Liang,2019).According to the World Health Organization(WHO),an estimated 296 million people live with chronic HBV infection,contributing to around 820,000 deaths annually due to complications such as liver cirrhosis and hepatocellular carcinoma(HCC)(Easterbrook et al.,2021).
基金supported by the National Natural Science Foundation of China(No.31070928,30600198)the Natural Science Foundation of Guangdong Province,China(No.06301101)the Medical Research Program of Guangdong Province,China(No.A2010259)
文摘Objective Cyclic nucleotide phosphodiesterase（PDE）is a critical component of the nitric oxide（NO）signaling pathway and plays critical roles in cognition and learning,Parkinson’s disease,attention deficit hyperactivity disorder, psychosis and depression.The PDEs in the brain of guinea pig have not yet been reported.The present study aimed to detect the unknown Pde cDNAs in the brain of guinea pig.Methods Reverse transcription polymerase chain reaction（RT-PCR）and sequence comparison analysis were performed to detect the expression of Pde cDNAs and to assess the identity rates of cDNA and amino acid sequences between guinea pig and human or mouse,respectvely.The RT-PCR primers were located on the conserved region of human PDE and mouse Pde cDNAs.Results Eleven novel Pde cDNAs were detected in the brain of guinea pig（Cavia porcellus）,including CpPde1a,CpPde1b,CpPde2a,CpPde4a,CpPde4d,CpPde5a,CpPde6c,CpPde7b, CpPde8a,CpPde9a,and CpPde10a.The identity rates of the Pde cDNA sequences between guinea pig and human ranged from 83.8%to 94.3%,and those of the amino acid sequences ranged from 91.9%to 100%.The identity rates of Pde cDNA sequences between guinea pig and mouse ranged from 84.6%to 92.1%,and those of amino acid sequences ranged from 91.2% to 99.2%.The average identity rate of the 11 Pde cDNA sequences between guinea pig and human was significantly higher（P 0.01）than that between guinea pig and mouse.The putative partial amino acid sequences of guinea pig contained at least one of the conserved domains of human and mouse PDE proteins.Conclusion These results indicate that the brainexpressed Pde genes are identified in guinea pig,which lays the foundation for further investigating the physiological roles of PDE proteins in the brain.
基金NationalNatural Science Foundation of China (81773698)Funding from Guangzhou Science and Technology Department (2015B020211007,201604020112).
文摘Parkinson disease(PD) is a chronic neurodegenerative disorder caused by progressive dopaminergic neuronal death in the substantia nigra pars compacta within the midbrain.There still is no cure,effective treatments for PD,available therapies are only capable of offering temporary and symptomatic relief to the patients.There are certain patents that claim phosphodiesterase(PDE) inhibitors as possible anti-PD drugs,PDE4 is a promising target for the treatment of PD and the underlying mechanism has not yet been well elucidated.PDE4 is an enzyme that specifically hydrolyzes intracellular cyclic adenosine monophosphate(cAMP)throughout the body,including the brain.Most of the available PDE4 inhibitors exert unpleasant and serious side effects,such as emesis and nausea,which hinder its clinical application.Therefore,more efforts are needed before PDE4 inhibitors with high therapeutic indices are available for treatment of PD.FCPR16 is a novel PDE4 inhibitor with little emetic potential,which exhibits excellent enzyme inhibition activity(IC50=90 nmol·L^(-1)).METHODS SH-SY5 Y cell was induced with 1-methyl-4-phenylpyridinium(MPP+)to mimic PD cell injury in vitro,and CCK-8 assay was used to investigate the viability effects of different concentration of FCPR16(3.1-50 μmol·L^(-1)) on MPP+-injured SH-SY5 Y cells.Detection of apoptosis was performed by flow cytometry.The level of ntracellular reactive oxygen species was detected with the fluorescent probe DCFH-DA,and the mitochondrial membrane potential of cells in different experimental groups was detected with the JC-1 fluorescent probe.AO staining and Lysotracker Red staining were used to detect the intracellular antophagy changes.The expression of apoptosis related proteins,autophagy and other related signal molecules were demonstrated by Western blotting.Different cellular signaling pathway inhibitors were used to invesitigate the specific cellular mechanisms of FCPR16 protecting MPP+-induced cell injury.RESULTS FCPR16(12.5-50 μmol·L^(-1)) dose-dependently reduced MPP+-induced decline of cell viability,accompanied by reductions in nuclear condensation and lactate dehydrogenase release.The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells.Furthermore,FCPR16(25 μmol·L^(-1)) significantly suppressed the accumulation of reactive oxygen species(ROS),prevented the decline of mitochondrial membrane potential(Δψm) and attenuated the expression of malonaldehyde level.Further studies disclosed that FCPR16 enhanced the levels of cA MP and the exchange protein directly activated by cA MP(Epac) in SHSY5 Y cel s.Western blotting analysis revealed that FCPR16 increased the phosphorylation of c AMP response element-binding protein(CREB) and protein kinase B(Akt)down-regulated by MPP+in SHSY5 Y cells.Moreover,the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401.CONCLUSION The novel PDE4 inhibitor FCPR16 can protect against damaging pathways including oxidative stress,mitochondrial dysfunction and apoptosis in SH-SY5 Y cells.FCPR16 preventes MPP+-induced neurotoxicity through activation of cAMP/PKA/CREB and Epac/Akt signaling pathways.These may lead to develop mechanism based therapeutics and improved pharmacotherapy for PD.It is reasonable to assume that FCPR16 is a potential candidate for the prevention and treatment of PD.
文摘The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology （ART） programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.
基金financial support of the Beijing Natural Science Foundation, China (6112007)the National Natural Science Foundation of China (31101851)+1 种基金the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality, China (PHR201107134)the Comprehensive Reforming Project to promote talents training of Beijing University of Agriculture, China (BNRC&GG201404)
文摘Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effects of anti-inflammation, anti-anaphylaxis, antitumor, antioxidant, protection of nervous system and so on, and has mainly been used for the treatment of respiratory inflammatory diseases, cancer and cardiovascular disease in clinic. PDE4, specific to hydrolyze cyclic AMP （cAMP）, is considered to be a new anti-inflammatory target due to the decisive role on cAMP signal in inflammatory cells such as neutrophils. In order to explore the anti-inflammatory mechanism, we further studied the effects of luteolin on the activity and expression of PDE4, the expression of lymphocyte function-associated antigen-1 （LFA-1） and macrophage-1 （MAC-l） in neutrophils, and the adhesion of neutrophils and endothelial cells. The results showed that luteolin had a dose-dependent inhibition on both bare PDE4 activity and PDE4 in cultured neutrophils, and had an obviously promotive effect on gene expressions of PDE4A, 4B and 4D in later period. Luteolin had a significant inhibitory effect on neutrophils adhesion and LFA-1 expression in early stage, and had no obvious effect on MAC-1 expression. Therefore, luteolin can inhibit LFA-1 expression of neutrophils, then inhibit the adhesion of neutrophils and endothelial cells, and the mechanism is at least related with the inhibition of PDE4 activity.
基金financial support of the Beijing Natural Science Foundation of China (6112007)the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality,China (PHR201107134)2012 Scientific Research Quality Raising Funds of Beijing University of Agriculture,China (PXM2012_014207_000010/ PXM2012_014207_000013)
文摘Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on c AMP-phosphodiesterase（PDE）. To explore the anti-inflammatory effect and mechanism, the influence of gallic acid on neutrophils PDE4 activity and expression, TNF-α and IL-6 content and rat arthritis model were further studied. PDE4 activity and gene express were calculated respectively by substrate c AMP change examined with HPLC and real-time RT-PCR. The concentration of IL-6 and TNF-α in supernatant were assayed by ELISA method. Model of rat arthritis was caused by complete Freund＇s adjuvant. Results showed that gallic acid had a dose-dependent restraint on PDE4 activity of neutrophils in vitro, promoted significantly PDE4 A expression（P〈0.01）, and had no influence on the expressions of PDE4 B and 4D. However, PDE4 C expression was not detected. Gallic acid could promote IL-6 release（P〈0.05）, and inhibit TNF-α release of neutrophils（P〈0.05）. The experiment in vivo showed that gallic acid had obvious restraint on local inflammation of animal model（P〈0.05）. Therefore, the anti-inflammatory effect of gallic acid may be mediated in part through an inhibition on PDE4 activity and further an increase of IL-6 and a decrease of TNF-α of neutrophils, and this effect seemed to have no relationship with PDE4 expression.
文摘The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate （sildenafil） and tadalafil for treating erectile dysfunction （ED） in Chinese men na＇ive to phosphodiesterase 5 （PDE5） inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire （PITPQ）. Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function （IIEF） erectile function （EF） domain, sexual encounter profile （SEP） Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men （91%） completed the randomized treatment phase. Two hundred and forty-two per 350 （69.1%） patients preferred 20-mg tadalafil, and 108/350 （30.9%） preferred lO0-mg sildenafil （P 〈 0.001） as their treatment in the 8 weeks extension. Ninety-two per 242 （38%） patients strongly preferred tadalafil and 37/108 （34.3%） strongly the preferred sildenafil. The SEP2 （penetration）, SEP3 （successful intercourse）, and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by 〉 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED na＇ive to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.
文摘The importance of nitric oxide(NO) in vascular physiology is irrefutable;it stimulates the intracellular production of cyclic guanosine monophosphate(cGMP),initiating vascular smooth muscle relaxation.This biochemical process increases the diameter of small arteries,regulating blood flow distribution between arterioles and the microvasculature.The kidney is no exception,since NO predominantly dilates the glomerular afferent arterioles.It is now evident that the vascular production of cGMP can be augmented by inhibitors of phosphodiesterase type 5(PDE 5),the enzyme which breakdowns this cyclic nucleotide.This has clinical relevance,since diabetic nephropathy(DN) a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease,increases intraglomerular capillary pressure,leading to glomerular hypertension.PDE 5 inhibitors may have,therefore,the potential to reduce glomerular hypertension.This review describes the use of PDE 5 inhibitors to improve the metabolic,haemodynamic and inflammatory pathways/responses,all of which are dysfunctional in DN.
文摘Summary： To further investigate the mechanisms of action of icariin （ICA）, we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of ^125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil （Sild）. Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type Ⅴ （PDE5） in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction （RT-PCR）. The results showed that ICA increased cGMP concentrations directly （P〈0.05）, but there was no significant effect on cAMP concentrations （P〉0.05）. In the presence of sodium nitroprusside （SNP）, a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose （P〈0.01）. Their EC50 was 4.62 （ICA） and 0.42 （Sild） μmol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly （P〉0.05）. There were PDE5A 1 and PDE5A2 mRNA expressions in rat cor- pus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly （P〈 0.01）. The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.
文摘Phosphodiesterase isoenzymes 5 inhibitors （PDE5-1s） are the first-line therapy for erectile dysfunction （ED）. The constant discoveries of nitric oxide （NO）/cyclic guanosine monophosphate （cGMP） cell-signaling pathway for smooth muscle （SM） control in other urogenital tracts （UGTs） make PDE5-1s promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-1s have been widely recognized. On-demand PDE5-1s are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase （sGC） stimulators also have promising role in the management of severe ED conditions. PDE5-1s are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-1s, especially combined with （z-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia （BPH） except on maximum urinary flow rate （Qmax） with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-1s are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie＇s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-1s in disorders of UGTs are required.
基金supported by Nationa1 Natural Science Foundation of China(No.8l172434,to XHW,No.81270843 and No.81160086 to xHZ).
文摘The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors(PDE5-1s)and(x-blockers used alone or combined for the treatment of lower urinary tract symptoms(LUTS)due to benign prostatic hyperplasia(BPH).An electronic search of PubMed,Cochrane Library and Embase up to January 2014 was performed to identify randomized controlled trials comparing the efficacy and safety of PDE5-Is and(x-blockers for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia,which assessed IPSS score,maximum flow rate,postvoided residual urine,quality of life and Erectile Function(IIEF)score as outcomes.Data were analyzed by fixed or random effect models using Cochrane Collaboration review manager software.A total of 12 studies were included,Our novel data demonstrated that there was a trend that(x-blockers were more efficacious than PDE5-Is on decreasing IPSS score and increasing maximum flow rate.(x-blockers were significantly more effective than PDE5-Is on reduction of postvoided residual urine with a mean difference of 3.67(95%CI 1.56 to 5.77,P=0.0006)and PDE5-Is showed greater effect than(x-blockers on increasing IIEF score with a mean difference of 9.82(95%CI 3.80 to 15.85,P=0.001).In conclusion,our novel data demonstrated that PDE5-Is plus ABs ranked the highest on the improvement of LUTS/BPH.PDE5-Is monotherapy was also effective in this kind of disorder except less reduction of PVR than ABs,In addition,both combined-or mono-therapy were safe.
文摘Aim： To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 （PDE5） inhibitor, on penile erection in obese rats. Methods： The rats were fed a high-energy diet for 12 weeks and divided into three groups： an obesity-resistant （OR） control group, an obesity-prone （OP） control group, and an OP-DA-8159 treatment （DA-8159） group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. Results： In the OP control group, the maximum intracavernous pressure （ICP） and ICP/blood pressure （ICP/BP） ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve （AUC） of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. Conclusion： These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction （ED） can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.
文摘The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction （ED） treated with phosphodiesterase type 5 inhibitors （PDE-5i） over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate cancer prior to 2000 were identified. These individuals were divided into two groups： 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 （4.1%） men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 （9.9%） men with ED in the non-treated group （P〈00001）. A higher percentage of African Americans were treated with PDE-5i vs. those who were not （10.5% vs. 7.1%; P〈O.O001）. The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen （10.0% vs. 13.1%; P=-0.0008） and higher percentage of benign prostatic hyperplasia （38.4% vs. 35.1%; P=0.0149）. Men with ED treated with PDE-5i tended to have less chance （adjusted odds ratio： 0.4; 95% confidence intervals： 0.3-0.5; P〈0.0001） of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of beine diaenosed with orostate cancer. Further research is warranted.
基金supported by the National Key Research and Development Program of China(2017YFD0200204)the National Natural Science Foundation of China(31972496,31572190)+1 种基金the Deutsche Forschungsgemeinschaft(328017493/GRK2366)the National Institutes of Health Grant(R15 GM 104876)to Jana Patton-Vogt。
文摘Phosphate deficiency is one of the leading causes of crop productivity loss.Phospholipid degradation liberates phosphate to cope with phosphate deficiency.Glycerophosphodiester phosphodiesterases(GPX-PDEs)hydrolyse the intermediate products of phospholipid catabolism glycerophosphodiesters into glycerol-3-phosphate,a precursor of phosphate.However,the function of GPX-PDEs in phosphate remobilization in maize remains unclear.In the present study,we characterized two phosphate deficiency-inducible GPX-PDE genes,ZmGPX-PDE1 and ZmGPX-PDE5,in maize leaves.ZmGPX-PDE1 and ZmGPX-PDE5 were transcriptionally regulated by ZmPHR1,a well-described phosphate starvation-responsive transcription factor of the MYB family.Complementation of the yeast GPX-PDE mutant gde1Δindicated that ZmGPX-PDE1 and ZmGPX-PDE5 functioned as GPX-PDEs,suggesting their roles in phosphate recycling from glycerophosphodiesters.In vitro enzyme assays showed that ZmGPX-PDE1 and ZmGPX-PDE5 catalysed glycerophosphodiester degradation with different substrate preferences for glycerophosphoinositol and glycerophosphocholine,respectively.ZmGPX-PDE1 was upregulated during leaf senescence,and more remarkably,loss of ZmGPXPDE1 inmaize compromised the remobilization of phosphorus fromsenescing leaves to young leaves,resulting in a stay-green phenotype under phosphate starvation.These results suggest that ZmGPX-PDE1 catalyses the degradation of glycerophosphodiesters in maize,promoting phosphate recycling from senescing leaves to new leaves.This mechanism is crucial for improving phosphorus utilization efficiency in crops.
文摘Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.
文摘We aimed to determine whether combination of LIM-kinase 2 inhibitor(LIMK2i)and phosphodiesterase type-5 inhibitor(PDE5i)could restore erectile function through suppressing cavernous fibrosis and improving caver nous apoptosis in a rat model of cavernous nerve crush injury(CNCI).Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows:(1)sham surgery(Group S),(2)CNCI(Group I),(3)CNCI treated with daily intraperitoneal administration of 10.0 mg kg^-1 LIMK2i(Group I+L),(4)daily oral administration of 20.0 mg kg-1 udenafil,PDE5i(Group I+U),and(5)combined administration of 10.0 mg kg^-1 LIMK2i and 20.0 mg kg^-1 udenafil(Group I+L+U).Rats in Groups I+L,I+U,and I+L+U were treated with respective regimens for 2 weeks after CNCI.At 2 weeks after surgery,erectile response was assessed using electrostimulation.Penile tissues were processed for histological studies and western blot.Group I showed lower intracavernous pressure(ICP)/mean arterial pressure(MAP),lower area under the curve(AUC)/MAP,decreased immunohistochemical staining for alpha-smooth muscle(SM)actin,higher apoptotic index,lower SM/collagen ratio,increased phospho-LIMK2-positive fibroblasts,decreased protein kinase B/endothelial nitric oxide synthase(Akt/eNOS)phosphorylation,increased LIMK2/cofilin phosphorylation,and increased protein expression of fibronectin,compared to Group S.In all three treatment groups,erectile responses,protein expression of fibronectin,and SM/collagen ratio were improved.Group I+L+U showed greater improvement in erectile response than Group I+L.SM content and apoptotic index in Groups I+U and I+L+U were improved compared to those in Group I.However,Group I+L did not show a significant improvement in SM content or apoptotic index.The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I+L and I+L+U,but not in Group I+U.Akt/eNOS phosphorylation was improved in Groups I+U and I+L+U,but not in Group I+L.LIMK2/cofilin phosphorylation was improved in Groups I+L and I+L+U,but not in Group I+U.Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis.Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.
文摘OBJECTIVE Alcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world. However,there are no ideal treatments for this disease in clinic.Phosphodiesterases(PDEs) are a superfamily of enzymes consisting of 11 PDE families that hydrolyze cyclicAMP(cA MP) and/or cyclicGMP(cGMP). Among them,PDE4 is critical in the control of intracellular cAMP levels and has been shown to play an important role in the regulation of ethanol consumption.However,the functional role of PDE4 in mediating alcoholism remains unclear. METHODS Ethanol drinking and preference were examined using the two-bottle choice and/or drinking-in-dark(DID) test in high alcohol preferring(HAP) animals,including C57,HAP,and PDE4-subtype knockout mice,and Fawn-Hooded(FH/Wjd) rats,treated with or without the PDE4 inhibitor rolipram or roflumilast. Ethanol withdrawal-induced anxiety-and depressive-like behaviors were examined using the elevated plusmaze,holeboard,forced-swim,and tail-suspension tests in C57 mice or FH rats in the presence of PDE4 inhibition. Levels of cAMP,CREB were determined in brain regions. RESULTS Treatment with rolipram or roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in C57 and HAP mice as well as FH rats. Mice deficient in PDE4 B,but not PDE4 D,displayed similar effects to general PDE4 inhibition. In addition,rolipram reversed ethanol withdrawal-induced anxietyand depressive-like behaviors 1 d and 14 d,respectively,following withdrawal from ethanol drinking in the two-bottle choice in C57 mice or FH rats. Locomotor activity was not changed in either mice or rats treated with the PDE4 inhibitors. Levels of cAMP,p CREB in the brain were increased by rolipram.CONCLUSION The results provide solid evidence for the important role of PDE4 in ethanol consumptionand ethanol withdrawal-induced symptoms. Inhibitors of PDE4,in particular the PDE4 B isoform,can be a novel class of treatment for alcoholism.
文摘The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.
