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Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal chronic interstitial lung disease characterized by a progressive decline in lung function, and current treatment options are limited. cAMP is one of the most important second messengers and plays a key role in relaxing airway smooth muscle cells and reducing inflammation. Phosphodiesterase (PDE) is a superfamily of enzymes, and PDE4 enzymes dominate 11 PDE superfamily enzymes, available in four isoforms-PDE4A, PDE4B, PDE4C and PDE4D, which selectively decompose cAMP, while PDE4 inhibitors increase cAMP levels by preventing cAMP from breaking down, thereby exerting anti-inflammatory, anti-remodeling effects and providing an attractive drug target for the treatment of IPF. This review summarizes knowledge about the association of pulmonary fibrosis with PKE4, as well as emerging preclinical studies and clinical trials regarding PDE4 inhibitors.
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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and typical chronic fibrotic lung disease. In recent years, significant progress has been made in the pathophysiology, clinical diagnosis and treatment of IPF. However, to date, there is still no cure for IPF. The second messenger cyclic adenosine monophosphate (cAMP) inhibits fibroblast proliferation or differentiation into myofibroblasts during the development of IPF. Phosphodiesterase 4 (PDE4) is a major camp-degrading enzyme in lung fibroblasts, which is up-regulated during the progression of fibrosis. PDE4 inhibitors have anti-fibrosis effects in vivo and in vitro in IPF models. In addition, PDE4 is widely involved in inflammatory processes, which are also active in the pathogenesis of IPF. Thus, PDE4 inhibition is a potential therapeutic approach for IPF. This article reviews the pathogenesis of IPF and the physiological function of PDE subtype 4 inhibitors in the treatment of IPF.
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This study aimed to explore the effect of miR-23b-3p on the differentiation of goat intramuscular preadipocytes, and to confirm whether miR-23b-3p plays its roles via targeting the PDE4B gene. Based on the pre-transcriptome sequencing data obtained previously, the miR-23b-3p, which was differentially expressed in goat intramuscular adipocytes before and after differentiation, was used as an entry point. real-time quantitative-polymerase chain reaction (qPCR) was used to detect the expression pattern of miR-23b-3p during the differentiation of goat intramuscular preadipocytes. The effects of miR-23b-3p on adipose differentiation and adipose differentiation marker genes were determined at the morphological and molecular levels. The downstream target genes of miR-23b-3p were determined using bioinformatics prediction as well as dual luciferase reporter assay to clarify the targeting relationship between miR-23b-3p and the predicted target genes. The results indicated that overexpression of miR-23b-3p reduced lipid droplet accumulation in goat intramuscular adipocytes, significantly down-regulated the expression levels of adipogenic marker genes AP2, C/EBPα, FASN, and LPL (P < 0.01). In addition, the expressions of C/EBPβ, DGAT2, GLUT4 and PPARγ were significantly downregulated (P < 0.05). After interfering with the expression of miR-23b-3p, lipid droplet accumulation was increased in goat intramuscular adipocytes. The expression levels of ACC, ATGL, AP2, DGAT2, GLUT4, FASN and SREBP1 were extremely significantly up-regulated (P < 0.01), and the expression levels of C/EBPβ, LPL and PPARγ were significantly up-regulated (P < 0.05). It was predicted that PDE4B might be a target gene of miR-23b-3p. The mRNA expression level of PDE4B was significantly decreased after overexpression of miR-23b-3p (P < 0.01), and the interference with miR-23b-3p significantly increased the mRNA level of PDE4B (P < 0.05). The dual luciferase reporter assay indicated that miR-23b-3p had a targeting relationship with PDE4B gene. MiR-23b-3p regulates the differentiation of goat intramuscular preadipocytes by targeting the PDE4B gene.
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Animales , MicroARNs/metabolismo , Cabras/genética , PPAR gamma/metabolismo , Adipogénesis/genética , Diferenciación Celular/genética , Luciferasas , ARN MensajeroRESUMEN
Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis (UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors, to explore the therapeutic capacity in dextran sulfate sodium (DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective cAMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated cAMP-predominant protein kinase A (PKA)-cAMP-response element binding protein (CREB) signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present study revealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.
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Acrodysostosis is a rare autosomal dominant disorder, which is caused by abnormalities in the GPCR-Gsα-cAMP-PKA signaling pathway due to mutations in the PRKAR1A gene or PDE4D gene.Acrodysostosis is mainly characterized by skeletal development disorders with or without hormone resistance, and it should be differentiated from pseudohypoparathyroidism, pseudopseudohypoparathyroidism and other related diseases.Diagnosis mainly depends on clinical diagnosis, and molecular genetic diagnosis is the gold standard.The mainstay of therapy is symptomatic treatment.The epidemiology of acrodysostosis has not been reported so far.This article reviewes recent publication of acrodysostosis at home and abroad.
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Aim: To investigate the effect of ZL-n-91, a novel phosphodiesterase 4 (PDE4) inhibitor, on proliferation, cell cycle and apoptosis of human glioma U87 cells. Methods In vitro the different concentrations of ZL-n-91 were set up to evaluate the proliferation of U87 cells by CCK-8 assay. The cell apoptosis and cell cycle distribution were examined by flow cytometry. The expression of CDK2, CDK4, cyclin Dl and apoptosis-related protein Bax and Bcl-2 proteins were detected by Western blot. A subcutaneous transplanted tumor model of U87 in nude mice was established for the in vivo experiment using a dosage of 5 mg · kg
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Objective To investigate the antidepressant effect of Bupleuri Radix and Paeoniae Alba Radix drug pair based on the cAMP-CREB-BDNF pathway. Methods The rat depression model was established by CUMS. The contents of cAMP, p-CREB, BDNF, and PDE4 in rat hippocampal and cAMP levels in rat plasma were determined by ELISA. The expression of BDNF mRNA in hippocampus, hypothalamus, and cortex were measured by RT-PCR. Results Compared with the model group, the positive drug group and Bupleuri Radix and Paeoniae Alba Radix drug pair can reverse the cAMP content in the hippocampus and plasma and the decreased contents of CREB and BDNF in the rat hippocampus. At the same time, the positive drug group, Bupleuri Radix, and Paeoniae Alba Radix can increase the expression of BDNF mRNA in hippocampus, cortex, and hypothalamus of rats. Conclusion The Bupleuri Radix and Paeoniae Alba Radix drug pair has obviously antidepressant effect on CUMS rat model, which can achieve antidepressant effect by regulating cAMP-CREB-BDNF pathway.
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Objective To explore the effect of aerobic exercises on synaptic plasticity and expression of PDE-4 in hippocampus during the aging process of rats.Methods Forty-five adult male SpragueDawley rats were randomly divided into a control group(group C),an D-galactose induced aging group (group A) and an D-galactose induced aging & aerobic exercise intervention group(group AE).All rats were induced aging for 6 weeks and group AE was given swimming exercise intervention of a moderate load simultaneously.Then Nissl's staining was conducted to observe the neurons in the dentate gyrus(DG).The immunofluorescence was employed to detect the number and density of synaptophysin (Syp) and metabotropi glutamate receptor 1(mGluR1).And the expression level of Phos-phodiesterase 4(PDE-4) mRNA and protein was observed using the,real-time PCR and Western blotting.Results Compared with group C,senile signs such as mental retardation,lethargy and tardy movement,significantly less neurons in the hippocampus,bigger cell spacing and shallower Nissl body in the cytoplasm were observed in group A.The integrated optical density(IOD) values of Syp and mGluR1 in group A decreased significantly compared to group C(P＜0.01),while those of group AE were significantly higher than group A(P＜0.01).The expression of PDE-4 mRNA and protein in Group A increased significantly compared with group C (P＜0.01),but that of group AE was significantly lower than group A (P＜ 0.01).The expression of PDE-4 mRNA was negatively correlated to the IOD value of Syp and mGluR1 (P＜0.01,P＜0.05).Conclusions The aerobic exercises can improve the morphology of hippocampal neurons and keep the number and density of Syp and mGluR1 at a certain level to maintain the synaptic plasticity,so as to improve brain function and delay the aging process.Moreover,exercise may affect brain function through down-regulating the expression of the PDE-4 gene.
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Objective To investigate the inhibition of Eriobotryae Folium from twenty different districts towards phosphodiesterase 4(PDF4) in vitro.Methods The Eriobotryae Folium were extracted with 95％ ethanol reflux and the inhibition rates against PDE4D2 were carried out by liquid scintillation counting method.Results All the samples exhibited inhibitory activities towards PDE4 at 5 mg/L.Among them,nine samples were of the inhibition rate less than 80％,eleven samples were of more than 80％ inhibition and eight samples were of more than 90％ inhibition.Conclusion The Eriobotryae Folium shows significantly different inhibitory activities towards PED4.
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Phosphodiesterase-4 ( PDE4 ) has been one of the most popular drug targets during recent years due to its critical role in the control of intracellular cyclic adenosine monophos-phate ( cAMP ) concentration and downstream signal transduc-tion. PDE4 is widely distributed in the central nervous system ( CNS) with different expression levels of its four subtypes. Re-cent data indicate that altered PDE4 expression and/or activity is relevant to multiple CNS disorders, such as depression, memory deficiency, drug dependence, and neural lesion. Selective PDE4 inhibitors exhibit therapeutic effects on these disorders and might be a promising pharmacotherapy. The paper highlights recent re-search progress in the roles of PDE4 in CNS function, and dis-cusses the prospects of PDE4 as a novel therapeutic target for CNS disorders.
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Current therapeutic approaches for the treatment of asthma have limitations in their ability to target all the features of the disease. Indeed, existing pharmacological asthma therapies are based on decades old strategies that were developed prior to the rapid growth in knowledge stemming from cell and molecular biology in the past decade. Thus, there is an unmet need for developing new drugs to target these features along with improved efficacy and safety. In the present review, the limitations of prevalent pharmacological asthma therapy are discussed briefly, and some explanations are suggested as to why new therapeutic targets are required to treat asthma, and finally directions for novel asthma therapies are proposed.
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Animales , Asma/tratamiento farmacológico , Asma/enzimología , Asma/genética , Asma/metabolismo , Broncodilatadores/metabolismo , Broncodilatadores/farmacología , Broncodilatadores/uso terapéutico , Citocinas/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Oligonucleótidos/metabolismo , Oligonucleótidos/uso terapéutico , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
Phosphodiesterase (PDE) 4 inhibitors have been shown to induce the cAMP-mediated signaling pathway by inhibiting cAMP hydrolysis. This study investigated the effect of a PDE4 inhibitor on the expression of the inducible cAMP early repressor (ICER), which is an endogenous inhibitor of CRE- mediated transcription, in osteoblastic cells. RT-PCR analysis revealed that rolipram, a PDE4 inhibitor, stimulates the ICER mRNA in a dose dependent manner. The induction of ICER mRNA expression by rolipram was suppressed by the inhibitors of protein kinase A (PKA) and p38 MAPK, suggesting the involvement of PKA and p38 MAPK activation in ICER expression by rolipram. It was previously shown that rolipram induced the expression of TNF-related activation-induced cytokine (TRANCE, also known as RANKL, ODF, or OPGL) in osteoblasts. This paper provides evidences that a transcriptional repressor like ICER might modulate TRANCE mRNA expression by rolipram in osteoblasts.
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Animales , Ratones , /antagonistas & inhibidores , Animales no Consanguíneos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al ADN/genética , Expresión Génica/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Rolipram/farmacología , Factores de Transcripción/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: PDE 4 inhibitor is known to be a bladder relaxant. In this study, the effects of PDE 4 inhibitor on the urinary bladder function were evaluated in vivo experiment. We postulated that PDE 4 inhibitor of appropriate concentration might be helpful in the treatment of overactive bladder. MATERIALS AND METHODS: Fifteen Spraque-dawley female rats, weighing approximately 250~300 mg, were used for this study and divided into three groups. PDE 4 inhibitor 486,051 was administrated to each rat by different drug concentrations(0.5 mg/kg, 1 mg/kg, 5 mg/kg). Cystometrogram(CMG) was performed before and 20~60 minutes afterV), bladder capacity(BC), maximal bladder voiding contraction pressure(MVP), intercontrac drug application considering first voiding. Cystometric parameters investigated were voided volume(VV), residual volume (RV), bladder capacity(BC), maximal bladder voiding contraction pressure(MVP), intercontraction interval(ICI). Mean blood pressure was monitored in all rats. RESULTS: PDE 4 inhibitor of 0.5 mg/kg increased the intercontraction interval but not the bladder capacity significantly. PDE 4 inhibitor of 5 mg/kg increased the bladder capacity significantly, but did not show the increased intercontraction interval compared to other groups, and showed the greatest increased residual volume among three groups. PDE 4 inhibitor of 1 mg/kg showed the most increased intercontraction interval and the bladder capacity, and the least decreased voided volume and maximal bladder voiding contraction pressure change. CONCLUSION: PDE 4 inhibitor of different concentrations affects cystometric parameters variably by bladder smooth muscle relaxant. PDE 4 inhibitor of appropriate concentration may be helpful in the treatment of overactive bladder. PDE 4 inhibitor, at the concentration of 1 mg/kg, increased the bladder capacity and intercontraction interval most significantly. This study may provide an important basic data in the future when drug effects were assessed in variable animal models of overactive bladder, etc. However, main limitations of drug use are the increase of residual urine and the decrease of blood pressure. Therefore more bladder specific drug is needed.
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Animales , Femenino , Humanos , Ratas , Presión Sanguínea , Modelos Animales , Músculo Liso , Volumen Residual , Vejiga Urinaria , Vejiga Urinaria HiperactivaRESUMEN
Aim To investigate the changes of phosphodiesterase4(PDE4,type 4 cAMP-specific PDE) activity,TNF-? and neutrophil recruitment in experimental rat lung injury(ALI).Methods ALI in the rat was induced by lipopolysacdharide(LPS).PDE4 activity was measured with HPLC,and the level of TNF-? was detected with ELISA,neutrophil infiltration in bronchoalveolar lavage fluid(BALF) and lung tissues was detected by cell count and morphological analysis.Result Lung tissue PDE4 activity significantly increased as early as 1 h,peaked 6 h,and then markedly lowered at 24 h after intratracheal administration of LPS,while there was a same time-course change of total white cell and neutrophil in the BALF(r=0.83,P