Cyclic-nucleotide phosphodiesterase 1(PDE1) is a unique enzyme family hydrolyzing both cyclic guanosine monophosphate(cGMP) and cyclic adenosine monophosphate(cAMP) intra-cellular signaling molecules. A unique aspect ...Cyclic-nucleotide phosphodiesterase 1(PDE1) is a unique enzyme family hydrolyzing both cyclic guanosine monophosphate(cGMP) and cyclic adenosine monophosphate(cAMP) intra-cellular signaling molecules. A unique aspect of this enzyme family is its activation by calcium-calmodulin upon excitation of excitatory cells such as neurons and cardiomyocytes. In chronic degenerative diseases such as Parkinson disease,Alzheimer disease and heart failure,over-stimulation and chronic excessive levels of intra-cellular calcium leads to cell death. Targeting the PDE1 enzyme family with enzyme inhibitors is a novel approach to develop therapeutic agents for degenerative disorders. ITI-214 is a potent,and selective PDE1 inhibitor that has been tested in four human clinical trials. It is safe and well tolerated even at high dose levels that lead to high plasma and cerebral spinal fluid levels. In animal models,ITI-214 has cognitive enhancing properties as demonstrated in the rat novel object recognition model. Using a unilateral 6-hydroxy-dopamine lesion mouse model,the cylinder test readout of front paw use indicated that ITI-214 displays L-DOPA sparing effects ITI-214 reverses catalepsy induced by the potent dopamine D2 receptor antagonist haloperidol,indicating potential applications in Parkinson disease and as an adjunctive treatment in schizophrenia. Aspects of the Intra-Cellular Therapies PDE1 inhibitor program wil be outlined and the potential application to multiple therapeutic areas wil be discussed.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
Objective To investigate the effects of novel selective phosphodiesterase4 (PDE4) inhibitors,Ariflo and SB242126A, on the endothelin-1 (ET-1) - induced contractility occurring in nonpregnant human myome-trium specimen...Objective To investigate the effects of novel selective phosphodiesterase4 (PDE4) inhibitors,Ariflo and SB242126A, on the endothelin-1 (ET-1) - induced contractility occurring in nonpregnant human myome-trium specimens. Methods Contractile responses to Ariflo and SB242126A were recorded cumulatively on isola-ted human longitudinal myometrium specimens obtained through surgical operations. Results Ariflo andSB242126A could inhibit both the frequency and amplitude of spontaneous contractions of myometrium (pD2 =8. 6and 7. 6,n =4) and ET-1 -induced contractions in a concentration-dependent manner (pD2 = 7. 7 and 8. 1 ,n =5) ,with a potency similar to that of Rolipram. Conclusion Ariflo and SB242126A have an obvious inhibitory effecton endothelin-1-induced contractility of isolated human myometrium. The finding suggested that PDE4 inhibitorsmight have clinical potential in treating preterm labour and dysmenorrhoea.展开更多
Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In...Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In order to verify the therapeutic potential of PDE1 inhibitors against VaD,the anti-neuroinflammation,memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 value of 4.5 nmol/L against PDE1C,high selectivity over PDEs,and remarkable metabolic stability,efficiently ameliorated neuron degeneration,cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.展开更多
Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cement...Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate （Pi） to mineral inhibitor pyrophosphate （PPi）, where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase （TNAP） and ectonucleotide pyrophosphatase/phosphodiesterase 1 （NPP1）. The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enppl null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enppl gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected.展开更多
Objective Findings from the previous studies have suggested a relationship between ectonucleotide pyrophosphatase /phosphodiesterase 1 （ENPP‐1） or plasma cell membrane glycoprotein 1 （PC‐1） gene single nucleotid...Objective Findings from the previous studies have suggested a relationship between ectonucleotide pyrophosphatase /phosphodiesterase 1 （ENPP‐1） or plasma cell membrane glycoprotein 1 （PC‐1） gene single nucleotide polymorphism （K121Q, rs1044498） and genetic susceptibility to obesity. However, such relationship is not reproduced by some currently available studies. In this context, the present study is aimed to quantitatively analyze the association of K121Q variant with obesity in all published case‐control studies in European adult populations. Methods Published literature from PubMed, EMBASE, and ISI web of science databases were retrieved. The studies evaluating the association of ENPP1/PC1 gene K121Q polymorphism with obesity were included, in which sufficient data were presented to calculate the odds ratio （OR） with 95% confidence intervals （CIs）. Results Ten case‐control studies meeting the inclusion criteria identified a total of 24,324 subjects including 11,372 obese and 12,952 control subjects. The meta‐analysis results showed a statistically significant association of K121Q with obesity [OR （95%CI）： 1.25 （1.04‐1.52） P=0.021] under a recessive model of inheritance （QQ vs. KK＋KQ） without heterogeneity or publication bias. Conclusions The results from the present study have indicated that ENPP1/PC1 Q121 variant may increase the risk of obesity and that more well‐designed studies based on a larger population will be required to further evaluate the role of ENPP1/PC1 gene K121Q polymorphism in obesity and other related metabolic syndromes.展开更多
Our study investigated effects of C-type natriuretic peptide (CNP) on atrial dynamics and hypoxia inducible factor 1 alpha (HIF-1α) activity in perfused beating rat atria, under hypoxic conditions. Hypoxia significan...Our study investigated effects of C-type natriuretic peptide (CNP) on atrial dynamics and hypoxia inducible factor 1 alpha (HIF-1α) activity in perfused beating rat atria, under hypoxic conditions. Hypoxia significantly increased the levels of HIF-1α, concomitant with decreased trial dynamics. CNP (0.1 μmol/L) further decreased atrial dynamics under hypoxia and suppressed hypoxia-induced stimulation of HIF-1α expression. An adenylylcyclase (AC) activator, forskolin (0.1 μmol/L), significantly up-regulated atrial phosphodiesterase subtype 3A (PDE 3A) protein without affecting hypoxia-induced dynamics. In the presence of forskolin, the inhibitory effects of CNP on hypoxia-induced atrial dynamics and HIF-1α levels were significantly attenuated. Forskolin also prevented hypoxia-induced downregulation of PDE3A protein. These findings suggested that CNP inhibited atrial dynamics and HIF-1α activity in the isolated perfused beating rat atria under hypoxic conditions. Furthermore, both effects were modulated by the AC activator forskolin, through activation of CNP-PDE 3A signaling.展开更多
文摘Cyclic-nucleotide phosphodiesterase 1(PDE1) is a unique enzyme family hydrolyzing both cyclic guanosine monophosphate(cGMP) and cyclic adenosine monophosphate(cAMP) intra-cellular signaling molecules. A unique aspect of this enzyme family is its activation by calcium-calmodulin upon excitation of excitatory cells such as neurons and cardiomyocytes. In chronic degenerative diseases such as Parkinson disease,Alzheimer disease and heart failure,over-stimulation and chronic excessive levels of intra-cellular calcium leads to cell death. Targeting the PDE1 enzyme family with enzyme inhibitors is a novel approach to develop therapeutic agents for degenerative disorders. ITI-214 is a potent,and selective PDE1 inhibitor that has been tested in four human clinical trials. It is safe and well tolerated even at high dose levels that lead to high plasma and cerebral spinal fluid levels. In animal models,ITI-214 has cognitive enhancing properties as demonstrated in the rat novel object recognition model. Using a unilateral 6-hydroxy-dopamine lesion mouse model,the cylinder test readout of front paw use indicated that ITI-214 displays L-DOPA sparing effects ITI-214 reverses catalepsy induced by the potent dopamine D2 receptor antagonist haloperidol,indicating potential applications in Parkinson disease and as an adjunctive treatment in schizophrenia. Aspects of the Intra-Cellular Therapies PDE1 inhibitor program wil be outlined and the potential application to multiple therapeutic areas wil be discussed.
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Supported by the grant of Sino-France Cooperation of INSERM and SSMU.
文摘Objective To investigate the effects of novel selective phosphodiesterase4 (PDE4) inhibitors,Ariflo and SB242126A, on the endothelin-1 (ET-1) - induced contractility occurring in nonpregnant human myome-trium specimens. Methods Contractile responses to Ariflo and SB242126A were recorded cumulatively on isola-ted human longitudinal myometrium specimens obtained through surgical operations. Results Ariflo andSB242126A could inhibit both the frequency and amplitude of spontaneous contractions of myometrium (pD2 =8. 6and 7. 6,n =4) and ET-1 -induced contractions in a concentration-dependent manner (pD2 = 7. 7 and 8. 1 ,n =5) ,with a potency similar to that of Rolipram. Conclusion Ariflo and SB242126A have an obvious inhibitory effecton endothelin-1-induced contractility of isolated human myometrium. The finding suggested that PDE4 inhibitorsmight have clinical potential in treating preterm labour and dysmenorrhoea.
基金supported by the National Natural Science Foundation of China(22077143,21977127,and 21877134)Science Foundation of Guangzhou City(201904020023,China)+2 种基金Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,China)Science of Guangdong Province(2019A1515011883,China)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China).
文摘Vascular dementia(VaD)is the second commonest type of dementia which lacks of efficient treatments currently.Neuroinflammation as a prominent pathological feature of VaD,is highly involved in the development of VaD.In order to verify the therapeutic potential of PDE1 inhibitors against VaD,the anti-neuroinflammation,memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 value of 4.5 nmol/L against PDE1C,high selectivity over PDEs,and remarkable metabolic stability,efficiently ameliorated neuron degeneration,cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.
基金supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) and extramural NIH funding(JLM-DE12889 and AR53102)
文摘Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate （Pi） to mineral inhibitor pyrophosphate （PPi）, where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase （TNAP） and ectonucleotide pyrophosphatase/phosphodiesterase 1 （NPP1）. The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enppl null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enppl gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected.
文摘Objective Findings from the previous studies have suggested a relationship between ectonucleotide pyrophosphatase /phosphodiesterase 1 （ENPP‐1） or plasma cell membrane glycoprotein 1 （PC‐1） gene single nucleotide polymorphism （K121Q, rs1044498） and genetic susceptibility to obesity. However, such relationship is not reproduced by some currently available studies. In this context, the present study is aimed to quantitatively analyze the association of K121Q variant with obesity in all published case‐control studies in European adult populations. Methods Published literature from PubMed, EMBASE, and ISI web of science databases were retrieved. The studies evaluating the association of ENPP1/PC1 gene K121Q polymorphism with obesity were included, in which sufficient data were presented to calculate the odds ratio （OR） with 95% confidence intervals （CIs）. Results Ten case‐control studies meeting the inclusion criteria identified a total of 24,324 subjects including 11,372 obese and 12,952 control subjects. The meta‐analysis results showed a statistically significant association of K121Q with obesity [OR （95%CI）： 1.25 （1.04‐1.52） P=0.021] under a recessive model of inheritance （QQ vs. KK＋KQ） without heterogeneity or publication bias. Conclusions The results from the present study have indicated that ENPP1/PC1 Q121 variant may increase the risk of obesity and that more well‐designed studies based on a larger population will be required to further evaluate the role of ENPP1/PC1 gene K121Q polymorphism in obesity and other related metabolic syndromes.
文摘Our study investigated effects of C-type natriuretic peptide (CNP) on atrial dynamics and hypoxia inducible factor 1 alpha (HIF-1α) activity in perfused beating rat atria, under hypoxic conditions. Hypoxia significantly increased the levels of HIF-1α, concomitant with decreased trial dynamics. CNP (0.1 μmol/L) further decreased atrial dynamics under hypoxia and suppressed hypoxia-induced stimulation of HIF-1α expression. An adenylylcyclase (AC) activator, forskolin (0.1 μmol/L), significantly up-regulated atrial phosphodiesterase subtype 3A (PDE 3A) protein without affecting hypoxia-induced dynamics. In the presence of forskolin, the inhibitory effects of CNP on hypoxia-induced atrial dynamics and HIF-1α levels were significantly attenuated. Forskolin also prevented hypoxia-induced downregulation of PDE3A protein. These findings suggested that CNP inhibited atrial dynamics and HIF-1α activity in the isolated perfused beating rat atria under hypoxic conditions. Furthermore, both effects were modulated by the AC activator forskolin, through activation of CNP-PDE 3A signaling.
