Bacterial or viral infections,such as Brucella,mumps virus,herpes simplex virus,and Zika virus,destroy immune homeostasis of the testes,leading to spermatogenesis disorder and infertility.Of note,recent research shows...Bacterial or viral infections,such as Brucella,mumps virus,herpes simplex virus,and Zika virus,destroy immune homeostasis of the testes,leading to spermatogenesis disorder and infertility.Of note,recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells,leading to male reproductive dysfunction.Due to the many side effects associated with antibiotic therapy,finding alternative treatments for inflammatory injury remains critical.Here,we found that Dmrt1 plays an important role in regulating testicular immune homeostasis.Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells.Chromatin immunoprecipitation sequencing(ChIP-seq)and RNA sequencing(RNA-seq)revealed that Dmrt1 positively regulated the expression of Spry1,an inhibitory protein of the receptor tyrosine kinase(RTK)signaling pathway.Furthermore,immunoprecipitation-mass spectrometry(IP-MS)and co-immunoprecipitation(Co-IP)analysis indicated that SPRY1 binds to nuclear factor kappa B1(NF-κB1)to prevent nuclear translocation of p65,inhibit activation of NF-κB signaling,prevent excessive inflammatory reaction in the testis,and protect the integrity of the blood-testis barrier.In view of this newly identified Dmrt1-Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis,our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.展开更多
Objective:To explore the relationship between bitter taste and bitter flavor(efficacy),their character-istics were analyzed at the target and pharmacodynamic points.Methods:Compounds with bitter receptor activity were...Objective:To explore the relationship between bitter taste and bitter flavor(efficacy),their character-istics were analyzed at the target and pharmacodynamic points.Methods:Compounds with bitter receptor activity were obtained by high-throughput screening models of the human bitter taste receptors(hTAS2Rs),which were used to analyze bitter taste.The efficacy of anti-asthma medications was used as an example to research bitter flavor(efficacy).The pharmacological effects of bitter taste and bitter flavor(efficacy)were classified according to the functional modules.The coverage for the same targets or pharmacological effects in the overall protein interaction network(PIN)of bitter taste and bitter flavor(efficacy)was analyzed to reveal their relationship.The effect of the compound polydatin with anti-asthma activation on hTAS2R14 was studied to verify the reliability of the aforementioned idea.Results:A total of 121 Chinese materia medica(CMM)compounds that activate hTAS2R10,hTAS2R14,and hTAS2R49 were obtained.The analysis results indicated that 108 same targets for bitter taste and bitter flavor(efficacy)were obtained,accounting for 13.9%in the PIN of bitter taste and 72.5%in the PIN of bitter flavor(efficacy).The pharmacological effects shared by bitter taste and bitter flavor(efficacy)accounted for 79%of the PIN of bitter taste and 81%of the PIN of bitter flavor(efficacy).The activating effect of the anti-asthma compound polydatin on hTAS2R14 was dose-dependent with EC 50 of 4.3 m M.Conclusion:In this study,the relationship between bitter taste and bitter flavor(efficacy)has been demonstrated from the target and pharmacodynamic points,which are based on hTAS2Rs and anti-asthma effect.Bitter taste and bitter flavor(efficacy)exhibited a high correlation.This study provides a theoretical and scientific basis for the hypothesis that“the property theory of CMM is the clinical pharmacodynamics of CMM.”展开更多
基金supported by the National Natural Science Foundation of China(32072806,31572399)National Key Research and Development Program of China(2022YFD1302201)+3 种基金Program of Shaanxi Province Science and Technology Innovation Team(2019TD-036)Major Projects of Natural Science Foundation of Inner Mongolia Autonomous Region(2020ZD10)Key Research and Development Program of Shaanxi Province(2022NY-044)Key Technologies Demonstration of Animal Husbandry in Shaanxi Province(20221086)。
文摘Bacterial or viral infections,such as Brucella,mumps virus,herpes simplex virus,and Zika virus,destroy immune homeostasis of the testes,leading to spermatogenesis disorder and infertility.Of note,recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells,leading to male reproductive dysfunction.Due to the many side effects associated with antibiotic therapy,finding alternative treatments for inflammatory injury remains critical.Here,we found that Dmrt1 plays an important role in regulating testicular immune homeostasis.Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells.Chromatin immunoprecipitation sequencing(ChIP-seq)and RNA sequencing(RNA-seq)revealed that Dmrt1 positively regulated the expression of Spry1,an inhibitory protein of the receptor tyrosine kinase(RTK)signaling pathway.Furthermore,immunoprecipitation-mass spectrometry(IP-MS)and co-immunoprecipitation(Co-IP)analysis indicated that SPRY1 binds to nuclear factor kappa B1(NF-κB1)to prevent nuclear translocation of p65,inhibit activation of NF-κB signaling,prevent excessive inflammatory reaction in the testis,and protect the integrity of the blood-testis barrier.In view of this newly identified Dmrt1-Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis,our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.
基金This study was supported by the National Natural Science Foundation of China(81430094).
文摘Objective:To explore the relationship between bitter taste and bitter flavor(efficacy),their character-istics were analyzed at the target and pharmacodynamic points.Methods:Compounds with bitter receptor activity were obtained by high-throughput screening models of the human bitter taste receptors(hTAS2Rs),which were used to analyze bitter taste.The efficacy of anti-asthma medications was used as an example to research bitter flavor(efficacy).The pharmacological effects of bitter taste and bitter flavor(efficacy)were classified according to the functional modules.The coverage for the same targets or pharmacological effects in the overall protein interaction network(PIN)of bitter taste and bitter flavor(efficacy)was analyzed to reveal their relationship.The effect of the compound polydatin with anti-asthma activation on hTAS2R14 was studied to verify the reliability of the aforementioned idea.Results:A total of 121 Chinese materia medica(CMM)compounds that activate hTAS2R10,hTAS2R14,and hTAS2R49 were obtained.The analysis results indicated that 108 same targets for bitter taste and bitter flavor(efficacy)were obtained,accounting for 13.9%in the PIN of bitter taste and 72.5%in the PIN of bitter flavor(efficacy).The pharmacological effects shared by bitter taste and bitter flavor(efficacy)accounted for 79%of the PIN of bitter taste and 81%of the PIN of bitter flavor(efficacy).The activating effect of the anti-asthma compound polydatin on hTAS2R14 was dose-dependent with EC 50 of 4.3 m M.Conclusion:In this study,the relationship between bitter taste and bitter flavor(efficacy)has been demonstrated from the target and pharmacodynamic points,which are based on hTAS2Rs and anti-asthma effect.Bitter taste and bitter flavor(efficacy)exhibited a high correlation.This study provides a theoretical and scientific basis for the hypothesis that“the property theory of CMM is the clinical pharmacodynamics of CMM.”
