Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids...Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids cells.Methods:A total of 65 female SD rats were randomly divided into five groups after being adaptively fed for 7 d.Except for the blank group,the remaining four groups of rats were injected with 0.05 mg/(100 g·d)estradiol benzoate and 0.5 mg/(100g·d)progesterone into the muscle to establish a uterine fibroids rat model.After successful modeling,the blank group and model group were given 200 mg/(kg·d)physiological saline by gavage,the low-dose group was given 100 mg/(kg·d)mifepristone by gavage,the medium-dose group was given 200 mg/(kg·d)mifepristone by gavage,and the high-dose group was given 300 mg/(kg·d)mifepristone by gavage.After continuous gavage treatment for 21 d,serum and uterine tissues were collected from rats to observe and compare the expression levels of MMP-2 mRNA,TIMP-2 mRNA,estradiol(E2),cAMP signaling pathway related proteins,and the migration and invasive ability of uterine fibroids cells in the five groups of rats.Results:The expression levels of MMP-2 mRNA and E2in the high-dose group were lower than those in the low-dose group and the medium-dose group,and the expression level of TIMP-2 mRNA was higher than that in the low-dose group and the medium-dose group(P<0.05).The number of cell migration in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The number of cell invasion in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The mRNA expression levels of cAMP,PDE and PK in the high-dose group were higher than those in the low-dose group,and the mRNA expression levels of AC in the high-dose group were lower than those in the low-dose group(P<0.05).The mRNA expression levels of cAMP and PDE in the high-dose group were higher than those in the mediumdose group(P<0.05).Conclusion:Letrozole may down-regulate the expression level of MMP-2 through the cAMP signaling pathway to inhibit the migration and invasion of uterine fibroids cells.With increasing doses of letrozole,its inhibitory effect on the migration and invasion of uterine fibroids cells will be enhanced.However,the optimal dosage of letrozole for inhibiting the migration and invasion of uterine fibroids cells is yet to be determined.展开更多
Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regul...Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.展开更多
Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hip...Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.展开更多
Fatty acid b-oxidation is critical for fatty acid degradation and cellular development.In the rice blast fungus Magnaporthe oryzae,fatty acid b-oxidation is reported to be important mainly for turgor generation in the...Fatty acid b-oxidation is critical for fatty acid degradation and cellular development.In the rice blast fungus Magnaporthe oryzae,fatty acid b-oxidation is reported to be important mainly for turgor generation in the appressorium.However,the role of fatty acid b-oxidation during invasive hyphal growth is rarely documented.We demonstrated that blocking peroxisomal fatty acid b-oxidation impaired lipid droplet(LD)degradation and infectious growth of M.oryzae.We found that the key regulator of pathogenesis,MoMsn2,which we identified previously,is involved in fatty acid b-oxidation by targeting MoDCI1(encoding dienoyl-coenzyme A[CoA]isomerase),which is also important for LD degradation and infectious growth.Cytological observations revealed that MoMsn2 accumulated from the cytosol to the nucleus during early infection or upon treatment with oleate.We determined that the low-density lipoprotein receptor-related protein MoLrp1,which is also involved in fatty acid b-oxidation and infectious growth,plays a critical role in the accumulation of MoMsn2 from the cytosol to the nucleus by activating the cyclic AMP signaling pathway.Our results provide new insights into the importance of fatty acid oxidation during invasive hyphal growth,which is modulated by MoMsn2 and its related signaling pathways in M.oryzae.展开更多
Small, cysteine-rich, highly stable antifungal proteins secreted by filamentous Ascomycetes have great po- tential for the development of novel antifungal strate- gies. However, their practical application is still li...Small, cysteine-rich, highly stable antifungal proteins secreted by filamentous Ascomycetes have great po- tential for the development of novel antifungal strate- gies. However, their practical application is still limited due to their not fully clarified mode of action. The aim of this work was to provide a deep insight into the anti-fungal mechanism of Neosartorya fischeri antifungal protein （NFAP）, a novel representative of this protein group. Within a short exposure time to NFAP, reduced cellular metabolism, apoptosis induction, changes in the actin distribution and chitin deposition at the hyphal tip were observed in NFAP-sensitive Aspergillus nidulans. NFAP did show neither a direct membrane disrupting- effect nor uptake by endocytosis. Investigation of A. nidulans signalling mutants revealed that NFAP acti- vates the cAMP/protein kinase A pathway via G-protein signalling which leads to apoptosis and inhibition of polar growth. In contrast, NFAP does not have any in- fluence on the cell wall integrity pathway, but an un- known cell wall integrity pathway-independent mitogen activated protein kinase A-activated target is assumed to be involved in the cell death induction. Taken to- gether, it was concluded that NFAP shows similarities, but also differences in its mode of antifungal action compared to two most investigated NFAP-related pro-teins from Aspergillus giganteus and Penicillium chrysogenum.展开更多
文摘Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids cells.Methods:A total of 65 female SD rats were randomly divided into five groups after being adaptively fed for 7 d.Except for the blank group,the remaining four groups of rats were injected with 0.05 mg/(100 g·d)estradiol benzoate and 0.5 mg/(100g·d)progesterone into the muscle to establish a uterine fibroids rat model.After successful modeling,the blank group and model group were given 200 mg/(kg·d)physiological saline by gavage,the low-dose group was given 100 mg/(kg·d)mifepristone by gavage,the medium-dose group was given 200 mg/(kg·d)mifepristone by gavage,and the high-dose group was given 300 mg/(kg·d)mifepristone by gavage.After continuous gavage treatment for 21 d,serum and uterine tissues were collected from rats to observe and compare the expression levels of MMP-2 mRNA,TIMP-2 mRNA,estradiol(E2),cAMP signaling pathway related proteins,and the migration and invasive ability of uterine fibroids cells in the five groups of rats.Results:The expression levels of MMP-2 mRNA and E2in the high-dose group were lower than those in the low-dose group and the medium-dose group,and the expression level of TIMP-2 mRNA was higher than that in the low-dose group and the medium-dose group(P<0.05).The number of cell migration in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The number of cell invasion in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The mRNA expression levels of cAMP,PDE and PK in the high-dose group were higher than those in the low-dose group,and the mRNA expression levels of AC in the high-dose group were lower than those in the low-dose group(P<0.05).The mRNA expression levels of cAMP and PDE in the high-dose group were higher than those in the mediumdose group(P<0.05).Conclusion:Letrozole may down-regulate the expression level of MMP-2 through the cAMP signaling pathway to inhibit the migration and invasion of uterine fibroids cells.With increasing doses of letrozole,its inhibitory effect on the migration and invasion of uterine fibroids cells will be enhanced.However,the optimal dosage of letrozole for inhibiting the migration and invasion of uterine fibroids cells is yet to be determined.
基金supported by the National Natural Science Foundation of China(31972217 and 32072369)the Central Government Guides Local Science and Technology Development Projects,China(206Z6501G and 216Z6502G)the Research Project of Basic Scientific Research Business Fees in Provincial Universities of Hebei Province,China(KY2021043 and KY2021044)。
文摘Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.
基金supported by the National Natural Science Foundation of China,No.91849104(to YW)。
文摘Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
基金supported by grants from the Natural Science Foundation of China(31871912 and 32061143045 to H.Z.)the Fundamental Research Funds for the Central Universities(KYZ201816 to H.Z.).
文摘Fatty acid b-oxidation is critical for fatty acid degradation and cellular development.In the rice blast fungus Magnaporthe oryzae,fatty acid b-oxidation is reported to be important mainly for turgor generation in the appressorium.However,the role of fatty acid b-oxidation during invasive hyphal growth is rarely documented.We demonstrated that blocking peroxisomal fatty acid b-oxidation impaired lipid droplet(LD)degradation and infectious growth of M.oryzae.We found that the key regulator of pathogenesis,MoMsn2,which we identified previously,is involved in fatty acid b-oxidation by targeting MoDCI1(encoding dienoyl-coenzyme A[CoA]isomerase),which is also important for LD degradation and infectious growth.Cytological observations revealed that MoMsn2 accumulated from the cytosol to the nucleus during early infection or upon treatment with oleate.We determined that the low-density lipoprotein receptor-related protein MoLrp1,which is also involved in fatty acid b-oxidation and infectious growth,plays a critical role in the accumulation of MoMsn2 from the cytosol to the nucleus by activating the cyclic AMP signaling pathway.Our results provide new insights into the importance of fatty acid oxidation during invasive hyphal growth,which is modulated by MoMsn2 and its related signaling pathways in M.oryzae.
文摘Small, cysteine-rich, highly stable antifungal proteins secreted by filamentous Ascomycetes have great po- tential for the development of novel antifungal strate- gies. However, their practical application is still limited due to their not fully clarified mode of action. The aim of this work was to provide a deep insight into the anti-fungal mechanism of Neosartorya fischeri antifungal protein （NFAP）, a novel representative of this protein group. Within a short exposure time to NFAP, reduced cellular metabolism, apoptosis induction, changes in the actin distribution and chitin deposition at the hyphal tip were observed in NFAP-sensitive Aspergillus nidulans. NFAP did show neither a direct membrane disrupting- effect nor uptake by endocytosis. Investigation of A. nidulans signalling mutants revealed that NFAP acti- vates the cAMP/protein kinase A pathway via G-protein signalling which leads to apoptosis and inhibition of polar growth. In contrast, NFAP does not have any in- fluence on the cell wall integrity pathway, but an un- known cell wall integrity pathway-independent mitogen activated protein kinase A-activated target is assumed to be involved in the cell death induction. Taken to- gether, it was concluded that NFAP shows similarities, but also differences in its mode of antifungal action compared to two most investigated NFAP-related pro-teins from Aspergillus giganteus and Penicillium chrysogenum.
