Background&Objective Knee osteoarthritis(OA)is a degenerative disease,which not only induces superficial cartilage defects and full-thickness cartilage defects,but also exacerbates the microenvironment of the knee...Background&Objective Knee osteoarthritis(OA)is a degenerative disease,which not only induces superficial cartilage defects and full-thickness cartilage defects,but also exacerbates the microenvironment of the knee joint and affects the mechano-chemical responses of the organ.As a growth/repair factor,mechanical growth factor(MGF)has the function of preventing OA,promoting cartilage regeneration and repairing damaged ligaments.activating transcription factor 2(ATF-2),a transcription factor,has the property of binding to cytokines,which makes it involved in the transcriptional regulation of various pathways in response to cellular stress,inflammatory cytokine and growth factors.At present,little is known about the effect of MGF on human osteoarthritis ligament fibroblasts(OA-LFs),and whether the approach can promote OA-LFs timely response to the mechanical injury and initiate signaling pathway for cell survival.Therefore,the purpose of this study is to investigate whether MGF promotes mechanical response to ligament fibroblasts in osteoarthritis knee cavity via ATF-2.Methods OA-LFs were seeded onto six-cell BioFlex plates and suffered from 12%static mechanical stretch[60 cycles/minute(1 Hz)]for 12 hours to mimic mechanical force mediated ligament injury.Meanwhile,OA-LFs were treated with MGF before and during mechanical stretch.Intracellular reactive oxygen species(ROS)and GRP78 mRNA expression were investigated to detect the cellular stress response of OA-LFs.The scratch test was performed to detect the migration ability of cells,gelatin zymography was used to examine the effect of MGF on the activity of matrix metalloproteinase 2(MMP-2)in OA-LFs,and cell deformation was detected by phalloidin-FITC staining after stretching.Quantitative real-time polymerase chain reaction(qRT-PCR)was used to screen the messenger RNA(mRNA)expression of ATF family members after OALFs treatment with MGF.Western blotting further proved that MGF is capable to activate the p-ATF-2.Results OA delays LFs response to mechanical injury,while MGF pretreatment can promote cells timely feedback the mechanically stimuli by inducing cellular stress.MGF treatment can alleviate the decline in cell migration ability caused by mechanical injury and further promote cell migration.In addition,MGF can reduce the activity of MM P-5 and alleviate the stretch-induced deformation of OA-LFs.Furthermore,the mRNA expression of ATF-2 up-regulated in a dose-dependent manner upon MGF treatment compared with control,while the expression of ATF-5 gene was down-regulated in a dose-dependent.Protein levels showed that the expression of p-ATF-2 increased with increasing MGF concentration.Conclusions Our study shows that MGF pretreatment of OA-LFs can respond quickly to mechanical damage and accelerate the ligament injury repair by promoting cell migration,decreasing the MMP-2 activity,and remitting the cell deformation.Therefore,MGF has potential as a therapeutic for OA patients.展开更多
In several filamentous fungi,incident light and environmental stress signaling share the mitogen-activated protein kinase(MAPK)HOG(SAK)pathway.It has been revealed that short-term illumination with blue light triggers...In several filamentous fungi,incident light and environmental stress signaling share the mitogen-activated protein kinase(MAPK)HOG(SAK)pathway.It has been revealed that short-term illumination with blue light triggers the activation of the HOG pathway in Trichoderma spp.In this study,we demonstrate the crucial role of the basic leucine zipper transcription factor ATF1 in blue light responses and signaling downstream of the MAPK HOG1 in Trichoderma guizhouense.The lack of ATF1 severely impaired photoconidiation and delayed vegetative growth and conidial germination.Upon blue light or H2O2 stimuli,HOG1 interacted with ATF1 in the nucleus.Genome-wide transcriptome analyses revealed that 61.8%(509 out of 824)and 85.2%(702 out of 824)of blue light-regulated genes depended on ATF1 and HOG1,respectively,of which 58.4%(481 out of 824)were regulated by both of them.Our results also show that blue light promoted conidial germination and HOG1 and ATF1 played opposite roles in controlling conidial germination in the dark.Additionally,the lack of ATF1 led to reduced oxidative stress resistance,probably because of the downregulation of catalase-encoding genes.Overall,our results demonstrate that ATF1 is the downstream component of HOG1 and is responsible for blue light responses,conidial germination,vegetative growth,and oxidative stress resistance in T.guizhouense.展开更多
The key regulators and regeneration-associated genes involved in axonal regeneration of neurons after injury have not been clarified.In high-throughput sequencing,various factors influence the final sequencing results...The key regulators and regeneration-associated genes involved in axonal regeneration of neurons after injury have not been clarified.In high-throughput sequencing,various factors influence the final sequencing results,including the number and size of cells,the depth of sequencing,and the method of cell separation.There is still a lack of research on the detailed molecular expression profile during the regeneration of dorsal root ganglion neuron axon.In this study,we performed lase r-capture microdissection coupled with RNA sequencing on dorsal root ganglion neurons at 0,3,6,and 12 hours and 1,3,and 7 days after sciatic nerve crush in rats.We identified three stages after dorsal root ganglion injury:early(3-12 hours),pre-regeneration(1 day),and regeneration(3-7 days).Gene expression patterns and related function enrichment res ults showed that one module of genes was highly related to axonal regeneration.We verified the up-regulation of activating transcription factor 3(Atf3),Kruppel like factor 6(Klf6),AT-rich inte raction domain 5A(Arid5α),CAMP responsive element modulator(Crem),and FOS like 1,AP-1 transcription factor Subunit(Fosl1) in dorsal root ganglion neurons after injury.Suppressing these transcription factors(Crem,Arid5o,Fosl1 and Klf6) reduced axonal regrowth in vitro.As the hub transcription factor,Atf3 showed higher expression and activity at the preregeneration and regeneration stages.G protein-coupled estrogen receptor 1(Gper1),inte rleukin 12a(Il12α),estrogen receptor 1(ESR1),and interleukin 6(IL6) may be upstream factors that trigger the activation of Atf3 during the repair of axon injury in the early stage.Our study presents the detailed molecular expression profile during axonal regeneration of dorsal root ganglion neurons after peripheral nerve injury.These findings may provide reference for the clinical screening of molecular targets for the treatment of peripheral nerve injury.展开更多
In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS...In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.展开更多
Sublytic complement C5b-9 complexes can cause cell apoptosis, but the mechanism of glomerular mesangial cell （GMC） apoptosis mediated by these complexes has not been well defined. The activating transcription factor...Sublytic complement C5b-9 complexes can cause cell apoptosis, but the mechanism of glomerular mesangial cell （GMC） apoptosis mediated by these complexes has not been well defined. The activating transcription factor 3 （ATF3） gene is an immediate early gene for the cell to cope with a variety of stress signals and can promote apoptosis of some cells. In this study, ATF3 expression and cell apoptosis in GMCs induced by sublytic C5b-9 were measured, and then the effects of ATF3 gene over-expression or knockdown on GMC apoptosis induced by sublytic C5b-9 were examined at a fixed time. The results showed that both ATF3 expression and GMC apoptosis were markedly increased and ATF3 over-expression obviously increased sublytic C5b-9-induced GMC apoptosis, whereas ATF3 gene silencing had a significant opposite effect. Collectively, these findings indicate that upregulation of ATF3 gene expression is involved in regulating GMC apoptosis induced by sublytic C5b-9 complexes.展开更多
1 Introduction Lady beetle (Coccinella septempunctata) is an important natural enemy of aphids.Our data show that JH produced in the corpora allata (CA) in the adult beetle playsa key role in regulating its reproducti...1 Introduction Lady beetle (Coccinella septempunctata) is an important natural enemy of aphids.Our data show that JH produced in the corpora allata (CA) in the adult beetle playsa key role in regulating its reproduction. Recently, it is demonstrated that CA ininsects are target tissues of allatostatin and allatotropin. Juvenile hormone (JH) issynthesized and released by CA and plays a vital role in insect development, primarilyin the control of metamorphosis, sexual maturation and reproduction. The activity ofCA during reproduction could be modulated by stimulatory factors (Allatotropicfactor, ATF), inhibitory factors (Allatostatic factor AST) or both.展开更多
Mouse dental papilla cells(mDPCs)are cranial neural crest-derived dental mesenchymal cells that give rise to dentin-secreting odontoblasts after the bell stage during odontogenesis.The odontoblastic differentiation of...Mouse dental papilla cells(mDPCs)are cranial neural crest-derived dental mesenchymal cells that give rise to dentin-secreting odontoblasts after the bell stage during odontogenesis.The odontoblastic differentiation of mDPCs is spatiotemporally regulated by transcription factors(TFs).Our previous work reveals that chromatin accessibility was correlated with the occupation of the basic leucine zipper TF family during odontoblastic differentiation.However,the detailed mechanism by which TFs regulate the initiation of odontoblastic differentiation remains elusive.Here,we report that phosphorylation of ATF2(p-ATF2)is particularly increased during odontoblastic differentiation in vivo and in vitro.ATAC-seq and p-ATF2 CUT&Tag experiments further demonstrate a high correlation between p-ATF2 localization and increased chromatin accessibility of regions near mineralization-related genes.Knockdown of Atf2 inhibits the odontoblastic differentiation of mDPCs,while overexpression of p-ATF2 promotes odontoblastic differentiation.ATAC-seq after overexpression of p-ATF2 reveals that p-ATF2 increases the chromatin accessibility of regions adjacent to genes associated with matrix mineralization.Furthermore,we find that p-ATF2 physically interacts with and promotes H2BK12 acetylation.Taken together,our findings reveal a mechanism that p-ATF2 promotes odontoblastic differentiation at initiation via remodeling chromatin accessibility and emphasize the role of the phosphoswitch model of TFs in cell fate transitions.展开更多
Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)a...Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)amino acid metabolism remains largely unknown.In this study,we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics.We further confirmed that UPF1 knockdown inhibited activating transcription factor 4(ATF4)and Ser51 phosphorylation of eukaryotic translation initiation factor 2α(eIF2α),the core proteins in amino acid metabolism reprogramming.In addition,UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells,which depends on the function of ATF4.Clinically,UPF1 mRNA expression is abnormal in LUAD tissues,and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival(OS)in LUAD patients.Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.展开更多
基金supported by the National Natural Science Foundation of China ( 11532004,31270990, 31600762)Innovation and Attracting Talents Program for College and University( “111”Project) ( B06023)
文摘Background&Objective Knee osteoarthritis(OA)is a degenerative disease,which not only induces superficial cartilage defects and full-thickness cartilage defects,but also exacerbates the microenvironment of the knee joint and affects the mechano-chemical responses of the organ.As a growth/repair factor,mechanical growth factor(MGF)has the function of preventing OA,promoting cartilage regeneration and repairing damaged ligaments.activating transcription factor 2(ATF-2),a transcription factor,has the property of binding to cytokines,which makes it involved in the transcriptional regulation of various pathways in response to cellular stress,inflammatory cytokine and growth factors.At present,little is known about the effect of MGF on human osteoarthritis ligament fibroblasts(OA-LFs),and whether the approach can promote OA-LFs timely response to the mechanical injury and initiate signaling pathway for cell survival.Therefore,the purpose of this study is to investigate whether MGF promotes mechanical response to ligament fibroblasts in osteoarthritis knee cavity via ATF-2.Methods OA-LFs were seeded onto six-cell BioFlex plates and suffered from 12%static mechanical stretch[60 cycles/minute(1 Hz)]for 12 hours to mimic mechanical force mediated ligament injury.Meanwhile,OA-LFs were treated with MGF before and during mechanical stretch.Intracellular reactive oxygen species(ROS)and GRP78 mRNA expression were investigated to detect the cellular stress response of OA-LFs.The scratch test was performed to detect the migration ability of cells,gelatin zymography was used to examine the effect of MGF on the activity of matrix metalloproteinase 2(MMP-2)in OA-LFs,and cell deformation was detected by phalloidin-FITC staining after stretching.Quantitative real-time polymerase chain reaction(qRT-PCR)was used to screen the messenger RNA(mRNA)expression of ATF family members after OALFs treatment with MGF.Western blotting further proved that MGF is capable to activate the p-ATF-2.Results OA delays LFs response to mechanical injury,while MGF pretreatment can promote cells timely feedback the mechanically stimuli by inducing cellular stress.MGF treatment can alleviate the decline in cell migration ability caused by mechanical injury and further promote cell migration.In addition,MGF can reduce the activity of MM P-5 and alleviate the stretch-induced deformation of OA-LFs.Furthermore,the mRNA expression of ATF-2 up-regulated in a dose-dependent manner upon MGF treatment compared with control,while the expression of ATF-5 gene was down-regulated in a dose-dependent.Protein levels showed that the expression of p-ATF-2 increased with increasing MGF concentration.Conclusions Our study shows that MGF pretreatment of OA-LFs can respond quickly to mechanical damage and accelerate the ligament injury repair by promoting cell migration,decreasing the MMP-2 activity,and remitting the cell deformation.Therefore,MGF has potential as a therapeutic for OA patients.
基金supported by the National Natural Science Foundation of China (NSFC) (Grant Nos.32070101 and 32270053)the Fundamental Research Funds for the Central Universities (Grant Nos.XUEKEN2023039,XUEKEN2023041,RENCAI2022005,and KYT2023001)the Jiangsu Agriculture Science and Technology Innovation fund (JASTIF) (Grant No.CX (21)2018).
文摘In several filamentous fungi,incident light and environmental stress signaling share the mitogen-activated protein kinase(MAPK)HOG(SAK)pathway.It has been revealed that short-term illumination with blue light triggers the activation of the HOG pathway in Trichoderma spp.In this study,we demonstrate the crucial role of the basic leucine zipper transcription factor ATF1 in blue light responses and signaling downstream of the MAPK HOG1 in Trichoderma guizhouense.The lack of ATF1 severely impaired photoconidiation and delayed vegetative growth and conidial germination.Upon blue light or H2O2 stimuli,HOG1 interacted with ATF1 in the nucleus.Genome-wide transcriptome analyses revealed that 61.8%(509 out of 824)and 85.2%(702 out of 824)of blue light-regulated genes depended on ATF1 and HOG1,respectively,of which 58.4%(481 out of 824)were regulated by both of them.Our results also show that blue light promoted conidial germination and HOG1 and ATF1 played opposite roles in controlling conidial germination in the dark.Additionally,the lack of ATF1 led to reduced oxidative stress resistance,probably because of the downregulation of catalase-encoding genes.Overall,our results demonstrate that ATF1 is the downstream component of HOG1 and is responsible for blue light responses,conidial germination,vegetative growth,and oxidative stress resistance in T.guizhouense.
基金supported by the National Natural Science Foundation of China,Nos. 31730031 and 32130060the National Major Project of Research and Development,No. 2017YFA0104700the Natural Science Foundation of Jiangsu Province,No. BK20202013 (all to XSG)。
文摘The key regulators and regeneration-associated genes involved in axonal regeneration of neurons after injury have not been clarified.In high-throughput sequencing,various factors influence the final sequencing results,including the number and size of cells,the depth of sequencing,and the method of cell separation.There is still a lack of research on the detailed molecular expression profile during the regeneration of dorsal root ganglion neuron axon.In this study,we performed lase r-capture microdissection coupled with RNA sequencing on dorsal root ganglion neurons at 0,3,6,and 12 hours and 1,3,and 7 days after sciatic nerve crush in rats.We identified three stages after dorsal root ganglion injury:early(3-12 hours),pre-regeneration(1 day),and regeneration(3-7 days).Gene expression patterns and related function enrichment res ults showed that one module of genes was highly related to axonal regeneration.We verified the up-regulation of activating transcription factor 3(Atf3),Kruppel like factor 6(Klf6),AT-rich inte raction domain 5A(Arid5α),CAMP responsive element modulator(Crem),and FOS like 1,AP-1 transcription factor Subunit(Fosl1) in dorsal root ganglion neurons after injury.Suppressing these transcription factors(Crem,Arid5o,Fosl1 and Klf6) reduced axonal regrowth in vitro.As the hub transcription factor,Atf3 showed higher expression and activity at the preregeneration and regeneration stages.G protein-coupled estrogen receptor 1(Gper1),inte rleukin 12a(Il12α),estrogen receptor 1(ESR1),and interleukin 6(IL6) may be upstream factors that trigger the activation of Atf3 during the repair of axon injury in the early stage.Our study presents the detailed molecular expression profile during axonal regeneration of dorsal root ganglion neurons after peripheral nerve injury.These findings may provide reference for the clinical screening of molecular targets for the treatment of peripheral nerve injury.
文摘In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.
文摘Sublytic complement C5b-9 complexes can cause cell apoptosis, but the mechanism of glomerular mesangial cell （GMC） apoptosis mediated by these complexes has not been well defined. The activating transcription factor 3 （ATF3） gene is an immediate early gene for the cell to cope with a variety of stress signals and can promote apoptosis of some cells. In this study, ATF3 expression and cell apoptosis in GMCs induced by sublytic C5b-9 were measured, and then the effects of ATF3 gene over-expression or knockdown on GMC apoptosis induced by sublytic C5b-9 were examined at a fixed time. The results showed that both ATF3 expression and GMC apoptosis were markedly increased and ATF3 over-expression obviously increased sublytic C5b-9-induced GMC apoptosis, whereas ATF3 gene silencing had a significant opposite effect. Collectively, these findings indicate that upregulation of ATF3 gene expression is involved in regulating GMC apoptosis induced by sublytic C5b-9 complexes.
基金Project supported by the National Natural Science Foundation of China.
文摘1 Introduction Lady beetle (Coccinella septempunctata) is an important natural enemy of aphids.Our data show that JH produced in the corpora allata (CA) in the adult beetle playsa key role in regulating its reproduction. Recently, it is demonstrated that CA ininsects are target tissues of allatostatin and allatotropin. Juvenile hormone (JH) issynthesized and released by CA and plays a vital role in insect development, primarilyin the control of metamorphosis, sexual maturation and reproduction. The activity ofCA during reproduction could be modulated by stimulatory factors (Allatotropicfactor, ATF), inhibitory factors (Allatostatic factor AST) or both.
基金supported by the National Natural Science Foundation of China (No. 82071110 and No. 82230029) to Zhi Chenthe National Natural Science Foundation of China (No. 82071077 and No.82270948)+1 种基金“the Fundamental Research Funds for the Central Universities”“The Young Top-notch Talent Cultivation Program of Hubei Province” to Huan Liu
文摘Mouse dental papilla cells(mDPCs)are cranial neural crest-derived dental mesenchymal cells that give rise to dentin-secreting odontoblasts after the bell stage during odontogenesis.The odontoblastic differentiation of mDPCs is spatiotemporally regulated by transcription factors(TFs).Our previous work reveals that chromatin accessibility was correlated with the occupation of the basic leucine zipper TF family during odontoblastic differentiation.However,the detailed mechanism by which TFs regulate the initiation of odontoblastic differentiation remains elusive.Here,we report that phosphorylation of ATF2(p-ATF2)is particularly increased during odontoblastic differentiation in vivo and in vitro.ATAC-seq and p-ATF2 CUT&Tag experiments further demonstrate a high correlation between p-ATF2 localization and increased chromatin accessibility of regions near mineralization-related genes.Knockdown of Atf2 inhibits the odontoblastic differentiation of mDPCs,while overexpression of p-ATF2 promotes odontoblastic differentiation.ATAC-seq after overexpression of p-ATF2 reveals that p-ATF2 increases the chromatin accessibility of regions adjacent to genes associated with matrix mineralization.Furthermore,we find that p-ATF2 physically interacts with and promotes H2BK12 acetylation.Taken together,our findings reveal a mechanism that p-ATF2 promotes odontoblastic differentiation at initiation via remodeling chromatin accessibility and emphasize the role of the phosphoswitch model of TFs in cell fate transitions.
基金supported by the National Natural Science Foundation of China(Nos.81803886,81774078,and 21907093)。
文摘Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)amino acid metabolism remains largely unknown.In this study,we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics.We further confirmed that UPF1 knockdown inhibited activating transcription factor 4(ATF4)and Ser51 phosphorylation of eukaryotic translation initiation factor 2α(eIF2α),the core proteins in amino acid metabolism reprogramming.In addition,UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells,which depends on the function of ATF4.Clinically,UPF1 mRNA expression is abnormal in LUAD tissues,and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival(OS)in LUAD patients.Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.
