Neuropathic pain,a debilitating condition caused by dysfunction of the somatosensory nervous system,remains difficult to treat due to limited understanding of its molecular mechanisms.Bioinformatics analysis identifie...Neuropathic pain,a debilitating condition caused by dysfunction of the somatosensory nervous system,remains difficult to treat due to limited understanding of its molecular mechanisms.Bioinformatics analysis identified cerebellin 2(CBLN2)as highly enriched in human and murine proprioceptive and nociceptive neurons.We found that CBLN2 expression is persistently upregulated in dorsal root ganglia(DRG)following spinal nerve ligation(SNL)in mice.In addition,transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription.SNL also induced SOX11 upregulation,with SOX11 and CBLN2 co-localized in nociceptive neurons.The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia.High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes,including upregulation of numerous NF-κB downstream targets.Consistently,CBLN2 activated NF-κB signaling,and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity,proinflammatory cytokines and chemokines production,and neuronal hyperexcitability.Together,these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.展开更多
To the Editor:Pulmonary arterial hypertension (PAH)is a hemodynamic disorder with elevated pressure of pulmonary circulation.Genetic studies in familial PAH (fPAH)and idiopathic PAH (iPAH)have discovered that transfor...To the Editor:Pulmonary arterial hypertension (PAH)is a hemodynamic disorder with elevated pressure of pulmonary circulation.Genetic studies in familial PAH (fPAH)and idiopathic PAH (iPAH)have discovered that transforming growth factor-β (TGF-β) superfamily plays an important role,and the identified mutations occur in bone morphogenetic protein type 2 receptor (BMPR2), activin receptor-like kinase type 1 (ALK1),Endoglin,and SMAD9. A genome-wide association study (GWAS)in patients without BMPR2 mutations discovered that one single-nucleotide polymorphism (SNP)rs2217560 had a significant association with i/fPAH,which located 52-kb downstream of the CBLN2 gene.展开更多
基金supported by STI2030-Major Projects(2022ZD0204700)the National Natural Science Foundation of China(32030048,32200817,and 82271256).
文摘Neuropathic pain,a debilitating condition caused by dysfunction of the somatosensory nervous system,remains difficult to treat due to limited understanding of its molecular mechanisms.Bioinformatics analysis identified cerebellin 2(CBLN2)as highly enriched in human and murine proprioceptive and nociceptive neurons.We found that CBLN2 expression is persistently upregulated in dorsal root ganglia(DRG)following spinal nerve ligation(SNL)in mice.In addition,transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription.SNL also induced SOX11 upregulation,with SOX11 and CBLN2 co-localized in nociceptive neurons.The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia.High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes,including upregulation of numerous NF-κB downstream targets.Consistently,CBLN2 activated NF-κB signaling,and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity,proinflammatory cytokines and chemokines production,and neuronal hyperexcitability.Together,these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.
基金grants from the Chinese National High Technology Research and Development Program,Ministry of Science and Technology (No.2012AA02A513)Chinese National Key Technology R&D Program (Nos.2017YFC0907601, 2017YFC0907602,and 2017YFC0907603)National Natural Science Foundation of China (Nos.81400278 and 81670054).
文摘To the Editor:Pulmonary arterial hypertension (PAH)is a hemodynamic disorder with elevated pressure of pulmonary circulation.Genetic studies in familial PAH (fPAH)and idiopathic PAH (iPAH)have discovered that transforming growth factor-β (TGF-β) superfamily plays an important role,and the identified mutations occur in bone morphogenetic protein type 2 receptor (BMPR2), activin receptor-like kinase type 1 (ALK1),Endoglin,and SMAD9. A genome-wide association study (GWAS)in patients without BMPR2 mutations discovered that one single-nucleotide polymorphism (SNP)rs2217560 had a significant association with i/fPAH,which located 52-kb downstream of the CBLN2 gene.
