The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia ...The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.展开更多
In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reverse...In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reversed osimertinib resistance in non-small cell lung cancer(NSCLC).Therefore,we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A(VEGFA)before and after the development of osimertinib resistance.The results revealed the downregulation of E-cadherin,coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance,compared with those in tissues from patients before receiving osimertinib.Subsequently,we established osimertinib-resistant(Osi-R)cell lines and found that the Osi-R cells acquired EMT features.Next,we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT.The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro.Finally,we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice.The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells,inhibited tumor growth,exerted antitumor activity,and ultimately reversed osimertinib resistance in mice.The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients,ultimately reversing osimertinib resistance.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071387(to HT),81971172(to YW)the Natural Science Foundation of Zhejiang Province,China,No.LY22H090012(to HT)the Basic Research Project of Wenzhou City,China,No.Y20220923(to MZ)。
文摘The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.
基金supported by the National Natural Science Foundation of China(Grant Nos.82172728,82370096).
文摘In the present study,we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition(EMT)and angiogenesis.In a clinical case,anlotinib reversed osimertinib resistance in non-small cell lung cancer(NSCLC).Therefore,we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A(VEGFA)before and after the development of osimertinib resistance.The results revealed the downregulation of E-cadherin,coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance,compared with those in tissues from patients before receiving osimertinib.Subsequently,we established osimertinib-resistant(Osi-R)cell lines and found that the Osi-R cells acquired EMT features.Next,we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT.The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro.Finally,we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice.The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells,inhibited tumor growth,exerted antitumor activity,and ultimately reversed osimertinib resistance in mice.The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients,ultimately reversing osimertinib resistance.
