Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S...Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.展开更多
Objective To investigate the effects of calprotectin(S100A8/A9)on the biological activity of acute myeloid leukemia(AML)cells harboring a DNA methyltransferase 3A(DNMT3A)mutation and to explore the underlying molecula...Objective To investigate the effects of calprotectin(S100A8/A9)on the biological activity of acute myeloid leukemia(AML)cells harboring a DNA methyltransferase 3A(DNMT3A)mutation and to explore the underlying molecular mechanisms involved.Methods AML monoclonal cell lines harboring the DNMT3A^(R882H) mutation were generated via lentiviral transduction and limiting dilution.RNA sequencing was used for differential gene expression analysis,followed by bioinformatic pathway enrichment and gene correlation analyses.The biological effects of paquinimod,a selective S100A8/A9 inhibitor,on DNMT3A^(R882H) AML cells were assessed via Cell Counting Kit(CCK-8)proliferation assays,Annexin V/PI staining,cell cycle analysis,cell adhesion assays,and transwell migration assays.Results Differential gene expression analysis revealed 442 upregulated and 535 downregulated genes in DNMT3A-mutated(DNMT3A^(mut))cells compared with those in DNMT3A wild-type(DNMT3A^(wt))cells,with the S100A8/A9 complex recurrently enriched in Reactome pathway analysis.Compared with healthy controls,patients with AML presented increased expression of S100A8 and S100A9 and increased expression of DNMT3A^(mut) cells relative to DNMT3A^(wt) cells,which was correlated with poor prognosis in patients with AML.There were no notable differences in proliferation among the DNMT3A^(mut),DNMT3A^(wt),and empty vector cells under normal or starvation conditions.However,paquinimod treatment notably inhibited the proliferation,migration,and adhesion of DNMT3A^(mut) AML cells in a dose-dependent manner,causing G0/G1 cell cycle arrest,whereas no significant effects on apoptosis were observed.Paquinimod also downregulated key adhesion molecules,including intercellular adhesion molecule 1(ICAM-1),vascular cell adhesion molecule 1(VCAM-1),monocyte chemoattractant protein-1(MCP-1),and matrix metalloproteinase-2(MMP-2).Additionally,S100A8 and S100A9 expression was upregulated in a dose-dependent manner in response to cytarabine treatment.Conclusion Elevated S100A8/A9 expression contributes to the abnormal proliferation,migration,adhesion,and chemoresistance of DNMT3A^(mut) AML cells.Targeting S100A8/A9 alone or in combination with other treatments represents a promising therapeutic strategy for DNMT3A^(mut) AML.展开更多
基金financially supported by the National Key Research and Development Program of China(2021YFA0910500)the National Natural Science Foundation of China(U22A20380,82373755,82173706,82404468)+2 种基金the Fundamental Research Funds for the Central Universities(2024BRA018,China)the Science and Technology Major Project of Hubei Province(2021ACA012,China)Hubei Provincial Natural Science Foundation of China(2025AFB227).
文摘Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.
基金funded by the National Natural Science Foundation of China(Grant No.82270177)the China Medicine Education Association 2024 Medical Science and Technology Research Project(Grant No.2024KTZ035).
文摘Objective To investigate the effects of calprotectin(S100A8/A9)on the biological activity of acute myeloid leukemia(AML)cells harboring a DNA methyltransferase 3A(DNMT3A)mutation and to explore the underlying molecular mechanisms involved.Methods AML monoclonal cell lines harboring the DNMT3A^(R882H) mutation were generated via lentiviral transduction and limiting dilution.RNA sequencing was used for differential gene expression analysis,followed by bioinformatic pathway enrichment and gene correlation analyses.The biological effects of paquinimod,a selective S100A8/A9 inhibitor,on DNMT3A^(R882H) AML cells were assessed via Cell Counting Kit(CCK-8)proliferation assays,Annexin V/PI staining,cell cycle analysis,cell adhesion assays,and transwell migration assays.Results Differential gene expression analysis revealed 442 upregulated and 535 downregulated genes in DNMT3A-mutated(DNMT3A^(mut))cells compared with those in DNMT3A wild-type(DNMT3A^(wt))cells,with the S100A8/A9 complex recurrently enriched in Reactome pathway analysis.Compared with healthy controls,patients with AML presented increased expression of S100A8 and S100A9 and increased expression of DNMT3A^(mut) cells relative to DNMT3A^(wt) cells,which was correlated with poor prognosis in patients with AML.There were no notable differences in proliferation among the DNMT3A^(mut),DNMT3A^(wt),and empty vector cells under normal or starvation conditions.However,paquinimod treatment notably inhibited the proliferation,migration,and adhesion of DNMT3A^(mut) AML cells in a dose-dependent manner,causing G0/G1 cell cycle arrest,whereas no significant effects on apoptosis were observed.Paquinimod also downregulated key adhesion molecules,including intercellular adhesion molecule 1(ICAM-1),vascular cell adhesion molecule 1(VCAM-1),monocyte chemoattractant protein-1(MCP-1),and matrix metalloproteinase-2(MMP-2).Additionally,S100A8 and S100A9 expression was upregulated in a dose-dependent manner in response to cytarabine treatment.Conclusion Elevated S100A8/A9 expression contributes to the abnormal proliferation,migration,adhesion,and chemoresistance of DNMT3A^(mut) AML cells.Targeting S100A8/A9 alone or in combination with other treatments represents a promising therapeutic strategy for DNMT3A^(mut) AML.
