Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-c...Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.展开更多
The authors regret that Fig.6B in the published article contained an incorrect image.This was due to their unintended negligence during the extraction and handling of a large volume of experimental data in the process...The authors regret that Fig.6B in the published article contained an incorrect image.This was due to their unintended negligence during the extraction and handling of a large volume of experimental data in the process of assembling figures.The authors have replaced the incorrect image for the HFD+Celastrol 0.75 mg/kg/day group with the correct representative image.The updated Fig.6B is provided below.The original data of the figures have been provided to the Editorial Office,and the corresponding authors or the Editorial Office can be contacted for original data access.展开更多
Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.H...Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.Here,we report celastrol,a traditional Chinese medicine,can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation.Mechanistically,celastrol binds to adenylyl cyclase associated protein 1(CAP1)and inhibits the interaction between CAP1 and resistin,which restrains the cyclic adenylate monophosphate(cAMP)-protein kinase A(PKA)-nuclear factor kappa-B(NF-kB)signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome.Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity.In contrast,overexpression of CAP1 in macrophages aggravated inflammation.Taken together,our study identifies celastrol,which directly targets CAP1 in macrophages,might be a promising drug candidate for the treatment of inflammatory metabolic diseases,such as metabolic syndrome.展开更多
Although strand-biased gene distribution （SGD） was described some two decades ago, the underlying molecular mechanisms and their relationship remain elusive. Its facets include, but are not limited to, the degree of...Although strand-biased gene distribution （SGD） was described some two decades ago, the underlying molecular mechanisms and their relationship remain elusive. Its facets include, but are not limited to, the degree of biases, the strand-preference of genes, and the influence of background nucleotide composition variations. Using a dataset composed of 364 non-redundant bacterial genomes, we sought to illus- trate our current understanding of SGD. First, when we divided the collection of bacterial genomes into non-polC and polC groups according to their possession of DnaE isoforms that correlate closely with taxonomy, the SGD of the polC group stood out more sig- nificantly than that of the non-polC group. Second, when examining horizontal gene transfer, coupled with gene functional conservation （essentiality） and expressivity （level of expression）, we realized that they all contributed to SGD. Third, we further demonstrated a weaker G-dominance on the leading strand of the non-polC group but strong purine dominance （both G and A） on the leading strand of the polC group. We propose that strand-biased nucleotide composition plays a decisive role for SGD since the polC-bearing genomes are not only AT-rich but also have pronounced purine-rich leading strands, and we believe that a special mutation spectrum that leads to a strong purine asymmetry and a strong strand-biased nucleotide composition coupled with functional selections for genes and their functions are both at work.展开更多
基金supported by the National Key Research and Development Plan(2022YFC3500202,China)the National Natural Science Foundation of China(Nos.82230116,81872877,82204715,81803142,82404639,and 82073975)+7 种基金the Natural Science Foundation of Jiangsu Province(No.BK20220476,China)the Jiangsu Provincial Double-Innovation Doctor Program(No.JSSCBS20220477,China)the Natural Science Foundation of Nanjing University of Chinese Medicine(No.XPT82204715,China)the Fundamental Research Funds for the Central Universities(Nos.020814380179 and 020814380174,China)the Fundamental Science(Natural Science)Research Project of the Jiangsu Higher Education Institutions of China(No.22KJB360005)the Innovation Project of Guangdong Provincial Education Department(No.2023KTSCX320,China)the Shenzhen Science and Technology Program(Nos.20231126130044001 and 20230731094501002,China)the School of Life Science(NJU)-Sipimo Joint Funds,and the Mountain-Climbing Talents Project of Nanjing.
文摘Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.
文摘The authors regret that Fig.6B in the published article contained an incorrect image.This was due to their unintended negligence during the extraction and handling of a large volume of experimental data in the process of assembling figures.The authors have replaced the incorrect image for the HFD+Celastrol 0.75 mg/kg/day group with the correct representative image.The updated Fig.6B is provided below.The original data of the figures have been provided to the Editorial Office,and the corresponding authors or the Editorial Office can be contacted for original data access.
基金supported by National Natural Science Foundation of China(Nos.81673436,91853109,81872877,and 81872838)Natural Science Foundation of Jiangsu Province(BK20180079,China)Mountain-Climbing Talents Project of Nanjing University(China)。
文摘Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.Here,we report celastrol,a traditional Chinese medicine,can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation.Mechanistically,celastrol binds to adenylyl cyclase associated protein 1(CAP1)and inhibits the interaction between CAP1 and resistin,which restrains the cyclic adenylate monophosphate(cAMP)-protein kinase A(PKA)-nuclear factor kappa-B(NF-kB)signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome.Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity.In contrast,overexpression of CAP1 in macrophages aggravated inflammation.Taken together,our study identifies celastrol,which directly targets CAP1 in macrophages,might be a promising drug candidate for the treatment of inflammatory metabolic diseases,such as metabolic syndrome.
基金supported by grants from Knowledge Innovation Program of the Chinese Academy of Sciences(Grant No.KSCX2-EW-R-01-04)Natural Science Foundation of China(Grant No.90919024 and 30900831)+2 种基金the Ministry of Science and Technology of China as the National Science and Technology Key Project (Grant No.2008ZX10004-013)the Special Foundation Work Program(Grant No.2009FY120100)the National Basic Research Program(Grant No. 2011CB944100)
文摘Although strand-biased gene distribution （SGD） was described some two decades ago, the underlying molecular mechanisms and their relationship remain elusive. Its facets include, but are not limited to, the degree of biases, the strand-preference of genes, and the influence of background nucleotide composition variations. Using a dataset composed of 364 non-redundant bacterial genomes, we sought to illus- trate our current understanding of SGD. First, when we divided the collection of bacterial genomes into non-polC and polC groups according to their possession of DnaE isoforms that correlate closely with taxonomy, the SGD of the polC group stood out more sig- nificantly than that of the non-polC group. Second, when examining horizontal gene transfer, coupled with gene functional conservation （essentiality） and expressivity （level of expression）, we realized that they all contributed to SGD. Third, we further demonstrated a weaker G-dominance on the leading strand of the non-polC group but strong purine dominance （both G and A） on the leading strand of the polC group. We propose that strand-biased nucleotide composition plays a decisive role for SGD since the polC-bearing genomes are not only AT-rich but also have pronounced purine-rich leading strands, and we believe that a special mutation spectrum that leads to a strong purine asymmetry and a strong strand-biased nucleotide composition coupled with functional selections for genes and their functions are both at work.
