{"title":"小分子α-亚甲基-γ-丁内酯是倍半萜内酯中的一个进化保守分子,可通过干扰 NF-κB 的 DNA 结合活性改善关节炎表型","authors":"","doi":"10.1016/j.apsb.2024.04.004","DOIUrl":null,"url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. <em>α</em>-Methylene-<em>γ</em>-butyrolactone (<em>α</em>-M-<em>γ</em>-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of <em>α</em>-M-<em>γ</em>-B as an independent small molecule <em>in vitro</em> and <em>in vivo</em>. <em>α</em>-M-<em>γ</em>-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. <em>α</em>-M-<em>γ</em>-B inhibited the production of pro-inflammatory mediators <em>via</em> repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that <em>α</em>-M-<em>γ</em>-B regulated the immune system pathway. Consistently, <em>α</em>-M-<em>γ</em>-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM <em>via</em> repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although <em>α</em>-M-<em>γ</em>-B did not prevent the trans-nucleus of NF-<em>κ</em>B it interfered with the DNA binding activity of NF-<em>κ</em>B <em>via</em> direct interaction with the sulfhydryl in cysteine residue of NF-<em>κ</em>B p65, which blocked the activation of NF-<em>κ</em>B. Inhibition of NF-<em>κ</em>B reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. <em>α</em>-M-<em>γ</em>-B failed to ameliorate CIA in the presence of <em>N</em>-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of <em>Rela</em>. In conclusion, <em>α</em>-M-<em>γ</em>-B significantly attenuated the CIA phenotype by directly targeting NF-<em>κ</em>B p65 and inhibiting its DNA binding ability. These results suggest that <em>α</em>-M-<em>γ</em>-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of <em>α</em>-M-<em>γ</em>-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why <em>α</em>-M-<em>γ</em>-B is evolutionarily conserved in the SLs by medical plants.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.7000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001321/pdfft?md5=8f8b8f0fb27d11def58e396ce288b705&pid=1-s2.0-S2211383524001321-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Small molecule α-methylene-γ-butyrolactone, an evolutionarily conserved moiety in sesquiterpene lactones, ameliorates arthritic phenotype via interference DNA binding activity of NF-κB\",\"authors\":\"\",\"doi\":\"10.1016/j.apsb.2024.04.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. <em>α</em>-Methylene-<em>γ</em>-butyrolactone (<em>α</em>-M-<em>γ</em>-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of <em>α</em>-M-<em>γ</em>-B as an independent small molecule <em>in vitro</em> and <em>in vivo</em>. <em>α</em>-M-<em>γ</em>-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. <em>α</em>-M-<em>γ</em>-B inhibited the production of pro-inflammatory mediators <em>via</em> repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that <em>α</em>-M-<em>γ</em>-B regulated the immune system pathway. Consistently, <em>α</em>-M-<em>γ</em>-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM <em>via</em> repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although <em>α</em>-M-<em>γ</em>-B did not prevent the trans-nucleus of NF-<em>κ</em>B it interfered with the DNA binding activity of NF-<em>κ</em>B <em>via</em> direct interaction with the sulfhydryl in cysteine residue of NF-<em>κ</em>B p65, which blocked the activation of NF-<em>κ</em>B. Inhibition of NF-<em>κ</em>B reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. <em>α</em>-M-<em>γ</em>-B failed to ameliorate CIA in the presence of <em>N</em>-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of <em>Rela</em>. In conclusion, <em>α</em>-M-<em>γ</em>-B significantly attenuated the CIA phenotype by directly targeting NF-<em>κ</em>B p65 and inhibiting its DNA binding ability. These results suggest that <em>α</em>-M-<em>γ</em>-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of <em>α</em>-M-<em>γ</em>-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why <em>α</em>-M-<em>γ</em>-B is evolutionarily conserved in the SLs by medical plants.</p></div>\",\"PeriodicalId\":6906,\"journal\":{\"name\":\"Acta Pharmaceutica Sinica. 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Small molecule α-methylene-γ-butyrolactone, an evolutionarily conserved moiety in sesquiterpene lactones, ameliorates arthritic phenotype via interference DNA binding activity of NF-κB
Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. α-Methylene-γ-butyrolactone (α-M-γ-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of α-M-γ-B as an independent small molecule in vitro and in vivo. α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that α-M-γ-B regulated the immune system pathway. Consistently, α-M-γ-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although α-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65, which blocked the activation of NF-κB. Inhibition of NF-κB reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela. In conclusion, α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability. These results suggest that α-M-γ-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of α-M-γ-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why α-M-γ-B is evolutionarily conserved in the SLs by medical plants.
Acta Pharmaceutica Sinica. BPharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
22.40
自引率
5.50%
发文量
1051
审稿时长
19 weeks
期刊介绍:
The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB).
Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics.
A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.