Scholarlink

Background <p>Endometriosis is an estrogen-dependent chronic inflammatory disease, however the mechanisms underlying inflammation remain unclear. Non-hormonal drugs that can prevent endometriosis progression and resolve endometriotic infertility are urgently required. We thus focused on cellular senescence as a novel feature of endometriosis. Senescent cells cause chronic inflammation via the senescence-associated secretory phenotype (SASP) factor. It has been reported the effects of senolysis for various diseases in recent years. The aim of this study was to validate the involvement of cellular senescence in endometriosis and as the effects of senolytic drug to develop a novel non-hormonal therapeutic strategy for endometriosis.</p> Methods <p>The senescence markers were assessed by morphological features and semiquantitative immunofluorescence staining (senescence-associated b-galactosidase [SA-b-Gal], the cyclin-dependent kinase inhibitor 2&#xa0;A locus [p16<sup>INK4a</sup>], and laminB1) to compare among cell types (normal endometrial stromal cells [nESCs], endometrial stromal cells with endometriosis [eESCs], and ovarian endometriosis [OE] cyst-derived stromal cells [CSCs]). Expression of SASP markers was examined in cell culture supernatants using a cytokine array. In addition, the effects of senolytic drugs (azithromycin [AZM] and navitoclax [ABT263]) on endometriosis were evaluated in vitro and in vivo. The in vivo study used the endometriosis mice model.</p> Results <p>CSCs exhibited stronger senescence markers. Semi-quantitative SA-β-Gal and p16<sup>INK4a</sup> staining intensities were significantly increased, and that of LaminB1 was decreased in CSCs compared to those in nESCs and eESCs (SA-b-Gal, <i>P</i> &lt; 0.001; p16<sup>INK4a</sup>, <i>P</i> &lt; 0.05; LaminB1, <i>P</i> &lt; 0.05). Cytokine array analysis revealed elevated SASP-related cytokine levels, including interleukin-6 (IL-6), in CSC supernatants compared to those in nESCs. AZM and ABT263 reduced the viable fraction in CSCs (AZM: <i>P</i> &lt; 0.001, ABT263: <i>P</i> &lt; 0.01). Furthermore, AZM suppressed IL-6 expression in CSC culture supernatants (<i>P</i> &lt; 0.05). In murine model, AZM administration reduced endometriotic lesion volume compared to that in vehicle (<i>P</i> &lt; 0.05). Proliferative activity, IL-6 expression levels, and fibrosis within endometriotic lesions also decreased (Ki67, <i>P</i> &lt; 0.01; IL-6, <i>P</i> &lt; 0.001; fibrosis, <i>P</i> &lt; 0.001).</p> Conclusions <p>Our findings show that cellular senescence is involved in the pathogenesis of endometriosis and that AZM may be useful for preventing endometriosis progression by suppressing the secretion of IL-6 as a SASP.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A novel senotherapeutic strategy with azithromycin for preventing endometriosis progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月26日

查看全文
  • Reina Sonehara,
  • Tomoko Nakamura,
  • Takehiko Takeda,
  • Satoshi Kaseki,
  • Tomomi Seki,
  • Hideaki Tanaka,
  • Atsushi Yabuki,
  • Natsuki Miyake,
  • Ayako Muraoka,
  • Satoko Osuka,
  • Akira Iwase,
  • Hiroaki Kajiyama

摘要

Background

Endometriosis is an estrogen-dependent chronic inflammatory disease, however the mechanisms underlying inflammation remain unclear. Non-hormonal drugs that can prevent endometriosis progression and resolve endometriotic infertility are urgently required. We thus focused on cellular senescence as a novel feature of endometriosis. Senescent cells cause chronic inflammation via the senescence-associated secretory phenotype (SASP) factor. It has been reported the effects of senolysis for various diseases in recent years. The aim of this study was to validate the involvement of cellular senescence in endometriosis and as the effects of senolytic drug to develop a novel non-hormonal therapeutic strategy for endometriosis.

Methods

The senescence markers were assessed by morphological features and semiquantitative immunofluorescence staining (senescence-associated b-galactosidase [SA-b-Gal], the cyclin-dependent kinase inhibitor 2 A locus [p16INK4a], and laminB1) to compare among cell types (normal endometrial stromal cells [nESCs], endometrial stromal cells with endometriosis [eESCs], and ovarian endometriosis [OE] cyst-derived stromal cells [CSCs]). Expression of SASP markers was examined in cell culture supernatants using a cytokine array. In addition, the effects of senolytic drugs (azithromycin [AZM] and navitoclax [ABT263]) on endometriosis were evaluated in vitro and in vivo. The in vivo study used the endometriosis mice model.

Results

CSCs exhibited stronger senescence markers. Semi-quantitative SA-β-Gal and p16INK4a staining intensities were significantly increased, and that of LaminB1 was decreased in CSCs compared to those in nESCs and eESCs (SA-b-Gal, P < 0.001; p16INK4a, P < 0.05; LaminB1, P < 0.05). Cytokine array analysis revealed elevated SASP-related cytokine levels, including interleukin-6 (IL-6), in CSC supernatants compared to those in nESCs. AZM and ABT263 reduced the viable fraction in CSCs (AZM: P < 0.001, ABT263: P < 0.01). Furthermore, AZM suppressed IL-6 expression in CSC culture supernatants (P < 0.05). In murine model, AZM administration reduced endometriotic lesion volume compared to that in vehicle (P < 0.05). Proliferative activity, IL-6 expression levels, and fibrosis within endometriotic lesions also decreased (Ki67, P < 0.01; IL-6, P < 0.001; fibrosis, P < 0.001).

Conclusions

Our findings show that cellular senescence is involved in the pathogenesis of endometriosis and that AZM may be useful for preventing endometriosis progression by suppressing the secretion of IL-6 as a SASP.