Diabetes & metabolism journal · 2020
Insulin Resistance Increases Serum Immunoglobulin E Sensitization in Premenopausal Women.
СтатьяНазвание и аннотация: Перевод в очереди
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Lin Dongxu, Li Kang, Kuang Wenbo, Chen Zhong, Zhang Mengyang
Аннотация
PURPOSE: Although low-intensity extracorporeal shock wave therapy (Li-ESWT) is used clinically for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), its mechanisms remain inadequately understood. This study aimed to explore Li-ESWT-mediated mechanotransduction signaling and its association with ferroptosis in CP/CPPS models.
MATERIALS AND METHODS: Experimental autoimmune prostatitis (EAP) was induced by intradermal prostate antigen immunization. Rats received Li-ESWT, with additional groups treated with the ferroptosis inducer RAS-selective lethal 3 (RSL3) or iron chelator deferoxamine (DFO). The rats were analyzed histologically and biochemically to assess immune responses, fibrosis, oxidative stress, ferroptosis markers, and related signaling. In vitro, Li-ESWT was applied to lipopolysaccharide (LPS)-stimulated RWPE-1 cells. The Integrin-β1-NRF2-xCT/GPX4 axis was modulated via siRNA or overexpression plasmid, with Ferrostatin-1 used as a reference control. The changes in NRF2-xCT/GPX4 expression, ferrous iron, and lipid peroxidation were evaluated to clarify the mechanisms by which Li-ESWT regulates ferroptosis.
RESULTS: EAP rats recapitulated key pathological features of CP/CPPS, which were alleviated by Li-ESWT. Specifically, Li-ESWT reduced the inflammatory response by inhibiting CD3⁺ T cells and CD68⁺ macrophages infiltration, suppressed fibrosis by preventing epithelial-mesenchymal transition and smooth muscle hyperplasia, and attenuated hyperalgesia by inhibiting mast cell degranulation. RSL3 exacerbated these pathological changes, whereas DFO attenuated them. Li-ESWT also suppressed oxidative stress and ferroptosis, as indicated by reduced reactive oxygen species and ferrous iron accumulation, lipid peroxidation, and ferroptosis-driving factors (ACSL4, LPCAT3, ALOX15, COX-2) levels. Li-ESWT also upregulated the Integrin-β1 and NRF2-xCT/GPX4 expression. In vitro, Integrin-β1 knockdown reduced NRF2, xCT, and GPX4 expression, abolishing the protective effects of Li-ESWT against LPS-induced ferroptosis, as evidenced by increased lipid peroxidation and ferrous iron accumulation. Similarly, NRF2 knockdown negated the anti-ferroptotic effect of Li-ESWT, whereas ectopic overexpression of xCT/GPX4 restored ferroptosis suppression.
CONCLUSIONS: Li-ESWT ameliorates inflammation, fibrosis, hyperalgesia in the CP/CPPS model, likely through ferroptosis mitigation via activating the Integrin-β1/NRF2 pathway.
MATERIALS AND METHODS: Experimental autoimmune prostatitis (EAP) was induced by intradermal prostate antigen immunization. Rats received Li-ESWT, with additional groups treated with the ferroptosis inducer RAS-selective lethal 3 (RSL3) or iron chelator deferoxamine (DFO). The rats were analyzed histologically and biochemically to assess immune responses, fibrosis, oxidative stress, ferroptosis markers, and related signaling. In vitro, Li-ESWT was applied to lipopolysaccharide (LPS)-stimulated RWPE-1 cells. The Integrin-β1-NRF2-xCT/GPX4 axis was modulated via siRNA or overexpression plasmid, with Ferrostatin-1 used as a reference control. The changes in NRF2-xCT/GPX4 expression, ferrous iron, and lipid peroxidation were evaluated to clarify the mechanisms by which Li-ESWT regulates ferroptosis.
RESULTS: EAP rats recapitulated key pathological features of CP/CPPS, which were alleviated by Li-ESWT. Specifically, Li-ESWT reduced the inflammatory response by inhibiting CD3⁺ T cells and CD68⁺ macrophages infiltration, suppressed fibrosis by preventing epithelial-mesenchymal transition and smooth muscle hyperplasia, and attenuated hyperalgesia by inhibiting mast cell degranulation. RSL3 exacerbated these pathological changes, whereas DFO attenuated them. Li-ESWT also suppressed oxidative stress and ferroptosis, as indicated by reduced reactive oxygen species and ferrous iron accumulation, lipid peroxidation, and ferroptosis-driving factors (ACSL4, LPCAT3, ALOX15, COX-2) levels. Li-ESWT also upregulated the Integrin-β1 and NRF2-xCT/GPX4 expression. In vitro, Integrin-β1 knockdown reduced NRF2, xCT, and GPX4 expression, abolishing the protective effects of Li-ESWT against LPS-induced ferroptosis, as evidenced by increased lipid peroxidation and ferrous iron accumulation. Similarly, NRF2 knockdown negated the anti-ferroptotic effect of Li-ESWT, whereas ectopic overexpression of xCT/GPX4 restored ferroptosis suppression.
CONCLUSIONS: Li-ESWT ameliorates inflammation, fibrosis, hyperalgesia in the CP/CPPS model, likely through ferroptosis mitigation via activating the Integrin-β1/NRF2 pathway.