Oridonin inhibits SASP by blocking p38 and NF-κB pathways in senescent cells
Shusuke Yasuda1, Mano Horinaka1, Yosuke Iizumi2
1Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Abstract:
Cellular senescence is a state of irreversible cell growth arrest that functions as a biological defense mechanism against severe DNA damage. Senescent cells with DNA damage produce pro-inflammatory cytokines, such as IL-6 and IL-8, and this phenomenon is called the senescence-associated secretory phenotype (SASP). SASP factors have been implicated in various disorders, including cancer. We performed a screening assay and identified oridonin as a candidate SASP inhibitor. Oridonin is an active diterpenoid that is isolated from Isodon plants and has been reported to exhibit anti-inflammatory, antibacterial, antioxidant, and antitumor activities. It reduced the secretion of IL-6 and IL-8 in senescent cells at the protein and mRNA levels. Oridonin also inhibited p65 subunit of NF-κB activity. However, oridonin did not affect SA β-gal activity and enhanced the expression of p21. The expression and phosphorylation of p38 were down-regulated by oridonin. The p38 inhibitor SB203580 inhibited the secretion of IL-8, slightly inhibited the secretion of IL-6, and did not affect NF-κB activity. Therefore, the NF-κB and p38 pathways may contribute to the inhibition of SASP by oridonin. Oridonin has potential as a therapeutic agent for SASP-related diseases.
Insights
Oridonin, a natural compound, effectively inhibits the senescence-associated secretory phenotype (SASP) by reducing pro-inflammatory cytokines IL-6 and IL-8. This suggests oridonin
Area of Science:
- Cellular Biology
- Molecular Biology
- Pharmacology
Background:
- Cellular senescence is a critical defense against DNA damage, but senescent cells can promote inflammation via the senescence-associated secretory phenotype (SASP).
- SASP factors, including IL-6 and IL-8, are linked to various diseases, notably cancer.
- Identifying therapeutic targets to modulate SASP is crucial for treating SASP-related disorders.
Purpose of the Study:
- To identify novel inhibitors of the senescence-associated secretory phenotype (SASP).
- To investigate the molecular mechanisms by which oridonin suppresses SASP.
- To evaluate the therapeutic potential of oridonin for SASP-related diseases.
Main Methods:
- Screening assays were employed to identify potential SASP inhibitors.
- Oridonin's effect on IL-6 and IL-8 secretion was assessed at protein and mRNA levels.
- NF-κB and p38 pathway activities were analyzed in response to oridonin treatment.
- SA β-gal activity and p21 expression were measured to assess senescence markers.
Main Results:
- Oridonin significantly reduced IL-6 and IL-8 secretion in senescent cells.
- Oridonin inhibited the activity of the p65 subunit of NF-κB.
- Oridonin down-regulated the expression and phosphorylation of p38.
- Oridonin did not affect SA β-gal activity but enhanced p21 expression.
Conclusions:
- Oridonin acts as a potent inhibitor of the senescence-associated secretory phenotype (SASP).
- The inhibitory effects of oridonin on SASP are mediated through the modulation of NF-κB and p38 signaling pathways.
- Oridonin demonstrates significant therapeutic potential for diseases associated with SASP.
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