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<p>The monocyclic monoterpenoid ocimene (OC) has undergone pharmacological testing as a possible inhibitor of pyroptosis triggered by TLR4/NLRP3 pathway, involved in progression of several diseases, such as rheumatoid arthritis (RA), inflammation, and chronic pain. Arthritis was evaluated using formaldehyde-induced arthritis rat model. Potential targets of OC against adjuvant-induced arthritis (AIA) in rats were examined using pharmacological testing and an integrative research strategy. CFA (o.1&#xa0;ml) was used to assess the anti-arthritic effects of OC during a 28-day study period. To ascertain the therapeutic effects and identify pharmacological mechanisms, a variety of techniques were used, including macroscopic examination, gene expression profiling using PCR, an estimate of PGE-2, anti-CCP, 5-LOX besides markers of oxidative stress via ELISA, as well as radiographic examination. Oral administration of OC (50, 100, and 200&#xa0;mg/kg) significantly (<i>p</i> &lt; 0.001) decreased paw edema in the formaldehyde-induced arthritis. Inhibition of the NLRP3 inflammasome led to a significant downregulation of NFκB, caspase-1, and ASC, a decrease in the release of IL-1β and IL-18, and a modulation of GSDMD-mediated pyroptosis, hence reducing bone erosion and joint inflammation by blocking TLR4/NLRP3/GSDMD signaling. Levels of IL-4 and IL-10 were elevated in comparison to the disease control group. In addition, ELISA revealed that levels of the primary mediators of inflammation PGE-2 and 5-LOX, as well as malondialdehyde (MDA), a marker of oxidative stress, were significantly lower in the treated rats. In contrast, other antioxidant markers, such as glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), were upregulated following the treatment. In addition, OC altered the actions of the COX enzyme, which reduced inflammation and eased RA-related discomfort. Therefore, it can be concluded that OC exhibited anti-arthritic attributes via modulation of TLR4/NLRP3/GSDMD signaling-mediated pyroptosis.</p>

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Ocimene mitigates pyroptosis through TLR4/NLRP3-mediated mechanisms in CFA-induced inflammation

  • 期刊论文

  • 发表日期：

    2025年4月23日

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  • Iqra Laraib,
  • Sumera Qasim,
  • Ambreen Malik Uttra,
  • Shaimaa R. Ahmed

摘要

The monocyclic monoterpenoid ocimene (OC) has undergone pharmacological testing as a possible inhibitor of pyroptosis triggered by TLR4/NLRP3 pathway, involved in progression of several diseases, such as rheumatoid arthritis (RA), inflammation, and chronic pain. Arthritis was evaluated using formaldehyde-induced arthritis rat model. Potential targets of OC against adjuvant-induced arthritis (AIA) in rats were examined using pharmacological testing and an integrative research strategy. CFA (o.1 ml) was used to assess the anti-arthritic effects of OC during a 28-day study period. To ascertain the therapeutic effects and identify pharmacological mechanisms, a variety of techniques were used, including macroscopic examination, gene expression profiling using PCR, an estimate of PGE-2, anti-CCP, 5-LOX besides markers of oxidative stress via ELISA, as well as radiographic examination. Oral administration of OC (50, 100, and 200 mg/kg) significantly (p < 0.001) decreased paw edema in the formaldehyde-induced arthritis. Inhibition of the NLRP3 inflammasome led to a significant downregulation of NFκB, caspase-1, and ASC, a decrease in the release of IL-1β and IL-18, and a modulation of GSDMD-mediated pyroptosis, hence reducing bone erosion and joint inflammation by blocking TLR4/NLRP3/GSDMD signaling. Levels of IL-4 and IL-10 were elevated in comparison to the disease control group. In addition, ELISA revealed that levels of the primary mediators of inflammation PGE-2 and 5-LOX, as well as malondialdehyde (MDA), a marker of oxidative stress, were significantly lower in the treated rats. In contrast, other antioxidant markers, such as glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), were upregulated following the treatment. In addition, OC altered the actions of the COX enzyme, which reduced inflammation and eased RA-related discomfort. Therefore, it can be concluded that OC exhibited anti-arthritic attributes via modulation of TLR4/NLRP3/GSDMD signaling-mediated pyroptosis.