A natural compound called ovalactone (OL) may offer a new treatment for rheumatoid arthritis (RA), according to research published in 2017. engineering. OL is a tetracyclic triterpenoid isolated from yellow leafy cortex. Researchers found that it reduces signs of arthritis by promoting the degradation of acyl-coenzyme A thioesterase 1 (ACOT1) through the ubiquitin-proteasome pathway and restoring the balance of unsaturated fatty acids.
This finding helps explain how OL acts at the molecular level against rheumatoid arthritis. They also identify ACOT1 as a potential new drug target and suggest that correcting disrupted fatty acid metabolism may be a useful strategy for treating RA.
Ovaclactone reduces joint swelling and damage
Researchers tested OL in rats with rheumatoid arthritis caused by complete Freund’s adjuvant (CFA). Animals were administered low (50 mg kg-1 d-1), medium (100 mg kg-1 d-1), and high (200 mg kg-1 d-1) doses of OL for 21 days.
The treatment significantly reduced the swelling in the joint. It also helped restore the normal structure of cartilage and synovium, the tissue that lines the inside of joints. Additionally, OL improved abnormal changes in immune organs such as the thymus and spleen.
The compound also altered immune activity within the joint. This resulted in the reduction of abnormally high levels of CD3+ T cells and CD68+ macrophages. At the same time, we transitioned macrophages from a pro-inflammatory M1 (CD86) state to an anti-inflammatory M2 (CD206) state. OL also restricted the development of CD4+ T cells into pro-inflammatory Th17 cells.
Blood tests showed that OL lowered several inflammatory molecules in a dose-dependent manner. These include IL-1β, IL-6, IL-17, and TNF-α. This treatment also reduced rheumatoid arthritis markers such as RF, CCP-Ab, CRP, and MMP-3.
Restoration of disturbed fatty acid metabolism
The researchers used multi-omics techniques, including metabolomics, MALDI mass spectrometry imaging, and proteomics, to examine how OLs influence biological processes throughout the body.
Their analysis found that rheumatoid arthritis inhibits the production and metabolism of several unsaturated fatty acids. OL helped correct these abnormalities, including changes related to arachidonic acid, linoleic acid, and alpha-linolenic acid.
In laboratory experiments, the effects of OL on RA synovial fibroblasts (SFs) were also investigated. These cells can overgrow in rheumatoid arthritis, causing inflammation, thickening of joint tissue, and damage to cartilage and bone.
OL slowed the proliferation of abnormal fibroblasts, promoted their apoptosis, and decreased the release of inflammatory cytokines.
ACOT1 is identified as a direct target
A series of tests, including cellular thermal shift assays, microscale thermophoresis, and surface plasmon resonance experiments, showed that OL binds directly to ACOT1.
The researchers measured the dissociation constants (Kd) of (6.18 ± 0.26) μmol·L-1 (analyzed by microscale thermophoresis (MST)) and (6.34 ± 0.38) μmol·L-1 (analyzed by surface plasmon resonance (SPR)).
OL increased proteasomal degradation of ACOT1 via ubiquitination. In this process, cells attach a molecular tag to a protein and send it to the proteasome, the cellular machinery responsible for breaking down unwanted proteins.
Reducing ACOT1 also reduced levels of the downstream protein stearoyl-CoA desaturase-1 (SCD1). This limited the activation of Janus kinase (JAK) signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K) protein kinase B (AKT) signaling pathways.
These pathways help regulate cell survival, growth, inflammation, and fibrosis. OL attenuated the inflammatory and fibrotic changes in SF by suppressing its activity.
Additional rescue experiments and studies using inhibitors supported the proposed mechanism. The results showed that OL produces anti-inflammatory, anti-proliferative, and pro-apoptotic effects by targeting ACOT1, regulating the arachidonic acid pathway, and influencing the downstream JAK-STAT/PI3K-AKT signaling pathway.
Possibility of new rheumatoid arthritis strategies
Rheumatoid arthritis is a chronic systemic autoimmune disease that affects approximately 1% of people worldwide. It occurs when the immune system mistakenly attacks healthy joint tissue, causing pain, swelling, stiffness, and progressive damage. Existing treatments are not equally effective for everyone and can cause serious side effects in some cases.
The new findings provide preclinical evidence that OL may serve as a potential therapeutic compound for rheumatoid arthritis. They also highlight ACOT1 and unsaturated fatty acid metabolism as promising targets for future drug development.
Because this study was conducted in rats and isolated cells, further research will be needed to determine whether OL is safe and effective in humans.
