Despite the increasing availability of treatments for rheumatoid arthritis (REA), the potential adverse effects and relatively high cost of long-term drugs remain constant concerns. This is why basic research is tasked with seeking alternatives, including those of natural origin. Increasing studies have shown that many herbal medicines are effective for REA treatments, such as Tripterygium wilfordii, Uncaria tomentosa and Curcuma longa, among others. Triptolide (TPL), a major active component isolated from Tripterygium wilfordii, plays a strong anti-inflammatory role in REA. However, the clinical use of TPL is limited due to its narrow therapeutic window and severe toxicities, including toxicity to the liver, kidneys, and gonads. Curcumin (CUR) is an active component of Curcuma longa, which has antioxidant, anti-inflammatory, antiangiogenic and antitumor effects.
Due to these effects, CUR could improve clinical outcomes and delay disease progression in patients with ARE. It has been shown that suitable combination therapy, new dosage forms and new administration routes can effectively reduce the dosage and increase the effect. Recently, it has been reported that TPL and CUR can enhance the level of IL-17 and inhibit NF-κB signaling. Therefore, scientists have speculated that TPL and CUR may be able to control the IL-17/NF-κB signaling pathway to mitigate the effects of ARE. Numerous studies have shown that a high number of Th17 cells and overexpression of IL-17 are consistently detected in patients with ARE. Th17 cells, which have a pro-inflammatory predisposition, play an important role in disease activity and severity of ARE by regulating the adaptive immune response.
IL-17, secreted by Th17 cells, stimulates the production of pro-inflammatory cytokines and chemokines such as IL-1, IL-6, and TNF-α, which contribute to abnormal synovial hyperplasia. In addition, macrophages and mast cells, which are associated with inflammatory responses and subsequently induce joint destruction, are also major sources of IL-17. Recent studies indicate that deregulated activation of NF-κB contributes to the pathogenesis of ARE. TPL and CUR have been found to suppress the increase in the IL-17/NF-κB signaling pathway, thereby reducing excessive pro-inflammatory factors, including IL-1β, IL-6, and TNF-α. Synovial fibroblast growth in REA likely results from an imbalance between cell proliferation, survival, and death, exhibiting aggressive behavior that increases invasiveness into the extracellular matrix and aggravates joint damage, similar to tumor conditions.
Experimentally, TPL+CUR inhibited this proliferation by regulating the abnormal expression of CDK2 and p21, two key regulators of the cell cycle. The efficacy of TPL in treating REA may be associated with the induction of apoptosis, reduction of pro-inflammatory cytokine production, mediation of NF-κB signaling pathway, and regulation of Bcl-2-related pathway. CUR has been studied for its anti-inflammatory and antioxidant properties, and it can also promote apoptosis in REA models by directly regulating the PI3K/AKT pathway. According to this evidence, it is suggested that an improved healing effect on REA may be achieved through the TPL+CUR combination. Their anti-inflammatory properties, inhibition of cell proliferation, and induction of apoptosis probably contribute to suppressing the IL-17/NF-κB signaling pathway.
Compared to other studies, scientists administered relatively low doses of TPL (100 µg/kg/day) and CUR (100 mg/kg/day) in vivo. This regimen significantly alleviated symptoms, joint inflammation and synovial damage in rats with REA. These results suggest that the combination of CUR+TPL may allow a reduction in TPL dosage while maintaining therapeutic efficacy, highlighting a synergistic effect in the treatment of RA. Furthermore, the integration of TPL with CUR may open new avenues for personalized medicine approaches in the treatment of RA. This strategy not only aims to optimize the therapeutic benefits of TPL, but also seeks to reduce the overall drug burden and improve the quality of life of patients suffering from this chronic and debilitating disease.
- edited by Dr. Gianfrancesco Cormaci, PhD, Specialist in Clinical Biochemistry.
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