Plumbagin relieves rheumatoid arthritis through nuclear factor kappa-B (NF-κB) pathway

Chen, Shu; Lv, Meiyan; Xi, Yiyuan; Zheng, Jujia; Xu, Xiangwei

doi:10.1080/21655979.2022.2081756

Cited by 18 publications

(9 citation statements)

References 46 publications

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“…We also showed that the administration of TMZ or MTX significantly decreased the level of NFkB together with a considerable increase in IkB levels, with the best results produced by the combination of both drugs ( Figure 9 ). These results are consistent with previously reported studies that showed that the antiarthritic effects of various plant extracts, including Morus mesozygia leaf, Moringa leaf, difengpienol, plumbagin, Chinese herbal Huayu Qiangshen-Tongbi and Kashayams, are associated with their ability to reduce NFκB levels while increasing IκB expression in an RA rat model ( Saleem et al, 2020 ; Aswathy et al, 2021 ; Ariyo et al, 2022 ; Chen et al, 2022 ; Martin et al, 2022 ; Shu et al, 2022 ).…”

Section: Discussionsupporting

confidence: 93%

Deciphering the therapeutic potential of trimetazidine in rheumatoid arthritis via targeting mi-RNA128a, TLR4 signaling pathway, and adenosine-induced FADD-microvesicular shedding: In vivo and in silico study

Omran,

Alzahrani,

Ezzat

et al. 2024

Front. Pharmacol.

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Rheumatoid arthritis (RA) is a debilitating autoimmune condition characterized by chronic synovitis, joint damage, and inflammation, leading to impaired joint functionality. Existing RA treatments, although effective to some extent, are not without side effects, prompting a search for more potent therapies. Recent research has revealed the critical role of FAS-associated death domain protein (FADD) microvesicular shedding in RA pathogenesis, expanding its scope beyond apoptosis to include inflammatory and immune pathways. This study aimed to investigate the intricate relationship between mi-RNA 128a, autoimmune and inflammatory pathways, and adenosine levels in modulating FADD expression and microvesicular shedding in a Freund’s complete adjuvant (FCA) induced RA rat model and further explore the antirheumatoid potency of trimetazidine (TMZ). The FCA treated model exhibited significantly elevated levels of serum fibrogenic, inflammatory, immunological and rheumatological diagnostic markers, confirming successful RA induction. Our results revealed that the FCA-induced RA model showed a significant reduction in the expression of FADD in paw tissue and increased microvesicular FADD shedding in synovial fluid, which was attributed to the significant increase in the expression of the epigenetic miRNA 128a gene in addition to the downregulation of adenosine levels. These findings were further supported by the significant activation of the TLR4/MYD88 pathway and its downstream inflammatory IkB/NFB markers. Interestingly, TMZ administration significantly improved, with a potency similar to methotrexate (MTX), the deterioration effect of FCA treatment, as evidenced by a significant attenuation of fibrogenic, inflammatory, immunological, and rheumatological markers. Our investigations indicated that TMZ uniquely acted by targeting epigenetic miRNA128a expression and elevating adenosine levels in paw tissue, leading to increased expression of FADD of paw tissue and mitigated FADD microvesicular shedding in synovial fluid. Furthermore, the group treated with TMZ showed significant downregulation of TLR4/MYD88 and their downstream TRAF6, IRAK and NF-kB. Together, our study unveils the significant potential of TMZ as an antirheumatoid candidate, offering anti-inflammatory effects through various mechanisms, including modulation of the FADD-epigenetic regulator mi-RNA 128a, adenosine levels, and the TLR4 signaling pathway in joint tissue, but also attenuation of FADD microvesicular shedding in synovial fluid. These findings further highlight the synergistic administration of TMZ and MTX as a potential approach to reduce adverse effects of MTX while improving therapeutic efficacy.

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Section: Discussionsupporting

confidence: 93%

Deciphering the therapeutic potential of trimetazidine in rheumatoid arthritis via targeting mi-RNA128a, TLR4 signaling pathway, and adenosine-induced FADD-microvesicular shedding: In vivo and in silico study

Omran,

Alzahrani,

Ezzat

et al. 2024

Front. Pharmacol.

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“…In experimental rat models, administration of plumbagin was found to prevent the pathogenesis of PCOS, this is due to plumbagin being able to rescue the pathologic low apoptotic rate of GCs in PCOS [ 27 ]. Further, plumbagin was proven to have anti-inflammatory effects to ameliorate inflammation diseases such as rheumatoid arthritis and sepsis [ 28 – 30 ]. This suggests plumbagin may also play a role in suppressing the inflammation-related signals to attenuate the development of PCOS pathology.…”

Section: Introductionmentioning

confidence: 99%

Plumbagin rescues the granulosa cell’s pyroptosis by reducing WTAP-mediated N6-methylation in polycystic ovary syndrome

ZhaoWei

Liu

et al. 2022

J Ovarian Res

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The survival of ovary granulosa cells (GC) is critical in the initiation and progression of polycystic ovary syndrome (PCOS) in females. Here, we found that the PCOS process is accompanied by massive GC pyroptosis resulting from Caspase-1 inflammasome activation. Administration of plumbagin, an effective compound isolated from plant medicine, can prevent the pyroptosis of GC and the onset of PCOS. Mechanistic study indicates the over-activation of the inflammasome in GC is due to the upregulation of WTAP, a key regulator of the RNA N6-methylase complex. WTAP mediates the mRNA N6-methylation of NLRP3 inflammasome component ASC and enhances ASC RNA stability, which results in the overactivation of the inflammasome in GCs from the PCOS model. Plumbagin treatment suppresses the WTAP-mediated N6-methylation of ASC mRNA and reduces the pyroptosis of GCs. This study supports the profound potential of plumbagin in PCOS treatment. Graphical Abstract

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“…[87] PLB has been shown to improve inflammatory diseases such as sepsis and rheumatoid arthritis by exerting anti-inflammatory effects. [88][89][90] In a preclinical study on PCOS, it was discovered that the administration of PLB effectively prevented the progression of PCOS by decreasing the rate of apoptosis in GCs. This was achieved by PI3K/Akt/mTOR cascades.…”

Section: Pharmaceutical Strategiesmentioning

confidence: 99%

Inhibition of NLRP3 inflammasome—A potential mechanistic therapeutic for treatment of polycystic ovary syndrome?

Chamanara,

Hozouri,

Irandoost

2023

J Biochem & Molecular Tox

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This review article explores the relationship between the NOD‐like receptor protein 3 (NLRP3) inflammasome and the risk of developing polycystic ovary syndrome (PCOS). The NLRP3 inflammasome, a fundamental element of the innate immune system, plays a crucial role in the production of proinflammatory mediators and pyroptosis, a type inflammatory cell death. We conducted a thorough search on scientific databases to gather relevant information on this topic, utilizing relevant keywords. The reviewed studies indicated a correlation between PCOS and a higher incidence of granulosa cell (GC) death and the presence of ovarian tissue fibrosis. NLRP3 inflammasome stimulation and subsequent pyroptosis in GCs play a significant role in the pathophysiology of PCOS. Active NLRP3 inflammasome is involved in the production of inflammatory mediators like interleukin‐1β (IL‐1β) and IL‐18, contributing to the development of PCOS, particularly in overweight patients. Therefore, inhibiting NLRP3 activation and pyroptosis could potentially offer novel therapeutic strategies for PCOS. Some limited studies have explored the use of agents with antioxidant and anti‐inflammatory properties, as well as gene therapy approaches, to target the NLRP3 and pyroptosis signaling pathways. This study overview the understanding of the relationship between NLRP3 inflammasome activation, pyroptosis, and PCOS. It highlights the potential of targeting the NLRP3 inflammasome as an approach for treating PCOS. Nonetheless, further research and clinical trials are imperative to validate these results and explore the effectiveness of NLRP3 inflammasome inhibition in the management of PCOS.

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Plumbagin relieves rheumatoid arthritis through nuclear factor kappa-B (NF-κB) pathway

Cited by 18 publications

References 46 publications

Deciphering the therapeutic potential of trimetazidine in rheumatoid arthritis via targeting mi-RNA128a, TLR4 signaling pathway, and adenosine-induced FADD-microvesicular shedding: In vivo and in silico study

Deciphering the therapeutic potential of trimetazidine in rheumatoid arthritis via targeting mi-RNA128a, TLR4 signaling pathway, and adenosine-induced FADD-microvesicular shedding: In vivo and in silico study

Plumbagin rescues the granulosa cell’s pyroptosis by reducing WTAP-mediated N6-methylation in polycystic ovary syndrome

Inhibition of NLRP3 inflammasome—A potential mechanistic therapeutic for treatment of polycystic ovary syndrome?

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