Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation

Hong, Zhongyang; Tie, Qingsong; Zhang, Lingling

doi:10.1016/j.intimp.2022.109271

Cited by 4 publications

(2 citation statements)

References 144 publications

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“…Similarly, the levels of the chemokine CXCL12 were elevated in the synovium and bone tissue of RA patients, and it has a pronounced activating effect on mature osteoclasts by inducing bone resorption activity and specific MMP-9 enzyme release [ 40 ]. Furthermore, recent studies have highlighted the importance of synovial hypoxia as a contributing factor in the development of RA, with the involvement of the hypoxia-inducible factor HIF1A being significant in this context [ 41 , 42 ]. Additionally, MIF has been suggested as a therapeutic target for RA [ 43 ], while JAK inhibitors appear to be an important treatment option for RA patients who are difficult to treat [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model

Liu,

Luo,

Fan

et al. 2024

BMC Complement Med Ther

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Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the destruction of synovial tissue and articular cartilage. Huangqi-Guizhi-Wuwu-Decoction (HGWD), a formula of Traditional Chinese Medicine (TCM), has shown promising clinical efficacy in the treatment of RA. However, the synergistic effects of key response components group (KRCG) in the treatment of RA have not been well studied. Methods The components and potential targets of HGWD were extracted from published databases. A novel node influence calculation model that considers both the node control force and node bridging force was designed to construct the core response space (CRS) and obtain key effector proteins. An increasing coverage coefficient (ICC) model was employed to select the KRCG. The effectiveness and potential mechanism of action of KRCG were confirmed using CCK-8, qPCR, and western blotting. Results A total of 796 key effector proteins were identified in CRS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses confirmed their effectiveness and reliability. In addition, 59 components were defined as KRCG, which contributed to 85.05% of the target coverage of effective proteins. Of these, 677 targets were considered key reaction proteins, and their enriched KEGG pathways accounted for 84.89% of the pathogenic genes and 87.94% of the target genes. Finally, four components (moupinamide, 6-Paradol, hydrocinnamic acid, and protocatechuic acid) were shown to inhibit the inflammatory response in RA by synergistically targeting the cAMP, PI3K-Akt, and HIF-1α pathways. Conclusions We have introduced a novel model that aims to optimize and analyze the mechanisms behind herbal formulas. The model revealed the KRCG of HGWD for the treatment of RA and proposed that KRCG inhibits the inflammatory response by synergistically targeting cAMP, PI3K-Akt, and HIF-1α pathways. Overall, the novel model is plausible and reliable, offering a valuable reference for the secondary development of herbal formulas.

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Section: Resultsmentioning

confidence: 99%

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model

Liu,

Luo,

Fan

et al. 2024

BMC Complement Med Ther

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“…In addition to the TFs discussed above, other TFs such as, hypoxiainducible factor (HIF) and nuclear factor-erythroid 2-related factor-2 (Nrf2), are also implicated in the pathogenesis of RA. In RA synovium, HIF is activated during hypoxia, which aggravates angiogenesis, synovial hyperplasia, and pannus formation (157)(158)(159). TNF, IL-1b, and IL-33 can induce the expression of HIF in RASFs and resident macrophages (157).…”

Section: Other Tfsmentioning

confidence: 99%

Targeting transcription factors for therapeutic benefit in rheumatoid arthritis

et al. 2023

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Rheumatoid arthritis (RA) is a destructive inflammatory autoimmune disease that causes pain and disability. Many of the currently available drugs for treating RA patients are aimed at halting the progression of the disease and alleviating inflammation. Further, some of these treatment options have drawbacks, including disease recurrence and adverse effects due to long-term use. These inefficiencies have created a need for a different approach to treating RA. Recently, the focus has shifted to direct targeting of transcription factors (TFs), as they play a vital role in the pathogenesis of RA, activating key cytokines, chemokines, adhesion molecules, and enzymes. In light of this, synthetic drugs and natural compounds are being explored to target key TFs or their signaling pathways in RA. This review discusses the role of four key TFs in inflammation, namely NF-κB, STATs, AP-1 and IRFs, and their potential for being targeted to treat RA.

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Intermittent fasting reduces inflammation and joint damage in a murine model of rheumatoid arthritis: insights from transcriptomic and metagenomic analyses

Cuevas-Martínez,

González-Chávez,

Bermúdez

et al. 2024

BMC Rheumatol

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Background Intermittent fasting (IF) has shown benefits in various pathological conditions. Although its anti-inflammatory potential has been recognized, its effects on the mechanism underlying rheumatoid arthritis (RA) remain insufficiently characterized. This study aimed to investigate the effects of IF in a murine model of RA. Methods Collagen-induced arthritis (CIA) was developed in sixteen male DBA/1 mice, randomly assigned to two groups, with one undergoing IF every other day for four weeks. The effects of IF on joint inflammation and remodeling were evaluated clinically, histologically, and through tomography. Transcriptomic changes were characterized using expression microarrays, validated by RT-qPCR, and confirmed by immunohistochemistry. Additionally, modifications in gut microbiota were assessed through 16 S sequencing. Results Mice subjected to IF significantly reduced the incidence and severity of clinical arthritis. Histological and radiographic assessments confirmed a decrease in inflammation and joint damage. Transcriptomic analysis revealed that IF led to the upregulation of 364 genes and the downregulation of 543 genes, with notable reductions in inflammatory signaling pathways associated with RA-related genes, including Cd72 , Cd79a , Ifna, Il33 , and Bglap 2. Notably, IL33 emerged as a pivotal mediator in the inflammatory processes mitigated by fasting. Key regulators associated with IF effects, such as CEBPA , FOXO1 , HIF1A , PPARG , and PPARA , were identified, indicating a complex interplay between metabolic and inflammatory pathways. Furthermore, differential expression of microRNAs and lncRNAs, including miR-15b , miR-103-2 , miR-302a , miR-6985 , and miR- 5624, was observed. Metagenomic analysis indicated that IF enhanced the abundance and diversity of the gut microbiome, explicitly promoting anti-inflammatory bacterial populations, notably within the genus Ruminococcaceae . Conclusion Our findings suggest that IF exerts significant anti-inflammatory and immunoregulatory effects in the context of CIA. Given its non-risky nature, further investigation into the potential benefits of IF in patients with RA is warranted. Clinical trial number Not applicable. Supplementary Information The online version contains supplementary material available at 10.1186/s41927-024-00436-0.

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Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation

Cited by 4 publications

References 144 publications

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model

Targeting transcription factors for therapeutic benefit in rheumatoid arthritis

Intermittent fasting reduces inflammation and joint damage in a murine model of rheumatoid arthritis: insights from transcriptomic and metagenomic analyses

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