BMP4 up-regulated by 630 nm LED irradiation is associated with the amelioration of rheumatoid arthritis.

Rheumatoid arthritis (RA) is caused by inflammatory response of joints with cartilage and damage of synovium and bone erosion. In our previous studies, it has showed that irradiation of 630 nm LED reduce inflammation of synovial fibroblasts and cartilage and bone destruction in RA. However, the key genes and mechanism in ameliorating RA by irradiation of 630 nm LED remains unknown. In this study, human fibroblast-like synoviocytes (FLS) cell line MH7A and primary human RA-FLSs were treated with TNF-α and 630 nm LED irradiation with the different energy density. The mRNA sequencing was performed to screen the differentially expressed genes (DEGs). In all datasets, 10 DEGs were identified through screening. The protein interaction network analysis showed that 8 out of the 10 DEGs interacted with each other including IL-6, CXCL2, CXCL3, MAF, PGF, IL-1RL1, RRAD and BMP4. This study focused on BMP4, which is identified as important morphogens in regulating the development and homeostasis. CCK-8 assay results showed that 630 nm LED irradiation did not affect the cell viability. The qPCR and ELISA results showed that TNF-α stimulation inhibited BMP4 mRNA and protein level and irradiation of 630 nm LED increased the BMP4 mRNA and protein level in MH7A cells. In CIA and transgenic hTNF-α mice models, H&E staining showed that irradiation of 630 nm LED decreased the histological scores assessed from inflammation and bone erosion, while BMP4 expression level was up-regulated after 630 nm LED irradiation. Pearson correlation analysis shown that BMP4 protein expression was negatively correlated with the histological score of CIA mice and transgenic hTNF-α mice. These results indicated that BMP4 increased by irradiation of 630 nm LED was associated with the amelioration of RA, which suggested that BMP4 may be a potential targeting gene for photobiomodulation.

The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts.

The FOX family of transcription factors was originally identified in 1989, comprising the FOXA to FOXS subfamilies. FOXO3, a well-known member of the FOXO subfamily, is widely expressed in various human organs and tissues, with higher expression levels in the ovary, skeletal muscle, heart, and spleen. The biological effects of FOXO3 are mostly determined by its phosphorylation, which occurs in the nucleus or cytoplasm. Phosphorylation of FOXO3 in the nucleus can promote its translocation into the cytoplasm and inhibit its transcriptional activity. In contrast, phosphorylation of FOXO3 in the cytoplasm leads to its translocation into the nucleus and exerts regulatory effects on biological processes, such as inflammation, aerobic glycolysis, autophagy, apoptosis, oxidative stress, cell cycle arrest and DNA damage repair. Additionally, FOXO3 isoform 2 acts as an important suppressor of osteoclast differentiation. FOXO3 can also interfere with the development of various diseases, including inhibiting the proliferation and invasion of tumor cells, blocking the production of inflammatory factors in autoimmune diseases, and inhibiting ß-amyloid deposition in Alzheimer's disease. Furthermore, FOXO3 slows down the aging process and exerts anti-aging effects by delaying telomere attrition, promoting cell self-renewal, and maintaining genomic stability. This review suggests that changes in the levels and post-translational modifications of FOXO3 protein can maintain organismal homeostasis and improve age-related diseases, thus counteracting aging. Moreover, this may indicate that alterations in FOXO3 protein levels are also crucial for longevity, offering new perspectives for therapeutic strategies targeting FOXO3.

The gut-joint axis mediates the TNF-induced RA process and PBMT therapeutic effects through the metabolites of gut microbiota.

The gut-joint axis, one of the mechanisms that mediates the onset and progression of joint and related diseases through gut microbiota, and shows the potential as therapeutic target. A variety of drugs exert therapeutic effects on rheumatoid arthritis (RA) through the gut-joint axis. However, the anti-inflammatory and immunomodulatory effect of novel photobiomodulatory therapy (PBMT) on RA need further validation and the involvement of gut-joint axis in this process remains unknown. The present study demonstrated the beneficial effects of PBMT on RA, where we found the restoration of gut microbiota homeostasis, and the related key pathways and metabolites after PBMT. We also discovered that the therapeutic effects of PBMT on RA mainly through the gut-joint axis, in which the amino acid metabolites (Alanine and N-acetyl aspartate) play the key role and rely on the activity of metabolic enzymes in the target organs. Together, the results prove that the metabolites of amino acid from gut microbiota mediate the regulation effect on the gut-joint axis and the therapeutic effect on rheumatoid arthritis of PBMT.