Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H2O2‐treated rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs) by the Nrf2–Keap1 signaling pathway. We found that 5 µM H2O2 promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA‐FLSs. However, Res could reverse these effects in 5 µMH2O2‐treated RA‐FLSs by (1) promoting expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), (2) reducing expression of Kelch‐like ECH–related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor‐κB (NF‐κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl‐2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA‐FLSs, Res addition did not increase the expression of Nrf2 or HO‐1 to reduce the production of mitochondrial ROS caused by 5 µM H2O2. Res reduced the Bcl‐2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF‐κB and proliferation and migration of RA‐FLSs, to induce apoptosis. Targeting the Nrf2–Keap1 pathway may be a relevant aim of using Res in the treatment of RA.
Resveratrol is a polyphenol derivatives which exhibits a pro-apoptotic effect in a variety of human cancers by triggering mitochondria apoptosis pathway and autophagy. However, there are scarcely reports on its apoptosis-promoting effect in abnormal proliferation fibroblast-like synoviocytes (FLSs). In this study, we investigated the underlying mechanism and apoptosis-inducing effects of resveratrol on the abnormal proliferation of FLSs in adjuvant-arthritis (AA) rats. Since using resveratrol for 12 days resulted in a significant decreasing the swelling degree of the paw, reducing malondialdehyde (MDA) content and enhancing superoxide dismutase (SOD) activity, antioxidant capacity, glutathione peroxidase and glutathione reductase ratio in AA rats. Moreover, we found that 5 μMH2O2 could increase cells viability, Beclin1, LC3A/B, MnSOD, SIRT3 protein expression in FLSs. But, resveratrol could reverse these effects by changing mitochondrial membrane potential (Δψm) to promote mitochondrial reactive oxygen species (mtROS) generation in 5 μMH2O2-treatment FLSs. These results suggest that oxidative stress existed in AA rats. Resveratrol could suppress oxidative stress in AA rats and increase mtROS production by reducing autophagy protein Beclin1, LC3A/B and oxidative stress protein MnSOD to promoted the apoptosis of FLSs. Thus, targeting of mtROS may be a crucial mechanism of resveratrol confers patients with rheumatoid arthritis.
Tumor‐infiltrating immune cells play a crucial role in tumor progression and response to treatment. However, the limited studies on infiltrating immune cells have shown inconsistent and even controversial results for osteosarcoma (OS). In addition, the dynamic changes of infiltrating immune cells after neoadjuvant chemotherapy are largely unknown. We downloaded the RNA expression matrix and clinical information of 80 OS patients from the TARGET database. CIBERSORT was used to evaluate the proportion of 22 immune cell types in patients based on gene expression data. M2 macrophages were found to be the most abundant immune cell type and were associated with improved survival in OS. Another cohort of pretreated OS samples was evaluated by immunohistochemistry to validate the results from CIBERSORT analysis. Matched biopsy and surgical samples from 27 patients were collected to investigate the dynamic change of immune cells and factors before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy was associated with increased densities of CD3+ T cells, CD8+ T cells, Ki67 + CD8+ T cells and PD‐L1+ immune cells. Moreover, HLA‐DR‐CD33+ myeloid‐derived suppressive cells (MDSC) were decreased after treatment. We determined that the application of chemotherapy may activate the local immune status and convert OS into an immune “hot” tumor. These findings provide rationale for investigating the schedule of immunotherapy treatment in OS patients in future clinical trials.
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, which is a heterogeneous disease and main risk factors are associated with inflammation, family history, genetic mutations, epigenetics, and so on. Ring finger domain proteins have been reported involved in carcinogenesis, whereas their roles in CRC are rarely studied. Here, we reanalyzed the expression of 202 RNF family members in CRC using published microarray data from GEO database and found that RNF183 is markedly upregulated in tumor tissues. RNF183 high expression is significantly associated with tumor size (P=0.012), tumor invasive depth (P=0.004), TNM stage (P=0.01), and distant metastasis (P=0.009). CRC patients with high expression of RNF183 have poor overall survival (P<0.001) and progression-free survival (P<0.001). Functional studies suggest that RNF183 facilitates growth, migration, and invasion of CRC cells in vitro and promotes tumor proliferation and metastasis in vivo. Mechanistically, RNF183 activates NF-κB signal pathway through P65 and stimulates the transcription of multifunctional chemokine IL-8. Blockage of NF-κB by small molecule inhibitor or depletion of IL-8 by siRNA attenuates the function of RNF183 to promote cell migration. Moreover, the regulation of RNF183 on IL-8 transcription and cell viability/motility is dependent on its E3 ubiquitin ligase activity. Our study provided proof of principle to show that RNF183 promotes proliferation and metastasis of CRC cells via activation of NF-κB-IL-8 axis.
The present study was designed to explore the biological role of resveratrol (RES) in rheumatoid arthritis (RA) and the underlying mechanism. The adjuvant‐induced arthritic rats were administered RES on the 12th day after model establishment, and then arthritis assessment, oxidative stress measurement, histological examination, and immunohistochemical staining were performed. The primary rat fibroblast‐like synoviocytes (FLS) were isolated and treated with RES in vitro and then cell proliferation and apoptosis assay were examined. Chromatin immunoprecipitation assay, luciferase reporter assay, intracellular reactive oxygen species (ROS) determination, western blot, and quantitative real time‐polymerase chain reaction (qRT‐PCR) were performed to investigate the mechanisms. RES administration decreased arthritis scores and serum levels of antioxidant enzymes, attenuated paw swelling, synovial hyperplasia, inflammatory cell infiltration, and cartilage degradation, as well as inhibited synoviocyte proliferation in synovial tissues. Further investigation indicated that RES inhibited ROS production and FLS proliferation through activating the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway. NF‐κB was confirmed to negatively regulate miR‐29a‐3p and miR‐23a‐3p expression by directly binding to its promoter. Mechanistic analyses further revealed that Kelch‐like erythroid cell‐derived protein with CNC homology (ECH)‐associated protein 1 (Keap1), a negative regulator of Nrf2, was a downstream target of miR‐29a‐3p, while miR‐23a‐3p directly targeted cullin3 (cul3), a master regulator of ubiquitination and degradation of Nrf2. Together, the present study provided evidence that RES ameliorated RA through activation of Nrf2‐ARE signaling pathway via SIRT1/NF‐κB/miR‐29a‐3p/Keap1 and SIRT1/NF‐κB/miR‐23a‐3p/cul3 signaling pathway.
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