ABSTRACT
Withaferin A (WFA) is a natural compound separated from the medicinal plant Withania somnifera. As reported, it has the potential to safely cure rheumatoid arthritis (RA) in animal models. Nevertheless, the action mechanism of WFA in treating RA has not been completely illuminated. The study was to explore the action and mechanism of WFA on arthritic rats. First, a collagen-induced arthritis rat model was established. WFA administration alleviated inflammation and injury in arthritic rats. Subsequently, fibroblast synovial cells (FLS) of arthritic rats were separated and cell proliferation and apoptosis abilities were tested. It was found that WFA was available to repress FLS cell proliferation and accelerate apoptosis. MicroRNA-1297 was downregulated in RA patients. Clinical correlation analysis suggested that miR-1297 in the serum of RA patients was negatively associated with pro-inflammatory factors interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and RA diagnostic indexes (RF, DAS28). In the meantime, miR-1297 had superior diagnostic value in differentiating RA patients from healthy people. Karyopherin α2 (KPNA2) was the downstream target of miR-1297, while miR-1297 negatively modulated KPNA2 expression. Importantly, WFA further restrained KPNA2 expression via elevating miR-1297 in functional rescue experiments, thereby treating inflammation and injury in arthritic rats and repressing FLS cell proliferation and activation. In short, WFA alleviated inflammation and joint damage in arthritic rats via elevating miR-1297 to target KPNA2.
Subject(s)
Arthritis, Rheumatoid , MicroRNAs , Withanolides , alpha Karyopherins , Animals , Humans , Rats , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Cell Proliferation/physiology , Cells, Cultured , Fibroblasts/metabolism , Inflammation/metabolism , Interleukin-6/metabolism , MicroRNAs/metabolism , Tumor Necrosis Factor-alpha/metabolism , Withanolides/therapeutic useABSTRACT
OBJECTIVE: To evaluate the molecular diagnosis marker of papillary thyroid carcinoma (PTC), the relationship between lymphatic metastasis of central neck compartment PTC, and the operation indication of prophylactic central neck dissection. METHODS: We conducted a retrospective study, including 275 PTC patients and detected their BRAF mutation rates during 2012 and 2014 and explored the risk factors of the central node lymphatic metastasis by Logistic regression model. RESULTS: Of the 275 PTC patients, 224 (81.5%) were female and 51 (18.5%) were male. BRAF mutational rates were 53.8% (148/275) and lymphatic metastasis 57.8% (159/275). Multivariate analysis showed calcification (OR(adjusted)=1.47, 95%CI: 1.10-1.98, P=0.01), tumor diameter (OR(adjusted)=1.48, 95%CI: 1.04-2.30, P=0.048) and age (OR(adjusted)=1.48, 95%CI: 1.04-2.30, P=0.048) were associated with lymphatic metastasis. In stratified analysis, BRAF mutation (OR(adjusted)=3.19, 95%CI: 1.18-9.43, P=0.023) in clear boarder group and BRAF mutation (OR(adjusted)=4.84, 95%CI: 1.68-13.84, P=0.003) in calcification group were more likely to have lymphatic metastases. CONCLUSION: Central neck metastasis takes up a high ratio in papillary thyroid cancer patients, BRAF mutation in papillary thyroid carcinoma is a characteristic molecular event. Furthermore, patients with calcification under ultrasound detection, lower age group and longer tumor diameter are more susceptible to suffer central neck metastasis. Especially for stratified analysis, non-calcified BRAF mutation or BRAF mutation with clear border under ultrasound detection are more susceptible to suffer central neck metastasis, and radical prophylactic central neck dissection should be carried on for these patients.
