17ß-estradiol attenuates rat articular chondrocyte injury by targeting ASIC1a-mediated apoptosis.

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17ß-estradiol (17ß-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17ß-E2 in acid-induced chondrocyte injury and to determine the effect of 17ß-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17ß-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17ß-E2 was shown to reduce protein levels of ASIC1a through the ERα receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17ß-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.

4-Amino-2-trifluoromethyl-phenyl retinate induced differentiation of human myelodysplastic syndromes SKM-1 cell lines by up-regulating DDX23.

Myelodysplastic syndrome (MDS) is a heterogeneously cloned hematopoietic stem cell malignancy with a high risk of developing acute myeloid leukemia (AML). 4-amino-2-trifluoromethyl-phenyl resinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed in our group, was proved to be a tumor inhibitor in diverse types of cancer cells in vitro. However, little has been known about the effects of ATPR on MDS. To analyze if and to what extent it's anti-tumor activity on MDS, we performed CCK-8, Flow Cytometry, Wright-Giemsa staining, qRT-PCR, and Western blot to analyze the SKM-1 cells state after ATPR treatment in multiplex detection angles. As expected, our results proved that ATPR could effectively induce cell differentiation and reduce cell proliferation of SKM-1 cell lines. Subsequently, to further analyze the potential mechanisms, we applied Label-free proteomic techniques to discover relevant protein that may be involved. Most notably, a series of factors related to RNA behavioral regulation were changed. Among them, we demonstrated that DEAD-box RNA helicase DDX23 was abnormally ablated in MDS patients and could be restored after ATPR treatment in vitro. Besides, our results suggested that ATPR-induced SKM-1 cell maturation was counteracted when knockdown DDX23, underscoring that DDX23 might be involved. In conclusion, we confirmed that ATPR could induce SKM-1 cells differentiation and its positive influence of DDX23 may provide a new idea to relieve MDS.

Necrostatin-1 ameliorates adjuvant arthritis rat articular chondrocyte injury via inhibiting ASIC1a-mediated necroptosis.

Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.