Suppression of HMGB1 inhibits neuronal autophagy and apoptosis to improve neurological deficits in rats following intracerebral hemorrhage / 南方医科大学学报

OBJECTIVE@#To investigate the effect of suppressing high-mobility group box 1 (HMGB1) on neuronal autophagy and apoptosis in rats after intracerebral hemorrhage (ICH) in rats.@*METHODS@#Rat models of ICH induced by intracerebral striatum injection of 0.2 U/mL collagenase Ⅳ were treated with 1 mg/kg anti-HMGB1 mAb or a control anti-IgG mAb injected via the tail immediately and at 6 h after the operation (n=5). The rats in the sham-operated group (with intracranial injection of 2 μL normal saline) and ICH model group (n=5) were treated with PBS in the same manner after the operation. The neurological deficits of the rats were evaluated using modified neurological severity score (mNSS). TUNEL staining was used to detect apoptosis of the striatal neurons, and the expressions of HMGB1, autophagy-related proteins (Beclin-1, LC3-Ⅱ and LC3-Ⅰ) and apoptosis-related proteins (Bcl-2, Bax and cleaved caspase-3) in the brain tissues surrounding the hematoma were detected using Western blotting. The expression of HMGB1 in the striatum was detected by immunohistochemistry, and serum level of HMGB1 was detected with ELISA.@*RESULTS@#The rat models of ICH showed significantly increased mNSS (P < 0.05), which was markedly lowered after treatment with anti- HMGB1 mAb (P < 0.05). ICH caused a significant increase of apoptosis of the striatal neurons (P < 0.05), enhanced the expressions of beclin-1, LC3-Ⅱ, Bax and cleaved caspase-3 (P < 0.05), lowered the expressions of LC3-Ⅰ and Bcl-2 (P < 0.05), and increased the content of HMGB1 (P < 0.05). Treatment with anti-HMGB1 mAb obviously lowered the apoptosis rate of the striatal neurons (P < 0.05), decreased the expressions of Beclin-1, LC3-Ⅱ, Bax and cleaved caspase-3 (P < 0.05), increased the expressions of LC3-Ⅰ and Bcl-2 (P < 0.05), and reduced the content of HMGB1 in ICH rats (P < 0.05).@*CONCLUSION@#Down- regulation of HMGB1 by anti-HMGB1 improves neurological functions of rats after ICH possibly by inhibiting autophagy and apoptosis of the neurons.

Oroxylin A attenuates osteoarthritis progression by dual inhibition of cell inflammation and hypertrophy.

The imbalance between the anabolism and catabolism of the extracellular matrix (ECM) is of great importance to osteoarthritis (OA) development. Aberrant inflammatory responses and hypertrophic changes of chondrocytes are the main contributors to these metabolic disorders. In the present study, we found that Oroxylin A (ORA), a flavonoid compound derived from Oroxylum indicum, maintained ECM hemostasis of chondrocytes by Interleukin-1ß (IL-1ß) stimulation. Besides, it was demonstrated that IL-1ß induced over-production of inflammatory mediators was attenuated by ORA treatment. Moreover, ORA could rescue IL-1ß mediated hypertrophic alterations of chondrocytes. Mechanistically, ORA's protective effects were found to be associated with both NF-κB and Wnt/ß-catenin signaling inhibition. Meanwhile, molecular docking analysis revealed that ORA could strongly bind to the inhibitor kappa B kinaseß (IKKß) and dishevelled, Dsh Homolog 2 (Dvl2), the upstream molecules of the NF-κB axis and ß-catenin axis, respectively. In addition, ORA driven chondroprotective effects were also affirmed in a surgically induced OA mouse model. Taken together, the current study suggested that ORA might be a promising therapeutic option for the treatment of OA.