ABSTRACT
BACKGROUND:Whether NOD-like receptor family,pyrin domain containing 3 (NLRP3) inflammasome is involved in hypoxia-induced skeletal muscle mitochondrial dysfunction,and the underlying mechanism remain unclear.OBJECTIVE:To observe the effect of NLRP3 inflammasome inhibitor VX-765 on skeletal muscle mitochondrial function,and to explore the role of NLRP3 inflammasome in hypoxia-induced mitochondrial dysfunction.METHODS:Thirty Sprague-Dawley rats were randomly divided into three groups:normoxia,hypoxia,and hypoxia plus VX-765 groups.The rats in the hypoxia group were subjected to hypoxia exposure in normobaric hypoxic tent with 11.3％ O2.The hypoxia plus VX-765 group rats were given the intraperitoneal injection of VX-765 (50 mg/kg) daily.All of the interventions lasted for 4 weeks.RESULTS AND CONCLUSION:VX-765 in hypoxia markedly inhibited the expression of NLRP3 and apoptosis-associated speck-like protein,attenuated caspase-1 activity and interleukin-1β content,and suppressed mitochondrial H2O2 generation.In addition,VX-765 in hypoxia markedly enhanced the expression of mitochondrial peroxisome proliferator-activated receptor y coactivator 1-α and cyclooxygenase ⅣV,elevated mitochondrial membrane potent and ATP synthetase activity.These results indicate that hypoxia induces skeletal muscle dysfunction through activating NLRP3 inflammasome and impairing mitochondrial function.The hypoxia-induced mitochondrial dysfunction enhances reactive oxygen species generation and further triggers interleukin-1 β production via the NLRP3 inflammasome activation.In turn,interleukin-lβ further impairs mitochondrial function through suppresseing peroxisome proliferator-activated receptor y coactivator 1 o,resulting in a vicious circle between NLRP3 inflammasome activation and mitochondrial dysfunction.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate effects of low-dose cyclophosphamide and prednisone (CP) metronomic chemotherapy on microvessel density of bone marrow, serum vascular endothelial growth factor (VEGF) and platelet derived growth factor BB (PDGF-BB)in multiple myeloma (MM) patients.</p><p><b>METHODS</b>54 refractory or relapsed MM patients were treated with CP metronomic chemotherapy consisted of oral cyclophosphamide (CTX, 50 mg/d) and prednisone (Pred, 15 mg/d). Bone marrow and peripheral blood of each patient were collected before and 2, 4, 6 months after treatment. Among the 37 assessable patients, 30 cases were responsive with the response rate of 81.08%. Another 17 cases were follow-uped less than 6 months or failure to obtain serum samples or lost to follow-up. Microvessel density of bone marrow was measured by immunohistochemistry and serum VEGF/PDGF-BB expression was analyzed by ELISA in the 37 assessable patients.</p><p><b>RESULTS</b>2, 4, 6 months following CP metronomic chemotherapy, microvessel densities of bone marrow in the responders were 33.1 ± 4.8/HP, 24.8 ± 3.7/HP, 19.7 ± 2.1/HP respectively; the expressions of VEGF were (394 ± 57) ng/L, (268 ± 32) ng/L and (217 ± 20) ng/L respectively; the expressions of PDGF-BB were (304 ± 31) ng/L, (274 ± 31) ng/L and (196 ± 22) ng/L respectively. After CP metronomic chemotherapy, there were significantly lower of microvessel density, VEGF and PDGF-BB levels than pretreatment \[MVD 48.5 ± 5.9/HP, VEGF (517 ± 60) ng/L, PDGF-BB (484 ± 60) ng/L\]in the responders (P < 0.01). While in the non-responders, after treated by CP metronomic chemotherapy for 2 months, microvessel density, the expression of VEGF and the expression of PDGF-BB were 32.5 ± 4.7/HP, 512 ± 39 ng/L and (452 ± 39) ng/L respectively. There were no significant changes of MVD, VEGF and PDGF-BB levels compared with pretreatment \[MVD 33.2 ± 5.6/HP,VEGF (498 ± 55) ng/L, PDGF-BB (488 ± 44) ng/L\] (P > 0.05).</p><p><b>CONCLUSIONS</b>Our findings suggested that continuous low-dose CP metronomic chemotherapy could decrease microvessel density of bone marrow in MM patients. Furthermore, it down-regulated expression of serum VEGF and PDGF-BB to exert its anti-angiogenesis in MM.</p>