Molecular mechanism for bone mass loss caused by staphylococcus aureus infection / 中华创伤骨科杂志

Objective:To explore the molecular mechanism for bone mass loss caused by staphylococcus aureus infection.Methods:Thirty 8-week-old male C57BL/6 mice were randomly divided into 3 groups ( n=10): control, infection and infection+JAK inhibitor (JAKi) ones. The mice were killed 2 weeks later for sampling from the femur and tibia. Micro-CT reconstruction was performed for analyses of BV/TV, Tb.N, Tb.Th and Tb.Sp to detect changes in bone mass; OCN immunohistochemistry and Goldner's trichrome staining were used to quantify osteoblasts; TRAP staining was used to quantify osteoclasts; the GSE166522 data set was downloaded and analyzed to explore the relationships between staphylococcus aureus infection and bone cell senescence and JAK/STAT pathway. Senescence β-Galactosidase staining, Osterix and P16 immunofluorescence colocalization were used to observe the changes in number of senescent cells. Results:MicroCT results showed a statistically significant difference in the loss of cancellous bone in the target area in the infection group compared with the control group ( P<0.05). The results of osteocalcin immunohistochemistry and Goldner's trichrome staining indicated that the number of osteoblasts in the infection group was significantly reduced ( P<0.05). TRAP staining indicated no significant difference in the number of osteoclasts between the infection and control groups ( P>0.05). Bioinformatics analysis found that staphylococcus aureus infection caused bone cell senescence and the JAK/STAT pathway was activated after the infection. Senescence β-Galactosidase staining suggested that senescent cells increased in the infection group compared with the control group. The number of Osterix and P16 positive senescent osteoprogenitor cells in the infection group was increased significantly compared with the control group. The number of senescent osteoprogenitor cells in the infection+JAKi group was significantly reduced and the bone loss was partially reversed after treatment of JAK inhibitor, compared with the infection group. Conclusion:Staphylococcus aureus may induce osteoprogenitor cell senescence through the JAK/STAT pathway and eventually lead to bone mass loss.

Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.

Salvianolic acid A alleviates renal injury in systemic lupus erythematosus induced by pristane in BALB/c mice

The purpose of this study was to investigate the effects of salvianolic acid A (SAA) in systemic lupus erythematosus (SLE) induced by pristane in BALB/c mice. Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane. Mice were then treated with daily oral doses of SAA for 5 months in parallel with mice treated with prednisone and aspirin as positive controls. The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. Western blot analysis of renal tissue was also employed. SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects. SAA treatment also significantly inhibited the phosphorylation of IKK, IB and NFB in renal tissues of lupus mice. In conclusion, the results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK, IB and NFB.

Research advances on regulatory effect of RhoA on myocardial ischemia reperfusion injury / 中国药理学通报

RhoA belongs to the small G binding proteins Rho subfamily, playing an important role in the various cellular func-tions, including migration, proliferation, adhesion and apopto-sis. Recent data indicate that RhoA/ROCK pathway causes myo-cardial damage by influencing the myocardial energy metabolism, inflammation, and endoplasmic reticulum stress. On the other hand, the activation of RhoA also has a positive role in MIRI. This article reviews the regulatory effect of RhoA on MIRI and its mechanisms, discusses the prospects of RhoA as a novel thera-peutic target for MIRI, and provides new therapeutic treatments and strategies for MIRI.

Protective effect of Salvianolic acid A against isoproterenol-induced myocardial infarction in mice / 中国药理学通报

Aim To investigate the effect of Salvianol-ic acid A (Sal A)on mice with isoproterenol (ISO)-induced myocardial infraction and its possible mecha-nisms.Methods The mice were subcutaneously in-jected with ISO (8 mg·kg-1 )to induce myocardial in-farction.The myocardial protective effect of Salvianolic acid A was evaluated from mortality rate,electrocardio-gram (ECG),heart function,myocardial infarction in-dex,serum myocardial enzymes and its action mecha-nisms were explored from inflammation,anti-oxidation and cells apoptosis.Results Salvianolic acid A dose-dependently enhanced the heart function of myocardial infarction mice,reduced the heart index,inhibited the myocardial enzyme leakage,showed obvious myocardi-al protection effects.ELISA results showed that Salvi- anolic acid A could reduce the expression of myocardial inflammatory cytokines such as IL-6(interleukin-6,IL-6),TNF-α(tumornecrosis factor-α,TNF-α).West-ern-blotting confirmed that Salvianolic acid A could in-crease the expression of anti-apoptotic proteins Bcl-2, reduce the expression of apoptosis protein Bax,and raise the phosphorylation level of PI3K and Akt.Con-clusion Salvianolic acid A displays a significant pro-tective effect against isoproterenol-induced myocardial infarction and its mechanism may be related to the in-crease of PI3K/Akt signal pathway and the inhibition of cell apoptosis and inflammatory reaction.