Heme oxygenase-1 protects rat liver against warm ischemia/reperfusion injury via TLR2/TLR4-triggered signaling pathways.

AIM: To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-ß (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies. RESULTS: HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the ZnPP-treated group. However, the expression of negative regulators Toll-interacting protein, suppressor of cytokine signaling-1, IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in CoPP treatment rats were markedly up-regulated as compared with ZnPP-treated rats. CONCLUSION: HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.

Downregulation of p38 MAPK involved in inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin.

Curcumin, as a main pharmacological component in the traditional Chinese medicine-turmeric, has shown anti-inflammatory, anti-oxidation, anti-tumor and anti-fibrotic effects. This study aimed to investigate the possible underlying signaling pathway which was involved in the inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin. Rat mesangial cells in vitro were incubated with low-density lipoprotein (LDL) and different concentrations of curcumin (0, 6.25, 12.5, 25.0 µmol/L) or p38 MAPK inhibitor, SB203580 (10 µmol/L). Under LDL incubation, mesangial cells proliferated, the expression of MMP-2 mRNA and protein was decreased, the expression of COX-2 mRNA and protein was increased, reactive oxygen species (ROS) generation was increased and p38 MAPK was activated significantly (P<0.05). When LDL-induced cells were treated with curcumin in the concentration of 12.5 or 25.0 µmol/L, LDL-induced proliferation of mesangial cells was suppressed, the expression of MMP-2 mRNA and protein increased, the expression of COX-2 mRNA and protein downregulated, the production of ROS inhibited and p38 MAPK inactivated (P<0.05). In conclusion, curcumin can inhibit the LDL-induced proliferation of mesangial cells and up-regulate the expression of MMP-2, which may be related with the inhibitory effect of curcumin on COX-2 expression, ROS production and p38 MAPK.

[Effects of oxymatrine on microinflammatory state in patients undergoing continuous hemodialysis: a randomized controlled trial].

BACKGROUND: Chronic microinflammatory state is common in the patients undergoing maintenance hemodialysis (MHD), which seriously affects the long-term survival rate of MHD patients. It is important to improve the microinflammatory state in MHD patients. OBJECTIVE: To investigate the effects of oxymatrine on microinflammatory state in patients undergoing continuous hemodialysis. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty MHD patients in Blood Purification Center, Wuhan No.1 Hospital, from June to September 2008, were randomized into treatment group (30 cases) and control group (30 cases). Oxymatrine Capsule was orally administered to the patients in the treatment group 0.4 g once a day for 3 months, while the patients in the control group were not given oxymatrine. MAIN OUTCOME MEASURES: The serum concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), albumin (Alb), pre-albumin (PAB), total cholesterol (TC) and triglyceride (TG) were detected before and after 3-month treatment. RESULTS: Three patients in the treatment group had a stomachache on the first day of treatment, and two out of the three quitted the trial. The stomachache disappeared in one patient after stopping taking the drug, and did not recur after continuing to receive the intervention. Two patients in the treatment group had skin rash with pruritus on the second day of treatment. The rash disappeared after the patients stopped taking the drug, and did not recur after continuing to receive the intervention. A total of 58 cases accessed to the statistical analysis, while 2 cases were excluded. In the treatment group, the concentrations of hs-CRP, IL-1beta and TNF-alpha significantly decreased (P<0.01) and the mean values of Alb, PAB, TC and TG significantly increased after the treatment as compared with those before the treatment (P<0.01), but there were no significant differences in all parameters between before and after treatment in the control group. There were significant differences in all parameters between the treatment group and the control group after treatment (P<0.01, P<0.05). CONCLUSION: Oxymatrine can improve the microinflammatory state in the patients undergoing continuous hemodialysis.

[Clinical effect and safety of miconazole nitrate 1200 mg in treating vulvovaginal candidiasis].

OBJECTIVE: To investigate the clinical effect and safety of miconazole nitrate 1200 mg in treating vulvovaginal candidiasis (VVC). METHODS: An open, multicentre, non case control clinical trial was conducted in 568 patients suffering from VVC from Jul 1, 2006 to Nov 30, 2006. Routine examination, score of clinical symptoms and physical signs, mycetology test and safety evaluation were done in all patients before treatment, 7 - 14 days after treatment and 30 days after treatment. RESULTS: Seven to fourteen days after treatment, 563 patients could be followed and 323 patients (57.3%) were cured. The overall effective rate was 90.2%. The mycologic cure rate was 91.3% (514). Thirty days after treatment, 480 patients could be followed and 411 patients (85.6%) were cured. The total effective rate was 96.0%. Mycologic cure rate was 92.3% (443/480). Adverse effect rate was 2.7% (15/563) and they were relieved without any treatment in one or two days. CONCLUSIONS: Miconazole nitrate 1200 mg is effective in the treatment of VVC, with good compliance and few adverse effects. Moreover, it can be accepted easily.