Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

BACKGROUND: Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis. METHODS: First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls in analysis of the platelet desialylation levels (study I). Next, we conducted an open-label randomized controlled trial (RCT) in which the patients who had severe sepsis with thrombocytopenia (platelet counts ≤50 × 109/L) were randomly assigned to receive antimicrobial therapy alone (control group) or antimicrobial therapy plus oseltamivir (oseltamivir group) in a 1:1 ratio (study II). The primary outcomes were platelet desialylation level at study entry, overall platelet response rate within 14 days post-randomization, and all-cause mortality within 28 days post-randomization. Secondary outcomes included platelet recovery time, the occurrence of bleeding events, and the amount of platelets transfused within 14 days post-randomization. RESULTS: The platelet desialylation levels increased significantly in the 127 septic patients with thrombocytopenia compared to the 134 patients without thrombocytopenia. A platelet response was achieved in 45 of the 54 patients in the oseltamivir group (83.3%) compared with 34 of the 52 patients in the control group (65.4%; P = 0.045). The median platelet recovery time was 5 days (interquartile range 4-6) in the oseltamivir group compared with 7 days (interquartile range 5-10) in the control group (P = 0.003). The amount of platelets transfused decreased significantly in the oseltamivir group compared to the control group (P = 0.044). There was no difference in the overall 28-day mortality regardless of whether oseltamivir was used. The Sequential Organ Failure Assessment score and platelet recovery time were independent indicators of oseltamivir therapy. The main reason for all of the mortalities was multiple-organ failure. CONCLUSIONS: Thrombocytopenia was associated with increased platelet desialylation in septic patients. The addition of oseltamivir could significantly increase the platelet response rate, shorten platelet recovery time, and reduce platelet transfusion. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16008542 .

Cardioprotection provided by Echinatin against ischemia/reperfusion in isolated rat hearts.

BACKGROUND: This study evaluated the protective effect of Echinatin against myocardial ischemia/reperfusion (I/R) injury in rats. METHODS: The effect of Echinatin on cardiac function in rats subjected to I/R was demonstrated through improved Langendorff retrograde perfusion technology. Adult Sprague-Dawley rats were randomly divided into five groups, and myocardial infarct size was macroscopically estimated through 2,3,5-triphenyltetrazolium chloride staining. The coronary effluent was analyzed for the release of lactate dehydrogenase (LDH) and creatine kinase (CK) to assess the degree of cardiac injury. The concentrations of malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined along with superoxide dismutase (SOD) activity using ELISA. Finally, cardiomyocyte apoptosis analysis was conducted with POD, an in situ cell death detection kit. RESULTS: Echinatin (0.5 and 2.5 µg/mL) pretreatment enhanced the maximum up/down rate of the left ventricular pressure (±dp/dtmax), improved the heart rate, increased the left ventricular developed pressure (LVDP), enhanced the coronary flow, and reduced the CK and LDH levels in the coronary flow of the treated group compared with the I/R group. Echinatin limited the contents of CK and LDH, improved the LVDP, reduced the contents of MDA, IL-6, and TNF-α, and increased the SOD activity. The infarct size and cell apoptosis in the hearts of the rats in the Echinatin-treated group were smaller and lower, respectively, than those in the hearts of the rats in the I/R control group. CONCLUSION: Echinatin exerts a protective effect against I/R-induced myocardial injury on hearts. This effect may be attributed to the antioxidant and anti-inflammatory activities of this compound.

Protective effect of fasudil hydrochloride against acute renal injury in septicopyemia rats.

OBJECTIVE: To observe the protective effect of fasudil hydrochloride against acute renal injury in septicopyemia rats. METHODS: A total of 60 Wister rats were included in the study and divided into control group (n = 10), model group (n = 25) and treatment group (n = 25). Model group and treatment group received intraperitoneal injection of endotoxin (ET) to establish acute renal injury models while the control group only received daily intraperitoneal injection of normal saline 1 mL. Five rats were taken out of model group and treatment group respectively at 1 h (T1), 6 h (T2), 12 h (T3), 24 h (T4) and 48 h (T5), for intraperitoneal injection of ET 30 mg/kg. Treatment group received intraperitoneal injection of fasudil hydrochloride 30 mg/kg 1 h before injection of ET. For three groups, 5 mL blood samples were collected from postcava for determination of serum creatinine and urea nitrogen levels at different time points. Concentrations of serum tumor necrosis factor α and ET-1 were determined by using ELISA. The renal pathologic changes were observed under the microscope. RESULTS: Serum creatinine levels in both model group and treatment group were significantly higher than control group at T2-T5 (P < 0.05) while the levels in treatment group were significantly lower than control group at T3-T5 (P < 0.05). At T2-T5, blood urea nitrogen levels in model group and treatment group were significantly higher than control group (P < 0.05) while the levels in treatment group were significantly lower than model group at T3-T5 (P < 0.05). Concentrations of serum tumor necrosis factor α in model group and treatment group were significantly higher than control group at T1-T5 (P < 0.05) while the levels in treatment group were significantly lower than model group at T1-T5 (P < 0.05). Serum ET-1 concentrations in model group and treatment group were significantly higher than control group at T1-T5 (P < 0.05) while the levels in treatment group at T1-T4 were significantly lower than model group (P < 0.05). Rats in control group showed no swelling or hyperemia in kidney cells but normal structure and normally arranged renal tubular epithelial cells. Obvious injury was observed in model group at T3 and renal tubular epithelial cells in disorder and at swelling condition, hyperemia and angiectasis in glomerulus, degenerative opacities and vacuolar degeneration, and maximized injury were observed at T4. Injury in renal tissue in treatment group was significantly milder than model group. CONCLUSIONS: Fasudil hydrochloride has the significantly protective effect against acute renal injury in septicopyemia rats.

Luteolin-induced protection of H2O2-induced apoptosis in PC12 cells and the associated pathway.

Increasing evidence has indicated that the generation of reactive oxygen species (ROS) contributes to H2O2­induced nerve injury. This may result in oxidative stress that leads to cell damage or death. Dietary or pharmaceutical augmentation of the endogenous antioxidant defense capacity is a potential means by which to prevent ROS­induced damage. The aim of the current study was to investigate the effect of luteolin on H2O2­induced cell apoptosis in cultured rat pheochromocytoma cells (PC12 cells) and to investigate the role of the phosphatidylinositol­3­kinase (PI3K)/protein kinase B (Akt) pathway on H2O2­induced apoptosis. The results demonstrated that luteolin was able to inhibit the reduction in cell viability induced by H2O2. In addition, luteolin reduced ROS generation and lactate dehydrogenase release in H2O2­treated PC12 cells. The levels of superoxide dismutase and glutathione peroxidase activity were increased following treatment with luteolin, however malondialdehyde levels were observed to be reduced. Additionally, luteolin increased the Bcl­2/Bax ratio and enhanced Akt phosphorylation. However, these alterations were attenuated by pretreatment with an inhibitor of the PI3K/Akt pathway. In conclusion, luteolin inhibited H2O2­induced apoptosis via reducing ROS levels and activating the PI3K/Akt pathway.