Butylphthalide sodium chloride injection for patients with acute cerebral infarction has a certain effect. Although there are several proposed mechanisms of drug action, no related research on improving the inflammatory cytokines that regulate the body's immune system through the hypothalamus-pituitary-adrenal axis has been published.To determine the impact of butylphthalide and sodium chloride injection on the hypothalamus-pituitary-adrenal (HPA) axis after acute cerebral infarction in the basal ganglia.Patients were randomly divided into treatment and control groups; the treatment group received intravenous drips of butylphthalide, while the control group did not. The levels of adrenocorticotropic hormone (ACTH) and cortisol (COR), along with the National Institutes of Health Stroke Scale (NIHSS) scores of both groups were detected using the radioimmunoassay method. This was done at regular intervals after cerebral infarction in the basal ganglia was detected.Fourteen days after treatment, the levels of serum ACTH and COR in both groups were higher than normal. The NIHSS score and levels of ACTH and COR of the treatment group were significantly lower than those of the control group (p<0.05). The data was computed and analyzed using SPSS17.0 software.Butylphthalide treatment for patients suffering from acute basal ganglia infarction can reduce the adverse effects on the HPA axis, thus improving patient prognosis.
Acute kidney injury (AKI) is defined as an abrupt deterioration in kidney function. Recent studies indicate that the prevalence of AKI is relatively high and associated with poor clinical outcomes including failure of other organs that include strokes. However, the effects of AKI on cerebrovascular function is poorly understood. Here we tested the hypothesis that AKI may promote strokes by cerebrovascular sensitization to angiotensin II (Ang II) in conjunction with FGF2 (fibroblast growth factor 2) plus the secreted FGF binding protein FGFBP1. Renal ischemia‐reperfusion (I/R) mice served as the AKI model and sham‐operated mice as controls. Brain medulla oblongata arterioles were dissected and microperfused. Also, brain basal and posterior communicating arteries were dissected and tested by vascular myography. We found that the effects of the vasoconstrictors endothelin 1 or norepinephrine were not impacted in the AKI model but observed that the effects of Ang II on cerebral arterioles and arteries were enhanced. Ang II effects were further amplified by treatment with FGF2 plus FGFBP1. Complementary to this, the FGF receptor (FGFR) kinase inhibitor PD173074 decreased the cerebrovascular response to Ang II indicating a crosstalk between Ang II and the FGFR pathway. Interestingly, Ang II type 2 receptor mRNA expression in isolated cerebral vessels was reduced in AKI model relative to controls. We conclude that synergism between the FGFR and Ang II pathway increases the brain vessel response to Ang II and this enhancement of the cerebral vascular responses may be due to the reduced expression of Ang II type 2 receptor.
Aim: To exam the hypothesis that fenofibrate improves vascular endothelial dysfunction via balancing endothelium-dependent relaxation and constriction of aorta in diabetic mice. Methods: The streptozotocin-induced diabetic mice were treated with fenofibrate (100 mg/Kg/d, 8 weeks). The responses were assessed from serum and aortic parameters, vascular reactivity by wire myograph and aortic protein expression of endothelial nitric oxide synthase (eNOS), peroxisome proliferator-activated receptor α (PPARα), AMP-activated protein kinase-α (AMPKα) and liver kinase B1 (LKB1) and cyclooxygenase-2 (COX-2) in control and diabetic mice given placebo or fenofibrate. Results: Comparing with the control mice (12.2±2.0 μmol/L), serum creatinine increased by 114.8% in diabetic mice (26.2±2.0 μmol/L) and by 66.2% in fenofibrate-treated diabetic mice (21.6±2.8 μmol/L, p<0.01). NO level in aorta was 49.5±8.2 (μmol/g) in diabetic mice and 71.7±5.2 (μmol/g) in fenofibrate-treated diabetic mice (p<0.01). Compared with placebo-treated diabetic group, phosphorylated-eNOS protein in aorta was 3.6±1.0 fold higher (p<0.01) and endothelium-dependent relaxation was increased in fenofibrate-treated diabetic mice (p<0.01). The aorta vasodilation by fenofibrate treatment was reversed with PPARα inhibitor or AMPKα inhibitor. Fenofibrate treatment elevated PPARα expression, subsequently induced LKB1 translocation from nucleus to cytoplasm to activate AMPKα, thus activated eNOS in diabetic aorta (p<0.01). Fenofibrate treatment reduced vascular contractility and expression of COX-2 in aorta from diabetic mice(p<0.01). Prostaglandin E2 and thromboxane A2 were 174.9±16.4 and 128.9±4.4 (pg/ml) in diabetic mice, and reduced to 142.7±14.1 and 105.9±5.7 (pg/ml) in fenofibrate-treated mice (p<0.01). Conclusion: Fenofibrate treatment in diabetic mice normalizes endothelial function by balancing vascular reactivity via increasing NO production and suppressing vasoconstrictor prostaglandin. Our results suggest that implication of fenofibrate as a putative mediator of diabetic vascular complications.
The present study determined the vasomotor effects of oxidized low-density lipoprotein (ox-LDL) in human saphenous veins and determined whether decreased availability of L-arginine was responsible for the impaired endothelial function. Human saphenous veins were obtained from white males undergoing coronary bypass surgery. We examined the effects of ox-LDL on ACh-induced endothelium-dependent relaxation, sodium nitroprusside-induced endothelium-independent relaxation and 5-HT-induced contraction. ACh-induced vasorelaxation in the presence of L-arginine and ox-LDL was also examined. In addition, we assessed the endothelial influence on the contractile response to 5-HT. ox-LDL significantly inhibited ACh-induced relaxation but did not affect sodium nitroprusside-induced relaxation. L-Arginine pretreatment did not prevent ox-LDL-induced impairment of the relaxation response to ACh. ox-LDL significantly potentiated 5-HT-induced contraction at concentrations between 3 x 10(-6) M and 10(-4) M, an effect that was endothelium-dependent. Denudation of endothelium also significantly enhanced the contractile response to 5-HT. These data suggest that ox-LDL impairs ACh-induced endothelium-dependent relaxation and enhances 5-HT-induced endothelium-dependent contraction in human saphenous vein. L-Arginine deficiency is not responsible for the endothelial dysfunction induced by ox-LDL in human saphenous vein.
The exact clinical significance of EGFR mutation status in NSCLC at the time of initial diagnosis remains disputable.The gene expression module in NSCLC for chemotherapy outcome prediction needs to be developed.We analyzed 56 patients with NSCLC received chemotherapy either with (n=20) or without EGFR-TKIs (n=36) between 2008 and 2012 in China.EGFR mutation test and gene expression profiling were performed in samples obtained before medication treatment by liquidchip platform.Significant association (P = 0.028) was seen between EGFR mutation status before first-line chemotherapy and EGFR-TKIs treatment outcomes, which even can be found from the status before second-or third-line treatment.A 14-gene expression profiling had been studied.Patients with low mRNA expression of ERCC1 or TYMS preferred higher DCR to cisplatin and pemetrexed than those with high expression (P = 0.39 and P = 0.11).Highly co-expression of TUBB3 and STMN1 gene has associated with the resistance to antimicrotubule drugs (P = 0.03).Our data suggest the EGFR mutations status, even at the time of initial diagnosis, is predictive of outcomes of TKIs treatment after chemotherapy.The mRNA expression profiling investigated in this study has a predictive value in NSCLC treatment, but further research with expanded samples is still required.
To investigate the clinical value of urine interleukin-18 (IL-8), neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) for the early diagnosis of acute kidney injury (AKI) in patients with ureteroscopic lithotripsy (URL) related urosepsis.A retrospective study was carried out in 157 patients with urosepsis after URL. The patients were divided into AKI group and non-AKI group according to the Kidigo guideline and urine IL-8, NGAL and KIM-1 levels were detected by enzyme-linked immunosorbent assay at 0, 4, 12, 24 and 48 h after the surgery. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of these three biomarkers for postoperative AKI.The level of urine IL-8, NGAL and KIM-1 in AKI group was significantly higher than that in non-AKI group at 4, 12, 24 and 48 h (p < 0.01). The ROC analysis showed the combined detection of urine IL-8, NGAL and KIM-1 at 12 h had a larger area under curve (AUC) than a single marker (0.997, 95% CI: 0.991-0.998), and the sensitivity and specificity were 98.2% and 96.7%, respectively. Pearson correlation analysis showed that the levels of urine NGAL at 4, 12, 24 and 48 h in AKI patients were positively correlated with the levels of urine KIM-1 and IL-18 (p < 0.01).AKI could be quickly recognized by the elevated level of urine IL-8, NGAL and KIM-1 in patients with URL-related urosepsis. Combined detection of the three urine biomarkers at 12 h after surgery had a better diagnostic performance, which may be an important reference for the early diagnosis of AKI.
OBJECTIVE To study the effects of rhubarb and the different routes of nutrition support on invasive fungal infection. METHODS One thousand and ninety patients, who suffered from sepsis subsequent to trauma, shock and infection were enrolled in this study. The patients were randomly divided into two groups, 637 cases in rhubarb preventive treatment group and 453 cases in non-preventive rhubarb treatment group. They were again divided into four subgroups: enteral nutrition support, and no nutrition support group. The incidence of invasive fungal infection was observed in those groups. RESULTS The incidence of invasive fungal infection in rhubarb preventive treatment group (3.0%) was much lower than that in non-preventive rhubarb treatment group (11.5%). There was significant difference between two groups (P<0.05). Furthermore, fewer patients developed invasive fungal infection in enteral nutrition support and enteral combined parenteral nutrition support subgroups after preventive rhubarb treatment (0.9% and 2.1%), compared with parenteral nutrition support and no nutrition support subgroups (30.4% and 61.3%) and corresponding subgroups with non-preventive treatment of rhubarb (3.9% and 7.1%, P<0.05 or P<0.01). In addition, the route of nutrition support also affected the incidence of invasive fungal infection. Patients in enteral nutrition support and enteral combined parenteral nutrition support subgroups had lower incidence of invasive fungal infection than in parenteral nutrition support and no nutrition support subgroups (all P<0.05), and the incidence was the highest in no nutrition support subgroup. There were no significant difference between parenteral nutrition support and no nutrition support subgroups. CONCLUSION Rhubarb and enteral nutrition support have preventive effects on invasive fungal infection via gut mechanism.
Reduced A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif member 13 (ADAMTS13) levels are observed in kidney disease. We test whether recombinant human ADAMTS13 (rhADAMTS13) mitigates renal injury in chronic kidney disease (CKD) and the potential mechanisms.CKD was established 3 months after ischaemia/reperfusion (IR). ADAMTS13 and von Willebrand factor (vWF) levels, renal function and morphological changes were analysed. Afferent arteriolar responses to angiotensin II (Ang II) and acetylcholine (ACh) were measured. Oxidative stress-related molecules were detected.Higher vWF and lower ADAMTS13 levels were observed in CKD mice, which were markedly attenuated by rhADAMTS13. rhADAMTS13 alleviated renal dysfunction, as documented by decreased blood urea nitrogen (BUN), serum creatinine, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) levels in CKD mice. Moreover, rhADAMTS13 attenuated transforming growth factor (TGF)-β1/Smad3 activation. Plasma vWF: ADAMTS13 ratio showed positive correlations with malondialdehyde (MDA), hydrogen peroxide (H2 O2 ) and proteinuria, and correlated inversely with superoxide dismutase (SOD) and catalase (CAT). Finally, rhADAMTS13 inhibited reactive oxygen species (ROS) levels and improved microvascular functional disorders, accompanied by the inhibition of glycogen synthase kinase (GSK) 3β hyperactivity and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression.Acute kidney injury (AKI) reduces the expression of ADAMTS13 that contributes to progressive CKD, microvascular dysfunction, oxidative stress, inhibition of Nrf2 activity and renal histopathological damage. All of which can be alleviated by administration of rhADAMTS13.
Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Ser473 and eNOS at Ser1177. Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis, and improving microvascular endothelial dysfunction. rhADAMTS13 could be a promising strategy to treat AKI in clinical settings.
Fenofibrate, a peroxisome proliferator-activated receptors α (PPARα) agonist, reduces vascular complications of diabetic patients but its protective mechanisms are not fully understood. Here we tested the hypothesis that fenofibrate improves vascular endothelial dysfunction by balancing endothelium-dependent relaxation and contractility of the aorta in diabetes mellitus (DM). In streptozotocin-induced diabetic mice, eight weeks of fenofibrate treatment (100 mg/Kg/d) improved endothelium dependent relaxation in the macro- and microvessels, increased nitric oxide (NO) levels, reduced renal damage markers and effects of the vasoconstrictor prostaglandin. Levels of superoxide dismutase and catalase were both reduced and hydrogen peroxide was increased in vehicle-treated DM, but these changes were reversed by fenofibrate treatment. Vasodilation of the aorta after fenofibrate treatment was reversed by PPARα or AMPKα inhibitors. Western blots showed that fenofibrate treatment elevated PPARα expression, induced liver kinase B1 (LKB1) translocation from the nucleus to the cytoplasm and activated AMP-activated protein kinase-α (AMPKα), thus activating endothelial NO synthase (eNOS). Also, fenofibrate treatment decreased NF-κB p65 and cyclooxygenase 2 proteins in aortas. Finally, incubation with indomethacin in vitro improved aortic contractility in diabetic mice. Overall, our results show that fenofibrate treatment in diabetic mice normalizes endothelial function by balancing vascular reactivity via increasing NO production and suppressing the vasoconstrictor prostaglandin, suggesting mechanism of action of fenofibrate in mediating diabetic vascular complications.
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