Acute kidney injury (AKI) to chronic kidney disease (CKD) progression has become a life-threatening disease. However, an effective therapeutic strategy is still needed. The pathophysiology of AKI-to-CKD progression involves chronic inflammation and renal fibrosis driven by macrophage activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In this study, we modulated macrophage infiltration through oral administration of the CSF-1R inhibitor GW2580 in an ischemia–reperfusion (I/R)-induced AKI model to evaluate its therapeutic effects on preventing the progression of AKI to CKD. We found that GW2580 induced a significant reduction in the number of macrophages in I/R-injured kidneys and attenuated I/R-induced renal injury and subsequent interstitial fibrosis. By flow cytometry, we observed that the reduced macrophages were primarily Ly6C+ inflammatory macrophages in the GW2580-treated kidneys, while there was no significant difference in the number and percentage of Ly6C−CX3CR1+ macrophages. We further found that these reduced macrophages also demonstrated some characteristics of M2-like macrophages, which have been generally regarded as profibrotic subtypes in chronic inflammation. These results indicate the existence of phenotypic and functional crossover between Ly6C+ and M2-like macrophages in I/R kidneys, which induces AKI worsening to CKD. In conclusion, therapeutic GW2580 treatment alleviates acute renal injury and subsequent fibrosis by reducing Ly6C+ M2-like macrophage infiltration in ischemia-induced AKI. 相似文献
Catheter ablation of ventricular tachycardia (VT) can reduce the burden of ventricular arrhythmia (VA) but its effect on health care utilization and costs after such therapy is poorly known. We sought to compare the rates of cardiovascular (CV)-related hospitalizations, survival, and health care costs in patients with recurrent VT treated either with VT ablation or with medical therapy.
Methods
One-hundred implantable cardioverter-defibrillator patients with structural heart disease who underwent VT ablation were included. Propensity score-matched patients with recurrent VT treated with medical therapy were identified from a prospective registry of approximately 7000 de novo implantable cardioverter-defibrillator patients. Outcomes and costs were ascertained using health administrative databases.
Results
Among patients who underwent VT ablation, the cumulative rates of VA-related hospitalizations were lower in the 2 years after their ablation procedure compared with the year before (rate ratio, 0.3; 95% confidence interval [CI], 0.22-0.43). Rates of CV-related hospitalization and hospitalization because of VA post index date were similar between the VT ablation and medical therapy groups (hazard ratio [HR], 0.94; 95% CI, 0.57-1.54 and HR, 1.04; 95% CI, 0.57-1.91, respectively). Health care costs in the VT ablation patients were not increased post-ablation compared with the medical management group. The risk of all-cause mortality was lower among patients in the VT ablation group relative to the medical therapy group (HR, 0.64; 95% CI, 0.4-0.99).
Conclusions
Patients who underwent VT ablation experienced a significant reduction in their rate of VA-related hospitalizations. Patients treated with VT ablation had similar rates of CV-related hospitalization compared with those treated with medical therapy without increased health care-related costs. 相似文献
Herein we report an efficient radiolabeling of a 18F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [18F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18F]FOMPyD showed moderate brain permeability in wild-type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers. 相似文献
Introduction: Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index.
Areas covered: Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile.
Expert opinion: Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression ‘fingerprints’ produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio. 相似文献
BackgroundIn the past two decades, enhanced understanding of the biology of G-protein-coupled receptors (GPRs) has led to the identification of several such receptors as novel targets for free fatty acids (FFAs). Two GPRs, FFAR1 and FFAR4, have received special attention in the context of chronic inflammatory diseases, thanks to their anti-inflammatory activities.MethodsThe present study investigates the influence of prolonged treatment with GW9508 – agonist of FFAR1 and FFAR4 – on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods.ResultsGW9508 administration has led to the reduction of atheroscletoric plaque size in an apoE-knockout mice model. Moreover, a FFAR1/FFAR4 agonist reduced the content of macrophages by almost 20%, attributed by immunohistochemical phenotyping to the pro-inflammatory M1-like activation state macrophages.ConclusionsProlonged administration of GW9508 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR1/FFAR4 receptors holds promise for a new approach to the prevention or treatment of atherosclerosis. 相似文献
AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism.METHODS: Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 μg/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1β, interferon-γ, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 μmol/L) before treatment with LPS.RESULTS: In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.CONCLUSION: FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages. 相似文献
The study aims to determine the high risk gestational week (GW) and/or birth weight (BW) of the preterm neonate, below which perinatal hypoxic cerebral injuries are expected to occur.
Material and methods
Eighty preterm neonates, born at or before 37 GW, were included. Twenty-three of them were <32 GW and 57 >32 GW. Also, 28 of them were <1500 g and 52 >1500 g. Imaging was done by transcranial ultrasound with 4–9 MHz curvilinear probe. CT scan was additionally performed for only 18 candidates. The study protocol was approved by the ethics committee in Al-Mana General Hospital (AGH).
Results
Intraventricular hemorrhage (IVH) was diagnosed in six preterm neonates <32 GW and two >32 GW. Three <32 GW and one >32 GW presented with hypoxic ischemic encephalopathy (HIE) with no hemorrhage. Two preterm neonates <32 GW had both IVH & HIE. All positive cases were below 1500 g BW.
Conclusion
Preterm neonates <32 GW and/or <1500 g are highly susceptible for HIE and/or IVH. Thus, special medical care, including post-labor hospitalization in well equipped special baby care units (SCBU) and routine transcranial ultrasound (TCUS) screening is recommended for those preterm neonates. 相似文献
AbstractAn estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer’s disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the db/db mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in db/db mice. PPAR-δ–mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory. 相似文献