No abstract

Background/Aims: Contrast-induced nephropathy (CIN) is at present the third leading cause of hospital-acquired acute kidney injury (AKI). Traditionally, it is diagnosed by measuring the increase of the serum creatinine concentration. However, in patients with acute changes in their glomerular filtration rate, serum creatinine is an insensitive marker. This clinical study was designed to investigate whether human urinary interleukin-18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL) are early predictive markers for AKI after coronary angiography and their correlation with later cardiac events. Methods: Patients undergoing coronary angiography using low-osmolar contrast medium were enrolled and then followed up for at least 17 months. Urine samples were collected before and 24 h after coronary angiography and IL-18 and NGAL levels measured by using an ELISA kit. Results: CIN was diagnosed in 13 of 150 (8.7%) patients (CIN group); 27 patients without CIN served as control group. At 24 h after the procedure, the urinary IL-18 and NGAL levels were significantly increased in the CIN group, but not in the control group (p < 0.05). The predictable time of AKI onset determined by IL-18 was 24 h earlier than determined by serum creatinine (p < 0.01). Receiver operating characteristic curve analysis showed that both IL-18 and NGAL showed a good performance in early diagnosis of CIN as compared with serum creatinine (p < 0.05). We also found that IL-18 is an independent predictive marker for later major cardiac events: relative risk = 2.09 (p < 0.01). Conclusions: We conclude that urinary IL-18 or NGAL could be early biomarkers of CIN and that urinary IL-18 is well associated with the later cardiac outcomes in patients after coronary angiography.

Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors RORs are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of RORs in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion (MI/R) injury pathogenesis. RORα and RORγ subtypes were detected in the adult mouse heart, and RORα but not RORγ was downregulated after MI/R. To determine the pathological consequence of MI/R-induced reduction of RORα, we subjected RORα-deficient staggerer mice and wild-type (WT) littermates to MI/R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, RORα deficiency promoted MI/R-induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, RORα deficiency augmented MI/R-induced oxidative/nitrative stress. Given the emerging evidence of RORα as an essential melatonin effects mediator, we further investigated the RORα roles in melatonin-exerted cardioprotection, in particular against MI/R injury, which was significantly attenuated in RORα-deficient mice, but negligibly affected by cardiac-specific silencing of RORγ. Finally, to determine cell type-specific effects of RORα, we generated mice with cardiomyocyte-specific RORα overexpression and they were less vulnerable to MI/R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor RORα is a novel endogenous protective receptor against MI/R injury and an important mediator of melatonin-exerted cardioprotection; melatonin-RORα axis signaling thus appears important in protection against ischemic heart injury.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 promises to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targeting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain (DBD) of STAT3, however, has been avoided due to its 'undruggable' nature and potentially limited selectivity. In a previous study, we reported an improved in silico approach targeting the DBD of STAT3 that resulted in a small-molecule STAT3 inhibitor (inS3-54). Further studies, however, showed that inS3-54 has off-target effect although it is selective to STAT3 over STAT1. In this study, we describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound (inS3-54A18) with increased specificity and pharmacological properties. InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Thus inS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics targeting the DBD of human STAT3 and DBD of transcription factors may not be 'undruggable' as previously thought.