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Previous studies indicated that Ca 2+ /calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca 2+-regulated protease μ-calpain to promote myocardial ischemia/ reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca 2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca 2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca 2+ flux using ryanodine and thapsigargin failed to prevent Ca 2+ paradox-induced heart injury. In contrast, the Ca 2+ paradox increased CaMKII auto-phosphorylation at Thr 287 , while the CaMKII inhibitor KN-62 and the Na + /Ca 2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca 2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/ reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

Emerging evidence demonstrates that WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) participates into carcinogenesis and tumor progression. In this review article, we will describe the association between dysregulated WWP1 expression and clinical features of cancer patients. Moreover, we summarize the both oncogenic and tumor suppressive functions of WWP1 in a variety of human cancers. Furthermore, we briefly describe the downstream substrates of WWP1 and its upstream factors to regulate the expression of WWP1. Notably, targeting WWP1 by its inhibitors or natural compounds is potentially useful for treating human malignancies. Finally, we provide the perspectives regarding WWP1 in cancer development and therapies. We hope this review can stimulate the research to improve our understanding of WWP1-mediated tumorigenesis and accelerate the discovery of novel therapeutic strategies via targeting WWP1 expression in cancers.

Background Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients. Methods A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3–6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio. Results There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03–25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14–5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27–4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06–3.01) during hospitalization than inpatients with the lowest quartile. Conclusions Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke.