Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown.

Patients with acute respiratory distress syndrome exhibit increased stromelysin1 activity in the blood samples.

Enzyme activity analyses in the blood are expected to be reliable, non-invasive diagnostic as well as prognostic markers to reflect disease progression in acute lung injury (ALI). The objective of the current study was to evaluate the enzymatic activity of stromelysin1 (matrix metalloprotease-3) in the plasma/serum samples collected from ALI patients compared to the samples collected from healthy controls. Gene expression omnibus (GEO) database analysis indicated a correlation between increased stromelysin1 gene expression and the incidence of ALI in various animal models.

Irisin is induced in renal ischemia-reperfusion to protect against tubular cell injury via suppressing p53.

Renal ischemia-reperfusion is a major cause of acute kidney injury, a disease currently without effective treatments. Irisin was initially identified as an important factor produced by muscles to mediate the health benefits of exercise, and recent work has further suggested its protective effect against lung and liver injury. However, the role of Irisin in kidney diseases, including renal ischemia-reperfusion injury (IRI), remains unknown.

PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling.

Metastatic prostate cancer (PCa) has high mortality and a poor 5-year survival rate primarily due to the lack of effective treatments. Bone is the primary site of PCa metastasis in humans and the development of reliable therapeutic options for bone metastatic PCa will make a huge impact in reducing the mortality among these patients. Although P21 activated kinases (PAKs) have been studied in the past for their role in cancer, the efficacy of targeting PAKs to treat lung and bone metastatic PCa has not been tested yet.

The Biomarker TCONS_00016233 Drives Septic AKI by Targeting the miR-22-3p/AIFM1 Signaling Axis.

The prediction of mortality for septic acute kidney injury (AKI) has been assessed by a number of potential biomarkers, including long noncoding RNAs (lncRNAs). However, the validation of lncRNAs as biomarkers, particularly for the early stages of septic AKI, is still warranted. Our results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold (9.

Mitophagy in Acute Kidney Injury and Kidney Repair.

Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD.

Effect of P21-activated kinase 1 (PAK-1) inhibition on cancer cell growth, migration, and invasion.

P21-activated kinase-1 (PAK-1) is a serine/threonine kinase involved in multiple signaling pathways that mediate cellular functions such as cytoskeletal motility, cell proliferation, and survival. PAK-1 expression is altered in various cancers, including prostate and breast. Our recent studies showed that prostate cancer cells expressing higher levels of PAK-1 were resistant to the cytotoxic effects of the PAK-1 inhibitor, inhibitor targeting PAK-1 activation-3 (IPA-3), compared to those with lower expression.

Cell Apoptosis and Autophagy in Renal Fibrosis.

Renal fibrosis is the final common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Autophagy, a highly conserved lysosomal degradation pathway, plays important roles in maintaining cellular homeostasis in all major types of kidney cells including renal tubular cells as well as podocytes, mesangial cells and endothelial cells in glomeruli. Autophagy dysfunction is implicated in the pathogenesis of various renal pathologies.

Genome atlas analysis based profiling of Akt pathway genes in the early and advanced human prostate cancer.

Recent studies conducted in the mouse and cellular models suggest a stage-specific, differential effect of Akt activity modulation on tumor growth and metastasis in various cancers. In prostate cancer (PCa), although the deletion of Akt1 gene in a neuroendocrine model of TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) blunted oncogenic transformation and tumor growth, Akt1 suppression in the advanced PCa resulted in the activation of transforming growth factor-β pathway and enhanced metastasis to the lungs. Such a dual role for the Akt isoforms and its signaling partners has not been investigated in human PCa.

Nodal pathway activation due to Akt1 suppression is a molecular switch for prostate cancer cell epithelial-to-mesenchymal transition and metastasis.

Several studies have unraveled the negative role of Akt1 in advanced cancers, including metastatic prostate cancer (mPCa). Hence, understanding the consequences of targeting Akt1 in the mPCa and identifying its downstream novel targets is essential. We studied how Akt1 deletion in PC3 and DU145 cells activates the Nodal pathway and promotes PCa epithelial-to-mesenchymal transition (EMT) and metastasis.

EGFR drives the progression of AKI to CKD through HIPK2 overexpression.

The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown. : The mice model of VAN drives AKI to CKD was developed to investigate the role and molecular mechanism of epidermal growth factor receptor (EGFR). The EGF receptor mutant (Wa-2) mice and gefitinib were used to inactivation of EGFR.

Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys.

Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI).

Pharmacological inhibition of β-catenin prevents EndMT in vitro and vascular remodeling in vivo resulting from endothelial Akt1 suppression.

Endothelial to mesenchymal transition (EndMT), where endothelial cells acquire mesenchymal characteristics has been implicated in several cardiopulmonary, vascular and fibrotic diseases. The most commonly studied molecular mechanisms involved in EndMT include TGFβ, Notch, interleukin, and interferon-γ signaling. As of today, the contributions of Akt1, an important mediator of TGFβ signaling and a key regulator of endothelial barrier function to EndMT remains unclear.

Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair.

Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions.

Multiple-microarray analysis for identification of hub genes involved in tubulointerstial injury in diabetic nephropathy.

Diabetic nephropathy (DN) is a primary cause of renal failure. However, studies providing renal gene expression profiles of diabetic tubulointerstitial injury are scarce and its molecular mechanisms still await clarification. To identify vital genes involved in the diabetic tubulointerstitial injury, three microarray data sets from gene expression omnibus (GEO) were downloaded.

Epigenetic regulation in AKI and kidney repair: mechanisms and therapeutic implications.

Acute kidney injury (AKI) is a major public health concern associated with high morbidity and mortality. Despite decades of research, the pathogenesis of AKI remains incompletely understood and effective therapies are lacking. An increasing body of evidence suggests a role for epigenetic regulation in the process of AKI and kidney repair, involving remarkable changes in histone modifications, DNA methylation and the expression of various non-coding RNAs.

Endothelial stromelysin1 regulation by the forkhead box-O transcription factors is crucial in the exudative phase of acute lung injury.

Enhanced vascular permeability is associated with inflammation and edema in alveoli during the exudative phase of acute respiratory distress syndrome (ARDS). Mechanisms leading to the endothelial contribution on the early exudative stage of ARDS are not precise. We hypothesized that modulation of endothelial stromelysin1 expression and activity by Akt1-forkhead box-O transcription factors 1/3a (FoxO1/3a) pathway could play a significant role in regulating pulmonary edema during the initial stages of acute lung injury (ALI).

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury.

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters.

Identification of key biomarkers in diabetic nephropathy via bioinformatic analysis.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Although intense efforts have been made to elucidate the pathogenesis, the molecular mechanisms of DN remain to be clarified. To identify the candidate genes in the progression of DN, microarray datasets GSE30122, GSE30528, and GSE47183 were downloaded from the Gene Expression Omnibus database.

RNA interference may suppress stress granule formation by preventing argonaute 2 recruitment.

RNA-induced silencing complex (RISC) is formed during RNA interference (RNAi), whereas stress granules (SG) are assembled in response to cellular stress. Here, we demonstrate an interesting connection between RISC and SG that may involve argonaute 2 (Ago2), a core component of RISC. We analyzed SG induction by arsenite, the commonly used SG inducer.

PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury.

Cisplatin is a widely used chemotherapeutic drug with notorious toxicity in the kidneys, which involves mitochondrial dysfunction and damage in renal tubular cells. Mitophagy is a form of selective autophagy that removes damaged or dysfunctional mitochondria to maintain cellular homeostasis. In this study, we have used mouse and cell models to examine the role and regulation of mitophagy in cisplatin nephrotoxicity.

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease.

Background: Acute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear.

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer.

Recent studies indicate a stage-specific, differential role for the oncogene Akt on various cancers. In prostate cancer (PCa), suppression of Akt activity in the advanced stages promoted transforming growth factor-β (TGFβ) pathway-mediated epithelial-to-mesenchymal transition (EMT) and metastasis to the lungs. In the current study, we performed Affymetrix analysis to compare the expression profile of microRNAs in the mouse prostate tissues collected at the prostatic inter-epithelial neoplasia (PIN) stage from Transgenic adenocarcinoma of the mouse versus mice, and at the advanced stage from mice treated with triciribine (Akt inhibitor) versus DMSO-treated control.

Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury.

Acute kidney injury (AKI) is a medical condition characterized by kidney damage with a rapid decline of renal function, which is associated with high mortality and morbidity. Recent research has further established an intimate relationship between AKI and chronic kidney disease. Perturbations of kidney cells in AKI result in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), leading to unfolded protein response (UPR) or ER stress.