OAS3 Deubiquitination Due to E3 Ligase TRIM21 Downregulation Promotes Epithelial Cell Apoptosis and Drives Sepsis-induced Acute Lung Injury.

Patients with sepsis-induced acute lung injury (SALI) show a high mortality rate, and there is no effective treatment in the clinic for SALI but only symptomatic treatment as an option. Therefore, searching for effective targets is critical for the management of SALI. Ubiquitination is an essential post-translational protein modification involved in most pathophysiological processes.

Endothelial β-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9.

Background: Diabetic angiogenesis is closely associated with disabilities and death caused by diabetic microvascular complications. Advanced glycation end products (AGEs) are abnormally accumulated in diabetic patients and are a key pathogenic factor for diabetic angiogenesis. The present study focuses on understanding the mechanisms underlying diabetic angiogenesis and identifying therapeutic targets based on these mechanisms.

Advanced glycation end products induce endothelial hyperpermeability via β-catenin phosphorylation and subsequent up-regulation of ADAM10.

Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. β-catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of β-catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked.

Interface-sensitized prodrug nanoaggregate as an effective in situ antitumor vaccine.

In situ antitumor vaccines have been widely explored as an effective strategy to inhibit tumor growth by stimulating antitumor immune responses. Herein, we reported a simple and effective in situ antitumor vaccine, which was prepared by co-assembling cationic lipids (DOTAP) with the disulfide bond-linked lipid-drug conjugates of camptothecin and resiquimod. The resulting vaccine had a rod-sharped morphology with nanoscale sizes (average hydrodynamic diameter of ∼163.

Kinetically-stable small-molecule prodrug nanoassemblies for cancer chemotherapy.

Self-delivering nanocarrier based on the small-molecule prodrug nanoassemblies (NAs) have been widely used for the efficient delivery of chemotherapeutics, but the effect of kinetic stability of NAs on their delivery performance has not been illuminated. In this study, two camptothecin (CPT)-oleic acid (OA) prodrugs were used to fabricate self-assembling nanorods with similar size distribution, zeta potential and morphology but having sharply different kinetic stability, which provided an ideal platform to investigate the effects of kinetic stability. It is found that the nanorods with high kinetic stability showed a lower in vitro cytotoxicity, but were more effective to inhibit the tumor growth probably by decreasing the premature CPT release and subsequent generation of the inactive carboxylate CPT.

Role of the Receptor for Advanced Glycation End Products in Heat Stress-Induced Endothelial Hyperpermeability in Acute Lung Injury.

Objective: To study the role of the receptor for advanced glycation end products (RAGE) in endothelial barrier dysfunction induced by heat stress, to further explore the signal pathway by which RAGE contributes to heat-induced endothelia response, and thereby find a novel target for the clinical treatment of ALI (acute lung injury) induced by heatstroke.

Methods: This study established the animal model of heatstroke using RAGE knockout mice. We observed the role of RAGE in acute lung injury induced by heatstroke in mice by evaluating the leukocytes, neutrophils, and protein concentration in BALF (Bronchoalveolar lavage fluids), lung wet/dry ratio, histopathological changes, and the morphological ultrastructure of lung tissue and arterial blood gas analysis.

The modulation relationship of genomic pattern of intratumor heterogeneity and immunity microenvironment heterogeneity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, with the second highest mortality rate among all cancer types. Growing evidence has demonstrated the notable effects of intratumor heterogeneity (ITH) and tumor immune microenvironment heterogeneity (TIMH) on the biological processes involved in HCC. However, the interactive mechanisms between ITH and TIMH is still unclear.

Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability.

Background/aims: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process.

Oxidative stress regulates mitogen‑activated protein kinases and c‑Jun activation involved in heat stress and lipopolysaccharide‑induced intestinal epithelial cell apoptosis.

Heat stress and gut‑derived endotoxinemia are common causes of multiple organ dysfunction syndrome in heat stroke patients. Evidence has demonstrated that cell apoptosis in the small intestine serves an important role in the pathogenesis of heatstroke, which leads to increased intestinal permeability to endotoxin or lipopolysaccharides (LPS) from the gut entering the circulation. However, little is known about the potential underlying mechanisms mediating heat stress combined with LPS‑induced intestinal epithelial cell apoptosis.

PAR1‑mediated c‑Jun activation promotes heat stress‑induced early stage apoptosis of human umbilical vein endothelial cells.

Our previous study indicated that when human umbilical vein endothelial cells (HUVECs), which are involved in endothelial barrier function, are heat stressed, levels of protease‑activated receptor 1 (PAR1) are increased significantly. In the present study, it was demonstrated that PAR1 serves a vital role in heat stress‑induced HUVEC apoptosis. When the PAR1 inhibitor, SCH79797 (SCH), or a small interfering RNA (siRNA) targeting PAR1 were used to inhibit PAR1 signaling, a marked decrease in cell apoptosis, caspase‑3 activity and the expression of the pro‑apoptotic protein B‑cell lymphoma 2 (Bcl‑2) associated X (Bax), as well as increased expression of the anti‑apoptotic Bcl‑2 family member, myeloid cell leukemia 1 (Mcl‑1), were observed.

Identification of phosphorylated MYL12B as a potential plasma biomarker for septic acute kidney injury using a quantitative proteomic approach.

Acute kidney injury (AKI) is a common and increasingly encountered complication in hospitalized patients with critical illness in intensive care units (ICU). According to the etiology, Sepsis-induced AKI (SAKI) is a leading contributor to AKI and significantly has very poor prognosis, which might be related to the late detection when the elevation of BUN and serum creatinine (SCr) is used. Many genes are up-regulated in the damaged kidney with the corresponding protein products appearing in plasma and urine.

Role of myosin light chain and myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability in vitro and in vivo.

We have previously reported that advanced glycation end products activated Rho-associated protein kinase and p38 mitogen-activated protein kinase, causing endothelial hyperpermeability. However, the mechanisms involved were not fully clarified. Here, we explored the role of myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability.

[Protective effects of ulinastatin against acute lung injury induced by heatstroke in mice].

Objective: To investigate the protective effect of ulinastatin (UTI) against acute lung injury induced by heatstroke in mice.

Methods: Sixty C57/BL6 mice were randomly divided into 6 groups, with 10 mice in each: control group, heatstroke group, UTI pretreatment group, saline pretreatment group, UTI post-treatment group, saline post-treatment group. The control mice were housed at a controlled room temperature of (22∓1) degrees; celsius, and the other groups were placed inside a temperature and humidity controlled chamber pre-set at 37 degrees; celsius and 60%.

Role of Src in Vascular Hyperpermeability Induced by Advanced Glycation End Products.

The disruption of microvascular barrier in response to advanced glycation end products (AGEs) stimulation contributes to vasculopathy associated with diabetes mellitus. Here, to study the role of Src and its association with moesin, VE-cadherin and focal adhesion kinase (FAK) in AGE-induced vascular hyperpermeability, we verified that AGE induced phosphorylation of Src, causing increased permeability in HUVECs. Cells over-expressed Src displayed a higher permeability after AGE treatment, accompanied with more obvious F-actin rearrangement.

NF-κB signaling is essential for resistance to heat stress-induced early stage apoptosis in human umbilical vein endothelial cells.

Cell apoptosis induced by heat stress is regulated by a complex signaling network. We previously reported that a p53-dependent pathway is involved. Here, we present evidence that NF-κB signaling plays a crucial role in preventing heat stress-induced early apoptosis.

Inhibition of microRNA-497 ameliorates anoxia/reoxygenation injury in cardiomyocytes by suppressing cell apoptosis and enhancing autophagy.

MiR-497 is predicted to target anti-apoptosis gene Bcl2 and autophagy gene microtubule-associated protein 1 light chain 3 B (LC3B), but the functional consequence of miR-497 in response to anoxia/reoxygenation (AR) or ischemia/reperfusion (IR) remains unknown. This study was designed to investigate the influences of miR-497 on myocardial AR or IR injury. We noted that miR-497 was enriched in cardiac tissues, while its expression was dynamically changed in murine hearts subjected to myocardial infarction and in neonatal rat cardiomyocytes (NRCs) subjected to AR.

[Mechanism of continuous venovenous hemofiltration combined with ulinastatin for the treatment of septic shock].

Objective: To investigate the molecular mechanisms of continuous venovenous hemofiltration (CVVH) combined with ulinastatin (ULI) (CVVH-ULI) for the treatment of septic shock.

Methods: Human umbilical endothelial cells (HUVECs) were incubated with serums isolated from normal healthy people (control), septic shock patients treated with conventional therapy (CT) or treated with CVVH combined with ULI (CVVH-ULI). Endothelial permeability was evaluated by the leakage of FITC-labeled albumin.

Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.

Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown.

Pharmacological modulation of autophagy to protect cardiomyocytes according to the time windows of ischaemia/reperfusion.

Background And Purpose: Targeted modulation of autophagy induced by myocardial ischaemia/reperfusion has been the subject of intensive investigation, but it is debatable whether autophagy is beneficial or harmful. Hence, we evaluated the effects of pharmacological manipulation of autophagy on the survival of cardiomyocytes in different time windows of ischaemia/reperfusion.

Experimental Approach: We examined the autophagy and apoptosis in cardiomyocytes subjected to different durations of anoxia/re-oxygenation or ischaemia/reperfusion, and evaluated the effects of the autophagic enhancer rapamycin and inhibitor wortmannin on cell survival.

Xuebijing injection reduces organ injuries and improves survival by attenuating inflammatory responses and endothelial injury in heatstroke mice.

Background: The pathogenesis of heatstroke is a multi-factorial process involved with an interplay among subsequent inflammation, endothelial injury and coagulation disturbances, which makes pharmacological therapy of heatstroke a challenging problem. Xuebijing injection (XBJ), a traditional Chinese medicine used to sepsis, has been reported to suppress inflammatory responses and restore coagulation disturbances. However, little is known about the role of XBJ in heatstroke.

Blockage of protease-activated receptor 1 ameliorates heat-stress induced intestinal high permeability and bacterial translocation.

Accumulated evidences indicate intestinal lesions play an important role in the pathogenesis of heatstroke. However, the underlying mechanisms by which heat stress causes intestinal barrier dysfunction and bacterial translocation remain unclear. In this study, we investigated the role of protease-activated receptor 1 (PAR1) in heat stress-induced intestinal hyper-permeability and bacterial translocation.

Persistence of systolic and diastolic regional dysfunction after brief episodes of myocardial ischemia evaluated with velocity vector imaging.

Background: The time course and characteristics of persistent regional dysfunction after ischemia remain unclear. Velocity vector imaging (VVI) allows accurate quantification of regional myocardial function. The aim of this study was to characterize the time course of regional diastolic and systolic abnormality after recovery from different durations of ischemia by VVI.

Pathological changes in the lung and brain of mice during heat stress and cooling treatment.

Background: Heatstroke often leads to multiple organ dysfunction syndrome (MODS) with a death rate of 40% or a neurological morbidity of 30%. These high rates in patients with heatstroke are largely due to the progression of heat stress to MODS, resulting in no specific treatment available. This study aimed to develop a mouse model of heat stress and determine the pathological changes in the lung and brain during heat stress and cooling treatment.

The effects of different sample labelling methods on signal intensities of a 60-mer diagnostic microarray.

The effects of four different labelling methods on signal intensities of a 60-mer diagnostic microarray were studied. Eighty of virus-specific oligonucleotide probes for human influenza virus were prepared in an array of 15x16 spots. RNA samples from cultured human influenza virus strains were labelled with four different methods, including direct cDNA labelling (DL), universal primer labelling (UPL), direct cDNA labelling with restriction display (DL-RD), and Cy-dUTP incorporated cDNA labelling with restriction display (IL-RD) in a signal color format.

A novel sample labeling method with restriction display PCR for 60-mer oligonucleotide microarray.

Objective: To investigate the value of restriction display PCR (RD-PCR) as a novel and expedient sample labeling method for high-density 60-mer oligonucleotide microarray.

Methods: Peripheral blood samples from three volunteers were collected and the total RNA was extracted from the peripheral blood mononuclear cells and labeled with RD-PCR protocol, followed by hybridization with Agilent Human 1B oligonucleotide microarrays in a two-color comparison format. The RNA from the same subject was divided into two aliquot and labeled with Cy3 and Cy5 respectively.