Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial cell dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions.

There Is Selective Increase in Pro-thrombotic Circulating Extracellular Vesicles in Acute Ischemic Stroke and Transient Ischemic Attack: A Study of Patients From the Middle East and Southeast Asia.

Stroke attacks were found to be present at a younger age in patients from Southeast Asia (SE) and the Middle East (ME) resident in the state of Qatar. Extracellular vesicles (EVs), which are small membrane vesicles with pro-thrombotic properties, may contribute to the high risk of stroke in this population. Thus, total and cell-specific medium size EVs were counted by flow cytometry in platelet-free plasma from healthy volunteers and patients with transient ischemic attacks (TIA) and acute ischemic stroke (AIS) from SE and ME. Acutely, within 48 h of attacks, there was an increase in total endothelial EVs in TIA (6.73 ± 1.77; P = 0.0156; n = 21) and AIS (11.23 ± 1.95; P = 0.0007; n = 66) patients compared to controls (2.04 ± 0.78; n = 24). Similar increases were also evident in EVs originating from platelets, erythrocytes, granulocytes, and leukocytes. Compared to controls, there was also an increase in EVs derived from activated endothelial cells, platelets, granulocytes, leukocytes, and pro-coagulant EVs (Annexin V+) at 5 and 30-days following the acute events, while a decrease was observed in erythrocyte-derived EVs. This is the first study characterizing EVs in TIA and AIS patients from ME and SE showing an increase in EVs associated with endothelial and platelet cell activation, which may contribute to the elevated risk of stroke at a younger age in this population.

Circulating microparticles as biomarkers of stroke: A focus on the value of endothelial- and platelet-derived microparticles.

Stroke is one of the leading causes of mortality and disability worldwide. Numerous pathophysiological mechanisms involving blood vessels, coagulation and inflammation contribute to the vascular occlusion. Perturbations in these pathways can be detected by numerous methods including changes in endoplasmic membrane remodeling and rearrangement leading to the shedding of microparticles (MPs) from various cellular origins in the blood. MPs are small membrane-derived vesicles that are shed from nearly all cells in the body in resting state or upon stimulation. MPs act as biological messengers to transfer information to adjacent and distant cells thus regulating various biological processes. MPs may be important biomarkers and tools for the identification of the risk and diagnosis of cerebrovascular diseases. Endothelial activation and dysfunction and altered thrombotic responses are two of the main features predisposing to stroke. Endothelial MPs (EMPs) have been recognized as both biomarkers and effectors of endothelial cell activation and injury while platelet-derived MPs (PMPs) carry a strong procoagulant potential and are activated in thrombotic states. Therefore, we reviewed here the role of EMPs and PMPs as biomarkers of stroke. Most studies reported high circulating levels of EMPs and PMPs in addition to other cell origins in stroke patients and have been linked to stroke severity, the size of infarction, and prognosis. The identification and quantification of EMPs and PMPs may thus be useful for the diagnosis and management of stroke.

BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models.

PURPOSE: Metastasis is the major cause of mortality in prostate cancer patients. Factors such as genetic makeup and race play critical role in the outcome of therapies. This study was conducted to investigate the relevance of BMI1 in metastatic prostate cancer disease in Caucasian and African-Americans. EXPERIMENTAL DESIGN: We employed race-specific prostate cancer models, clinical specimens, clinical data mining, gene-microarray, transcription-reporter assay, chromatin-immunoprecipitation (ChIP), IHC, transgenic-(tgfl/fl) zebrafish, and mouse metastasis models. RESULTS: BMI1 expression was observed to be elevated in metastatic tumors (lymph nodes, lungs, bones, liver) of Caucasian and African-American prostate cancer patients. The comparative analysis of stage III/IV tumors showed an increased BMI1 expression in African-Americans than Caucasians. TCGA and NIH/GEO clinical data corroborated to our findings. We show that BMI1 expression (i) positively correlates to metastatic (MYC, VEGF, cyclin D1) and (ii) negative correlates to tumor suppressor (INKF4A/p16, PTEN) levels in tumors. The correlation was prominent in African-American tumors. We show that BMI1 regulates the transcriptional activation of MYC, VEGF, INKF4A/p16, and PTEN. We show the effect of pharmacological inhibition of BMI1 on the metastatic genome and invasiveness of tumor cells. Next, we show the anti-metastatic efficacy of BMI1-inhibitor in transgenic zebrafish and mouse metastasis models. Docetaxel as monotherapy has poor outcome on the growth of metastatic tumors. BMI1 inhibitor as an adjuvant improved the taxane therapy in race-based in vitro and in vivo models. CONCLUSIONS: BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced prostate cancer in patients (including those belonging to high-risk group).