Oxygen sensors mediated HIF-1α accumulation and translocation: A pivotal mechanism of fine particles-exacerbated myocardial hypoxia injury.

Epidemiological studies have demonstrated a strong association of ambient fine particulate matter (PM2.5) exposure with the increasing mortality by ischemic heart disease (IHD), but the involved mechanisms remain poorly understood. Herein, we found that the chronic exposure of real ambient PM2.5 led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM2.5-induced HIF-1α accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1α-mediated energy metabolism remodeling from ß-oxidation to glycolysis had a critical role in the PM2.5-increased myocardial hypoxia injury. The in-depth analysis delineated that PM2.5 exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1α and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1α. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM2.5, resulting in the enhanced translocation of HIF-1α to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1α stabilization and translocation in PM-exacerbated myocardial hypoxia injury, we suggest this adds significantly to understanding the mechanisms of haze particles-caused burden of cardiovascular disease.

TBBPA stimulated cell migration of endometrial cancer via the contribution of NOX-generated ROS in lieu of energy metabolism.

Due to the extensive applications and deleterious effects of Tetrabromobisphenol A (TBBPA), the health risk and possible mechanisms have been a topic of concern. However, the knowledge on carcinogenic risk of TBBPA and corresponding mechanisms remains scarce. In this study, endometrial cancer cells were exposed to low doses of TBBPA and its main derivatives including TBBPA bis (2,3-dibromopropyl ether) (TBBPA-BDBPE) and TBBPA bis (2-hydroxyethyl ether) (TBBPA-BHEE). The data from wound healing and transwell assays demonstrated that TBBPA treatment exhibited the strongest enhanced effect on cell migration among other tested treatments. Of note, the process of invasion rather than epithelial-mesenchymal transition (EMT) was accompanied by the occurrence of migration elevated by TBBPA. Furthermore, the levels of several metabolite indicators were measured to assess the underlying mechanisms involved in TBBPA-induced cell migration. The findings suggested that NADPH oxidase (NOX)-driven ROS instead of energy metabolism was sensitive to TBBPA stimulation. In addition, molecular docking supported a link between TBBPA ligand and NOX receptor. Accordingly, this study has provided new insights for TBBPA-induced carcinogenic effects and may arise peoples' vigilance to environmental pollution of brominated flame retardant.

Critical biomarkers for myocardial damage by fine particulate matter: Focused on PPARα-regulated energy metabolism.

Fine particulate matter is one of the leading threats to cardiovascular health worldwide. The exploration of novel and sensitive biomarkers to detect damaging effect of fine particulate matter on cardiac tissues is of great importance in the better understanding of haze-caused myocardial injury. A link between heart failure and PPARα-regulated energy metabolism has been confirmed previously. Herein, the study intends to reveal the critical biomarkers of fine particulate matter induced myocardial damage from the PPARα-regulated energy metabolism. Ambient fine particulate matter induced severe pathological alterations in cultured cells, accompanied by the decrease in ATP content. Additionally, the expressions of CPT1/CPT2 and levels of CS and MDH, crucial members in ß-oxidation and the TCA cycle, were significantly decreased. In direct contrast, fine particulate matter increased the biomarkers of glycolysis, as measured by the accumulation of pyruvate and lactate contents, and the enhanced activities of HK and PKM1/2. Importantly, fine particulate matter-exposed cardiomyocytes exhibited the reduced PPARα level, that increased when cardiomyocytes were co-incubation with WY-14643 and fine particulate matter. Simultaneously, the adverse impact of fine particulate matter on critical biomarkers were observed in ß-oxidation, TCA cycle and glycolysis, associated with WY-14643 additional complement. Fine particulate matter caused the myocardial energy metabolism transformation through the regulation of PPARα expression and translation, which provided novel and critical biomarkers for haze particles-caused myocardial damage.

Fine particles cause the abnormality of cardiac ATP levels via PPARɑ-mediated utilization of fatty acid and glucose using in vivo and in vitro models.

Ambient fine particle (PM2.5) is one of the potential risk factors for the cardiovascular disease, which is characterized by a marked shift in energy substrate preference leading to the reduction of adenosine triphosphate (ATP) synthesis. The metabolic adaptation is brought about by alterations in substrate transporters. Hence, this study aimed to investigate the effects and possible mechanisms of seasonal PM2.5 exposure on alteration of cardiac ATP content. Sprague Dawley (SD) rats were exposed to summer and winter PM2.5 for two months to generate a cardiac damage phenotype, characterized by apoptosis, lipid peroxidation, and ATP depletion. Reduced fatty acid content and elevated glucose content were observed in haze dose PM2.5-exposed SD rats and rat cardiomyocyte cells. Expressions of their transporters in PM2.5-treated groups exhibited the homologous trends. Moreover, PM2.5 exposure repressed the expression and translocation of peroxisome proliferator-activated receptor alpha (PPARα) in a dose-dependent manner. However, the addition of WY-14643 (an inhibitor of PPARα) prominently alleviated the above phenomenons. The effect of PM2.5 in winter was found to be more serious than in summer. These results demonstrated that seasonal PM2.5 exposure causes the abnormality of cardiac ATP generation through the regulation of PPARα-mediated selection and utilization of energy substrates and their transporters. This study contributes in better understanding of haze-induced cardiovascular disease by revealing crucial indicators involved in this phenomenon.

Coexisting JAK2V617F and CALR Exon 9 Mutation in Essential Thrombocythemia.

Classic "BCR-ABL1-negative" MPN is an operational sub-category of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) harboring JAK2V617F as the most common mutation. JAK2V617F can be detected in about 95 % of patients with PV while remaining 5 % of PV patients carry a somatic mutation of JAK2 exon 12. Approximately one-third of patients with ET or PMF do not carry any mutation in JAK2 or MPL. In December 2013, mutations were described in calreticulin (CALR) gene in 67-71 and 56-88 % of JAK2V617F and MPL negative patients with ET and PMF, respectively. Since this discovery CALR mutations have been reported to be mutually exclusive with JAK2V617F or MPL mutations. However recently few studies (eleven published reports) reported the coexistence of JAK2V617F and CALR in MPN. In the present study we are reporting JAK2V617F positive ET patient from our center with coexisting CALR exon 9 mutation type c.1214_1225del12 (p.E405_D408del) that was never reported before as a coexisting mutation and describing in detail the clinical outcomes.

Coexisting JAK2V617F and CALR Exon 9 Mutations in Myeloproliferative Neoplasms - Do They Designate a New Subtype?

The classic BCR-ABL1-negative myeloproliferative neoplasm is an operational sub-category of MPNs that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2V617F mutation is found in ~ 95% of PV and 50-60% of ET or PMF. In most of the remaining JAK2V617F- negative PV cases, JAK2 exon 12 mutations are present. Amongst the JAK2V617F-negative ET or PMF 5-10% of patients carry mutations in the MPL gene. Prior to 2013, there was no specific molecular marker described in the remaining 30-40% ET and PMF. In December 2013, two research groups independently reported mutations in the gene CALR found specifically in ET (67-71%) and PMF (56-88%) but not in PV. Initially CALR mutations were reported mutually exclusive with JAK2 or MPL. However, co-occurrence of CALR mutations with JAK2V617F has been reported recently in a few MPN cases. Many studies have reported important diagnostic and prognostic significance of CALR mutations in ET and PMF patients and CALR mutation screening has been proposed to be incorporated into WHO diagnostic criteria for MPN. It is suggestive in diagnostic workup of MPN that CALR mutations should not be studied in MPN patients who carry JAK2 or MPL mutations. However JAK2V617F and CALR positive patients might have a different phenotype and clinical course, distinct from the JAK2-positive or CALR-positive subgroups and identification of the true frequency of these patients may be an important factor for defining the prognosis, risk factors and outcomes for MPN patients.