Project description:Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood. Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq).
Project description:Although chest pain in association with ST-segment electrocardiographic deviation is often indicative of cardiac ischemia, it has also been associated with noncardiac conditions. The case of a 63-year-old woman that we report here is extraordinary because her presentation of "acute abdomen" did not appear severe enough to warrant urgent surgical intervention, whereas the chest pain and electrocardiographic changes (supported by rising troponin levels) created strong clinical suspicion of acute coronary syndrome. Was the evidence of cardiac ischemia a primary event, or was it a sequela of an acute surgical condition? Noncardiac surgical cases associated with evidence of myocardial injury can be extremely challenging from a diagnostic and management perspective. We believe that the accuracy of the clinical diagnosis is crucial to a well-considered approach.
Project description:Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia-reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle-mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C-C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30-45 minutes) after reperfusion, whereas C-C chemokine receptor 2 contributes to IR injury at later time point (45-60 minutes) after reperfusion. Double deficiency of CypD and C-C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C-C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly-6Chigh monocytes after myocardial IR injury. In CypD-knockout mice, administration of interleukin-1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly-lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte-mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle-mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.
Project description:BackgroundEvidence indicated that the early stage transition of macrophages' polarization stages yielded a superior prognosis for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Rhein (cassic acid) is one major component of many traditional Chinese medicines, and has been reported to perform with strong anti-inflammation capabilities. However, the role rhein played and the mechanism via which it did so in LPS-induced ALI/ARDS remain unclear.MethodsALI/ARDS was induced by LPS (3 mg/kg, i.n, st), accompanied by the applications of rhein (50 and 100 mg/kg, i.p, qd), and a vehicle or NFATc1 inhibitor (10 mg/kg, i.p, qd) in vivo. Mice were sacrificed 48 h after modeling. Lung injury parameters, epithelial cell apoptosis, macrophage polarization, and oxidative stress were examined. In vitro, conditioned medium from alveolar epithelial cells stimulated by LPS was used for culturing a RAW264.7 cell line, along with rhein administrations (5 and 25 μM). RNA sequencing, molecule docking, biotin pull-down, ChIP-qPCR, and dual luciferase assay were performed to clarify the mechanisms of rhein in this pathological process.ResultsRhein significantly attenuated tissue inflammation and promoted macrophage M2 polarization transition in LPS-induced ALI/ARDS. In vitro, rhein alleviated the intracellular ROS level, the activation of P65, and thus the M1 polarization of macrophages. In terms of mechanism, rhein played its protective roles via targeting the NFATc1/Trem2 axis, whose function was significantly mitigated in both Trem2 and NFATc1 blocking experiments.ConclusionRhein promoted macrophage M2 polarization transition by targeting the NFATc1/Trem2 axis to regulate inflammation response and prognosis after ALI/ARDS, which shed more light on possibilities for the clinical treatments of this pathological process.
Project description:ObjectiveLittle is known regarding the functional role of microRNA-193-3p (miR-193-3p) in sepsis. Hence, the aim of the present study was to investigate the effect of miR-193-3p on myocardial injury in mice with sepsis and its mechanism through the regulation of signal transducers and activators of transcription 3 (STAT3).MethodsThe mice model of sepsis was established by cecal ligation and puncture (CLP), septic mice were injected with miR-193-3p agomir, miR-193-3p antagomir or siRNA-STAT3. The expression of miR-193-3p, STAT3 and HMGB1 in the myocardial tissue of septic mice were detected. Cardiac ultrasound, hemodynamics, myocardial injury markers, inflammatory factors and cardiomyocyte apoptosis in septic mice were measured.ResultsMiR-193-3p expression was reduced while STAT3 expression was increased in septic mice. Down-regulated STAT3 or up-regulated miR-193-3p improved cardiac function, attenuated myocardial injury, inflammation and cardiomyocyte apoptosis in septic mice. Knockdown STAT3 reversed the role of inhibited miR-193-3p for mice with sepsis. miR-193-3p targeted STAT3, thereby inhibiting HMGB1 expression.ConclusionThis study provides evidence that miR-193-3p targets STAT3 expression to reduce HMGB1 expression, thereby reducing septic myocardial damage. MiR-193-3p might be a potential candidate marker and therapeutic target for sepsis.
Project description:Aims: The inflammatory response and apoptosis are the major pathological features of myocardial ischemia/reperfusion injury (MI/RI). Maslinic acid (MA), a natural pentacyclic triterpene with various bioactivities, plays critical roles in the multiple cellular biological processes, but its protective effects on the pathophysiological processes of MI/RI have not been extensively investigated. Our study aimed to determine whether MA treatment alleviate ischemia/reperfusion (I/R)-induced myocardial inflammation and apoptosis both in vitro and in vivo, and further reveal the underlying mechanisms. Methods and results: An MI/RI rat model was successfully established by ligating the left anterior descending coronary artery and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to mimic I/R injury. In addition, prior to H/R stimulation or myocardial I/R operation, the H9c2 cells or rats were treated with varying concentrations of MA or vehicle for 24 h and two consecutive days, respectively. In this study, our results showed that MA could obviously increase the cell viability and decrease the cardiac enzymes release after H/R in vitro. MA could significantly improve the H/R-induced cardiomyocyte injury and I/R-induced myocardial injury in a dose-dependent manner. Moreover, MA suppressed the expression of inflammatory cytokines (tumor necrosis factor alpha [TNF-α, interleukin-1β [IL-1β and interleukin-6 [IL-6]) and the expressions of apoptosis-related proteins (cleaved caspase-3 and Bax) as well as increased the levels of anti-apoptotic protein Bcl-2 expression both in vitro and in vivo. Mechanistically, MA significantly inhibited nuclear translocation of nuclear factor-κB (NF-κB) p65 after H/R via regulating high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) axis. Conclusion: Taken together, MA treatment may alleviate MI/RI by suppressing both the inflammation and apoptosis in a dose-dependent manner, and the cardioprotective effect of MA may be partly attributable to the inactivation of HMGB1/TLR4/NF-κB pathway, which offers a new therapeutic strategy for MI/RI.
Project description:Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies only offer modest protection. Using stem cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified OCT3 (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in mice revealed that targeting OCT3 can attenuate cardiac dysfunction without compromising the anticancer properties of doxorubicin. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity
Project description:Microscale devices must overcome fluid reversibility to propel themselves in environments where viscous forces dominate. One approach, used by colloidal microwheels (?wheels) consisting of superparamagnetic particles assembled and powered by rotating ac magnetic fields, is to employ a nearby surface to provide friction. Here, we used total internal reflection microscopy to show that individual 8.3 ?m particles roll inefficiently with significant slip because of a particle-surface fluid gap of 20-80 nm. We determined that both gap width and slip increase with the increasing particle rotation rate when the load force is provided by gravity alone, thus providing an upper bound on translational velocity. By imposing an additional load force with a dc magnetic field gradient superimposed on the ac field, we were able to decrease the gap width and thereby enhance translation velocities. For example, an additional load force of 0.2 Fg provided by a dc field gradient increased the translational velocity from 40 to 80 ?m/s for a 40 Hz rotation rate. The translation velocity increases with the decreasing gap width whether the gap is varied by dc field gradient-induced load forces or by reducing the Debye length with salt. These results present a strategy to accelerate surface-enabled rolling of microscale particles and open the possibility of high-speed ?wheel rolling independent of the gravitational field.