Gooddrake1172

Targeting the cell cycle checkpoints and DNA damage response are promising therapeutic strategies for cancer. Adavosertib is a potent inhibitor of WEE1 kinase, which plays a critical role in regulating cell cycle checkpoints. However, the effect of adavosertib on hepatocellular carcinoma (HCC) treatment, including sorafenib-resistant HCC, has not been thoroughly studied. In this study, we comprehensively investigated the efficacy and pharmacology of adavosertib in HCC therapy. Adavosertib effectively inhibited the proliferation of HCC cells in vitro and suppressed tumor growth in HCC xenografts and patient-derived xenograft (PDX) models in vivo. Additionally, adavosertib treatment effectively inhibited the motility of HCC cells by impairing pseudopodia formation. Further, we revealed that adavosertib induced DNA damage and premature mitosis entrance by disturbing the cell cycle. Thus, HCC cells accumulating DNA damage underwent mitosis without G2/M checkpoint arrest, thereby leading to mitotic catastrophe and apoptosis under adavosertib administration. Given that sorafenib resistance is common in HCC in clinical practice, we also explored the efficacy of adavosertib in sorafenib-resistant HCC. Notably, adavosertib still showed a desirable inhibitory effect on the growth of sorafenib-resistant HCC cells. Adavosertib markedly induced G2/M checkpoint arrest and cell apoptosis in a dose-dependent manner, confirming the similar efficacy of adavosertib in sorafenib-resistant HCC. Collectively, our results highlight the treatment efficacy of adavosertib in HCC regardless of sorafenib resistance, providing insights into exploring novel strategies for HCC therapy.Lactucopicrin, a bitter sesquiterpene lactone of leafy vegetables, such as chicory, curly escarole, and lettuce, possesses anti-malarial, anti-cancer and analgesic properties. However, it remains unknown whether lactucopicrin could inhibit vascular endothelial nuclear factor-κB (NF-κB) activation, a hallmark of vascular inflammatory diseases including sepsis. In tumor necrosis factor-α-stimulated human or mouse aortic endothelial cells, lactucopicrin dose-dependently inhibited NF-κB activation, and concomitantly repressed both vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1)-mediated monocyte adhesion. The lactucopicrin effect was not due to modulation of inhibitor of NF-κB kinases (IKK) α/β/γ, inhibitor of NF-κB alpha (IκBα), and NF-κB/p65 DNA binding activity. Instead, lactucopicrin inhibited importin-α3 expression by destabilization of its mRNA, an effect mediating the lactucopicrin effect on NF-κB activity. More importantly, in lipopolysaccharide (LPS)-elicited septic mice, oral gavage with lactucopicrin decreased mortality by 30.5% as compared with the control treatment. This effect was associated with inhibited importin-α3 expression, suppressed NF-κB activation and VCAM-1/ICAM-1 expression, and inhibited leukocyte influx in the vascular endothelium of both lung and aorta. Collectively, our novel data suggest that dietary supplementation with lactucopicrin inhibits endothelial NF-κB activation by down-regulation of importin-α3 and thereby improves sepsis.The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects on the body, especially on the cardiac system and gastrointestinal tract. ACE II is responsible for converting Ang II into the active peptide Ang-(1-7), which in turn binds to a metabotropic receptor, the Mas receptor (MasR). Recent studies have demonstrated that Diminazene Aceturate (DIZE), a trypanosomicide used in animals, activates the ACE II pathway. In this study, we aimed to evaluate the antidiarrheal effects promoted by the administration of DIZE to activate the ACE II/Ang-(1-7)/MasR axis in induced diarrhea mice models. The results show that activation of the ACE II pathway exerts antidiarrheal effects that reduce total diarrheal stools and enteropooling. In addition, it increases Na+/K+-ATPase activity and reduces gastrointestinal transit and thus inhibits contractions of intestinal smooth muscle; decreases transepithelial electrical resistance, epithelial permeability, PGE2-induced diarrhea, and proinflammatory cytokines; and increases anti-inflammatory cytokines. Enzyme-linked immunosorbent assay (ELISA) demonstrated that DIZE, when activating the ACE II/Ang-(1-7)/MasR axis, can still interact with GM1 receptors, which reduces cholera toxin-induced diarrhea. Therefore, activation of the ACE II/Ang-(1-7)/MasR axis can be an important pharmacological target for the treatment of diarrheal diseases.Mitochondrial dependent oxidative stress (OS) and subsequent cell death are considered as the major cytotoxicity caused by Triethylene glycol dimethacrylate (TEGDMA), a commonly monomer of many resin-based dental composites. SMI-4a mw Under OS microenvironment, autophagy serves as a cell homeostatic mechanism and maintains redox balance through degradation or turnover of cellular components in order to promote cell survival. However, whether autophagy is involved in the mitochondrial oxidative damage and apoptosis induced by TEGDMA, and the cellular signaling pathways underlying this process remain unclear. In the present study, we demonstrated that TEGDMA induced mouse preodontoblast cell line (mDPC6T) dysfunctional mitochondrial oxidative response. In further exploring the underlying mechanisms, we found that TEGDMA impaired autophagic flux, as evidenced by increased LC3-II expression and hindered p62 degradation, thereby causing both mitochondrial oxidative damage and cell apoptosis. These results were further verified by treatment with chloroquine (autophagy inhibitor) and rapamycin (autophagy promotor). More importantly, we found that the JNK/MAPK pathway was the key upstream regulator of above injury process. Collectively, our finding firstly demonstrated that TEGDMA induced JNK-dependent autophagy, thereby promoting mitochondrial dysfunction-associated oxidative damage and apoptosis in preodontoblast.

The efficacy of balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension would be promising. However, some patients showed residual dyspnea or symptoms, despite normalized hemodynamics. We aimed to clarify the clinical impact of oxygenation parameters on BPA outcome.

Ninety-nine consecutive patients who underwent BPA from September 2011 to December 2019 were enrolled. We evaluated hemodynamics with right heart catheterization, arterial blood gas examination, New York Heart Association functional class (NYHA-FC), respiratory function tests, nocturnal oximetry, and exercise capacity (6-min walk test and cardiopulmonary exercise testing) at baseline and after BPA.

Nearly normal hemodynamics was achieved after BPA (mean pulmonary artery pressure (PAP) 37.5 ± 10.0 to 20.6 ± 4.9 mmHg, p < 0.01). Oxygenation slightly improved (partial pressure of arterial oxygen; 61.5 ± 12.3 to 67.7 ± 12.7 mmHg, p < 0.01). Exertional desaturation remained unchanged (-8.