Induction of apoptotic cell death in human bladder cancer cells by ethanol extract of Zanthoxylum schinifolium leaf,through ROS-dependent inactivation of the PI3K/Akt signaling pathway

BACKGROUND/OBJECTIVESZanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells.MATERIALS/METHODSSubsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis.RESULTSEEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability.CONCLUSIONSTaken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.     

Impact of the COVID-19 Pandemic on Patient Delay and Clinical Outcomes for Patients With Acute Myocardial Infarction

BackgroundIt has been known that the fear of contagion during the coronavirus disease 2019 (COVID-19) creates time delays with subsequent impact on mortality in patients with acute myocardial infarction (AMI). However, difference of time delay and clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI between the COVID-19 pandemic and pre-pandemic era has not been fully investigated yet in Korea. The aim of this study was to investigate the impact of COVID-19 pandemic on time delays and clinical outcome in patients with STEMI or non-STEMI compared to the same period years prior.MethodsA total of 598 patients with STEMI (n = 195) or non-STEMI (n = 403) who underwent coronary angiography during the COVID-19 pandemic (February 1 to April 30, 2020) and pre-pandemic era (February 1 to April 30, 2017, 2018, and 2019) were analyzed in this study. Main outcomes were the incidence of time delay, cardiac arrest, and in-hospital death.ResultsThere was 13.5% reduction in the number of patients hospitalized with AMI during the pandemic compared to pre-pandemic era. In patients with STEMI, door to balloon time tended to be longer during the pandemic compared to pre-pandemic era (55.7 ± 12.6 minutes vs. 60.8 ± 13.0 minutes, P = 0.08). There were no significant differences in cardiac arrest (15.6% vs. 10.4%, P = 0.397) and in-hospital mortality (15.6% vs. 10.4%, P = 0.397) between pre-pandemic and the pandemic era. In patients with non-STEMI, symptom to door time was significantly longer (310.0 ± 346.2 minutes vs. 511.5 ± 635.7 minutes, P = 0.038) and the incidence of cardiac arrest (0.9% vs. 3.5%, P = 0.017) and in-hospital mortality (0.3% vs. 2.3%, P = 0.045) was significantly greater during the pandemic compared to pre-pandemic era. Among medications, angiotensin converting enzyme inhibitors/angiotensin type 2 receptor blockers (ACE-I/ARBs) were underused in STEMI (64.6% vs. 45.8%, P = 0.021) and non-STEMI (67.8% vs. 57.0%, P = 0.061) during the pandemic.ConclusionDuring the COVID-19 pandemic, there has been a considerable reduction in hospital admissions for AMI, time delay, and underuse of ACE-I/ARBs for the management of AMI, and this might be closely associated with the excess death in Korea.     

SYNCRIP controls miR-137 and striatal learning in animal models of methamphetamine abstinence

Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome. Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA–target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine (MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR, LC–MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.     

Sleep-promoting activity of lotus (Nelumbo nucifera) rhizome water extract via GABAA receptors

ContextThe sleep-promoting activity of Nelumbo nucifera Gaertn. (Nymphaeaceae) alkaloids in leaves or seeds are well known. However, the sleep-promoting activity of the lotus rhizome (LE), which is used mainly as food, has not yet been evaluated.ObjectiveWe investigated the sleep-promoting activity of LE water extract.Materials and methodsInstitute of Cancer Research (ICR) mice (n = 8) were subject to a pentobarbital-induced sleep test to assess changes in sleep latency and duration following the administration of LE (80–150 mg/kg). In addition, electroencephalography analysis was performed to determine the sleep quality after LE treatment as well as the sleep recovery effect of LE using a caffeine-induced insomnia SD rat model. Real-time PCR and western blot analysis were performed to investigate the expression of neurotransmitter receptors, and the GABA_A receptor antagonists were used for receptor binding analysis.ResultsAn oral administration of 150 mg/kg LE significantly increased sleep duration by 24% compared to the control. Furthermore, LE increased nonrapid eye movement (NREM) sleep by increasing theta and delta powers. In the insomnia model, LE increased sleep time by increasing NREM sleep. Moreover, treatment with picrotoxin and flumazenil decreased the sleep time by 33% and 23%, respectively, indicating an involvement of the GABA_A receptor in the sleep-enhancing activity of LE. The expression of GABA_A receptors and the concentration of GABA in the brain were increased by LE.Discussion and conclusionsThe results suggest that the sleep-promoting activity of LE was via the GABA_A receptor. Collectively, these data show that LE may promote sleep.     

Triple Therapy-Based on Tegoprazan,a New Potassium-Competitive Acid Blocker,for First-Line Treatment of Helicobacter pylori Infection: A Randomized,Double-Blind,Phase III,Clinical Trial

Background/AimsWe examined the efficacy and safety of tegoprazan as a part of first-line triple therapy for Helicobacter pylori eradication.MethodsA randomized, double-blind, controlled, multicenter study was performed to evaluate whether tegoprazan (50 mg)-based triple therapy (TPZ) was noninferior to lansoprazole (30 mg)-based triple therapy (LPZ) (with amoxicillin 1 g and clarithromycin 500 mg; all administered twice daily for 7 days) for treating H. pylori. The primary endpoint was the H. pylori eradication rate. Subgroup analyses were performed according to the cytochrome P450 (CYP) 2C19 genotype, the minimum inhibitory concentration (MIC) of amoxicillin and clarithromycin, and underlying gastric diseases.ResultsIn total, 350 H. pylori-positive patients were randomly allocated to the TPZ or LPZ group. The H. pylori eradication rates in the TPZ and LPZ groups were 62.86% (110/175) and 60.57% (106/175) in an intention-to-treat analysis and 69.33% (104/150) and 67.33% (101/150) in a per-protocol analysis (non-inferiority test, p=0.009 and p=0.013), respectively. Subgroup analyses according to MICs or CYP2C19 did not show remarkable differences in eradication rate. Both first-line triple therapies were well-tolerated with no notable differences.ConclusionsTPZ is as effective as proton pump inhibitor-based triple therapy and is as safe as first-line H. pylori eradication therapy but does not overcome the clarithromycin resistance of H. pylori in Korea (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT03317223","term_id":"NCT03317223"}}NCT03317223).