Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells

Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling might contribute to TK-10 cell apoptosis. We investigated the apoptotic effects of cordycepin by evaluating the activation of the ERK-JNK signaling pathway in renal cancer TK-10 cells. We found that cordycepin downregulated ERK and DUSP5, upregulated phosphorylated-JNK (p-JNK), and induced apoptosis. Moreover, we showed that siRNA-mediated inhibition of ERK downregulated DUSP5, whereas ERK overexpression upregulated DUSP5, and that DUSP5 knockdown by siRNA upregulated p-JNK. The JNK-specific inhibitor SP600125 upregulated nuclear translocation of β-catenin, and downregulated Dickkopf-1 (Dkk1), which has been shown to be a potent inhibitor of Wnt signaling. Dkk1 knockdown by siRNA upregulated nuclear β-catenin, suggesting the involvement of the Wnt/β-catenin signaling pathway. DUSP5 overexpression in TK-10 cells decreased p-JNK and increased nuclear β-catenin. The decreased Bax activation markedly protected against cordycepin-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Taken together, we show that JNK signaling activation by cordycepin mediated ERK inhibition, which might have induced Bax translocation and caspase-3 activation via regulation of DUSP5 in TK-10 cells, thereby promoting the apoptosis of TK-10 cells. Targeting ERK-JNK signaling via the apoptotic effects of cordycepin could be a potential therapeutic strategy to treat renal cancer

Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma

Forkhead transcription factor (Foxo3a) is a downstream effector of JNK-induced tumor suppression. However, it is not clear whether the caveolin-1 (CAV1)-mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK) and subsequent Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK, whereas CAV1 siRNA downregulated p-JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which downregulated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax protein and attenuated A549 apoptosis, indicating that the CAV1-mediated JNK/Foxo3a pathway induces the apoptosis of A549 lung cancer cells. Cordycepin significantly decreased tumor volume in nude mice. Taken together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation, inducing apoptosis in lung cancer cells, and support its potential as a therapeutic agent for lung cancer

Ketamine use for endotracheal intubation in severe sepsis and septic shock

Objective. We conducted this study to evaluate the clinical outcomes of patients with severe sepsis and septic shock who were treated with ketamine for endotracheal intubation. Methods. A single-center, retrospective study was carried out to compare the outcomes of patients with severe sepsis and septic shock who received a ketamine or non-ketamine agent for rapid sequence intubation (RSI). We analyzed the sepsis registry for adult patients who presented to the emergency department (ED), met the criteria for severe sepsis or septic shock, and underwent endotracheal intubation between August 2008 and March 2014. Te primary outcome was 28-day mortality. We performed a multivariable logistic regression analysis to assess the association between ketamine use for intubation and 28-day mortality. Results. In all, 170 patients were intubated during the study period. Of the eligible patients, 95 received ketamine and 75 received a non-ketamine agent. Te 28-day mortality of the ketamine group was not signifcantly diferent from that of the nonketamine group (38% vs. 40%, respectively,P=0.78). Te unadjusted odds ratio (OR) of ketamine use for 28-day mortality was 0.92 (95% CI: 0.49–1.70, P=0.78). Te association remained insignifcant afer adjusting for age, gender, malignancy, initial lactate level on ED admission, time to frst antibiotic administration, Acute Physiology and Chronic Health Evaluation II score on admission day, and propensity score regarding ketamine use (adjusted OR: 1.09; 95% confdence interval [CI]: 0.49–2.40;P=0.84). Initial serum lactate on ED admission was the only signifcant predictive factor of 28-day mortality (adjusted OR: 1.23; 95% CI: 1.10–1.38; P<0.01). Conclusions. For patients with severe sepsis and septic shock who were intubated using RSI, we found no signifcant diference in 28-day mortality between those who received ketamine as a sedative agent and those who received alternative sedatives

Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway

The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NF-κB activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer

Effect of typhoons on the Korean national emergency medical service system

Objective While the effect of typhoons on emergency medicine has been evaluated, data are scarce on their effects on the emergency medical service (EMS). This study evaluated the effect of typhoons on EMS patients and performance. Methods The study period was January 2010 to December 2012. Meteorological data regarding typhoons were provided by the Korean Meteorological Administration. EMS data were retrieved from the EMS database of the national emergency management agency. The database includes ambulance run sheets, which contain clinical and operational data. In this case-crossover study, the cases and controls were EMS calls on the day of typhoon warnings and calls one week prior to the typhoon warnings, respectively. Results During the study period, 11 typhoons affected Korea. A total of 14,521 cases were selected for analysis. Overall, there were no obvious differences between the case and control groups. However, there were statistically significant differences in age, place, and time requests. There were fewer patients between 0 and 15 years of age (P=0.01) and more unconscious patients (P=0.01) in the case group. The EMS operational performance, as measured by the times elapsed between call to start, call to field, and call to hospital did not differ significantly. There was also no significant difference in the time from hospital arrival between the cases (28.67, standard deviation 16.37) and controls (28.97, standard deviation 28.91) (P=0.39). Conclusion Typhoons did not significantly affect the EMS system in this study. Further study is necessary to understand the reasons for this finding

Combination therapy of vitamin C and thiamine for septic shock in a multicentre, double-blind, randomized, controlled study (ATESS): study protocol for a randomized controlled trial

Background Septic shock is a life-threatening condition with underlying circulatory and cellular/metabolic abnormalities. Vitamin C and thiamine are potential candidates for adjunctive therapy; they are expected to improve outcomes based on recent experimental and clinical research. The aim of the Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) trial is to evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock. Methods This study is a randomized, double-blind, placebo-controlled, multicentre trial in adult patients with septic shock recruited from six emergency departments in South Korea. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 116 septic shock patients (58 per group). For the treatment group, vitamin C (50 mg/kg) and thiamine (200 mg) will be mixed in 50 ml of 0.9% saline and administered intravenously every 12 h for a total of 48 h. For the placebo group, an identical volume of 0.9% saline will be administered in the same manner. The primary outcome is the delta Sequential Organ Failure Assessment (SOFA) score (ΔSOFA = initial SOFA at enrolment – follow-up SOFA after 72 h). Discussion This trial will provide valuable evidence about the effectiveness of vitamin C and thiamine therapy for septic shock. If effective, this therapy might improve survival and become one of the main therapeutic adjuncts for patients with septic shock. Trial registration ClinicalTrials.gov, NCT03756220. Registered on 5 December 2018.This work was supported by a National Research Foundation of Korea grant funded by the Korean government (No. 2018R1C1B6006821). The government did not have any role in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication