Protective Effects of Apamin on Acetaminophen-Induced Hepatotoxicity in Mice.

Acetaminophen (APAP) overdose can cause severe liver damage, but therapeutic options are limited. Apamin is a natural peptide present in bee venom and has antioxidant and anti-inflammatory properties. Accumulating evidence suggests that apamin has favorable actions in rodent models of inflammatory disorders. Here, we examined the effect of apamin on APAP-evoked hepatotoxicity. Intraperitoneal administration of apamin (0.1 mg/kg) alleviated histological abnormalities and reduced serum levels of liver enzymes in mice injected with APAP. Apamin inhibited oxidative stress through an increase in the amount of glutathione and activation of the antioxidant system. Apamin also attenuated apoptosis with inhibition of caspase-3 activation. Moreover, apamin reduced serum and hepatic levels of cytokines in APAP-injected mice. These effects were accompanied by suppression of NF-κB activation. Furthermore, apamin inhibited chemokine expression and inflammatory cell infiltration. Our results suggest that apamin dampens APAP-evoked hepatotoxicity through inhibiting oxidative stress, apoptosis, and inflammation.

Eupatilin Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Apoptosis in Mice.

Acute kidney injury (AKI) is a common complication of sepsis. Eupatilin (EUP) is a natural flavone with multiple biological activities and has beneficial effects against various inflammatory disorders. However, whether EUP has a favorable effect on septic AKI remains unknown. Here, we examined the effect of EUP on lipopolysaccharide (LPS)-evoked AKI in mice. LPS-evoked renal dysfunction was attenuated by EUP, as reflected by reductions in serum creatinine and blood urea nitrogen levels. LPS injection also induced structural damage such as tubular cell detachment, tubular dilatation, brush border loss of proximal tubules, and upregulation of tubular injury markers. However, EUP significantly ameliorated this structural damage. EUP decreased serum and renal cytokine levels, prevented macrophage infiltration, and inhibited mitogen-activated protein kinase and NF-κB signaling cascades. Lipid peroxidation and DNA oxidation were increased after LPS treatment. However, EUP mitigated LPS-evoked oxidative stress through downregulation of NPDPH oxidase 4 and upregulation of antioxidant enzymes. EUP also inhibited p53-mediated apoptosis in LPS-treated mice. Therefore, these results suggest that EUP ameliorates LPS-evoked AKI through inhibiting inflammation, oxidative stress, and apoptosis.

Protective Effects of Carnosic Acid on Lipopolysaccharide-Induced Acute Kidney Injury in Mice.

Septic acute kidney injury (AKI) is an important medical problem worldwide, but current treatments are limited. During sepsis, lipopolysaccharide (LPS) activates various signaling pathways involved in multiorgan failure. Carnosic acid is a natural phenolic diterpene and has multiple bioactivities, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, the effect of carnosic acid on septic AKI has not been explored. Therefore, this study aimed to determine whether carnosic acid has a therapeutic effect on LPS-induced kidney injury. Administration of carnosic acid after LPS injection ameliorated histological abnormalities and renal dysfunction. Cytokine production, immune cell infiltration, and nuclear factor-κB activation after LPS injection were also alleviated by carnosic acid. The compound suppressed oxidative stress with the modulation of pro-oxidant and antioxidant enzymes. Tubular cell apoptosis and caspase-3 activation were also inhibited by carnosic acid. These data suggest that carnosic acid ameliorates LPS-induced AKI via inhibition of inflammation, oxidative stress, and apoptosis and could serve as a useful treatment agent for septic AKI.

Zoletil promotes apoptosis in BV-2 microglial cells via induction of oxidative stress and neural inflammation.

Zoletil® (ZOL) is a combination drug of tiletamine, a dissociative anesthetic and zolazepam, a minor tranquilize, which has been used to induce short-term anesthesia in various animals. Depending on the administered dose, the effects of ZOL can range from sedation to anesthesia. Here, we aimed to determine the neurotoxicity of ZOL and elucidate its mechanism of action using BV-2 microglial cells. The results of MTT reduction assay and TUNEL staining revealed that ZOL induced neuronal toxicity and apoptosis in BV-2 cells. ZOL caused apoptosis via phosphorylation of c-Jun N-terminal kinase, increased ratio of Bax to Bcl-2, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, reactive oxygen species were involved in ZOL-induced neuronal cell death as assessed by 2',7'-dichlorofluorescein diacetate staining. Moreover, BV-2 cells treated with ZOL exhibited increased expression of inflammatory enzymes, such as inducible nitric oxide synthase and cyclooxygenase-2, along with subsequent production of nitric oxide and prostaglandin E2. ZOL upregulated the expression of interleukin-1ß, a proinflammatory cytokine. With respect to its molecular mechanism, ZOL increased the nuclear translocation and DNA binding of redox-sensitive transcription factor NF-κB, which seemed to be mediated by activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. These findings suggest that ZOL leads to apoptosis in BV-2 cells by inducing oxidative stress and inflammatory responses.

Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation.

Acetaminophen (APAP) can cause acute liver failure, but treatment options are still limited. Kahweol is the main diterpene compound of coffee and possesses antioxidant and anti-inflammatory properties. Emerging evidence suggests that this natural diterpene exerts favorable effects on several inflammatory diseases. However, the action of kahweol on APAP toxicity has not been addressed. The purpose of this study was to explore whether kahweol has a protective activity against APAP-induced hepatotoxicity and to investigate the mechanism. Administration of kahweol reduced serum levels of liver injury indicators and ameliorated histological abnormalities in APAP-treated mice. Kahweol inhibited lipid peroxidation and nucleic acid oxidation with restoration of glutathione content and stimulation of nuclear factor erythroid-2-related factor 2-dependent cellular defense system. Hepatocyte death was also decreased by kahweol, which was associated with inhibition of endoplasmic reticulum (ER) stress. Moreover, kahweol reduced hepatic levels of inflammatory mediators, inhibited nuclear factor-κB activation, and attenuated infiltration of neutrophils and macrophages. These findings suggest that kahweol has a protective activity against APAP-induced liver injury and this effect is related to the suppression of oxidative stress, hepatocyte death, ER stress, and inflammation.

Protective Effects of Bee Venom-Derived Phospholipase A2 against Cholestatic Liver Disease in Mice.

Hepatocyte apoptosis and inflammation play important roles in cholestatic liver diseases. Bee venom-derived secretory phospholipase A2 (bvPLA2) has been shown to ameliorate various inflammatory diseases. However, whether bvPLA2 has a therapeutic effect against cholestatic liver disease has not been evaluated. Therefore, we investigated the effects of bvPLA2 on cholestatic liver injury and fibrosis in a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding. The administration of bvPLA2 ameliorated liver damage, cholestasis, and fibrosis in DDC diet-fed mice, as assessed by serum biochemical tests and histological examinations. In addition, bvPLA2 reduced myofibroblast accumulation, concomitant with suppression of transforming growth factor-ß signaling cascade. The administration of bvPLA2 inhibited hepatocyte apoptosis in DDC diet-fed mice as represented by a reduction in the number of cells stained with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and suppression of caspase-3 activation. Moreover, bvPLA2 reduced cytokine production along with the inhibition of the nuclear factor kappa-B pathway. The number of regulatory T-cells was increased by bvPLA2, while the number of other immune cells, including neutrophils, macrophages, and CD8+ T-cells, was decreased. Our data indicate that the administration of bvPLA2 ameliorates cholestatic liver injury and fibrosis by inhibiting hepatocyte apoptosis and inflammation.

Effects of dynamic response to coronavirus disease outbreak in a regional emergency medical center: A retrospective study.

ABSTRACT: Emergency departments (EDs) are on the frontline of the coronavirus disease (COVID-19) outbreak. To resolve the abrupt overloading of COVID-19-suspected patients in a community, each ED needs to respond in various ways. In our hospital, we increased the isolation beds through temporary remodeling and by performing in-hospital COVID-19 polymerase chain reaction testing rather than outsourcing them. The aim of this study was to verify the effects of our response to the newly developed viral outbreak.The medical records of patients who presented to an ED were analyzed retrospectively. We divided the study period into 3: pre-COVID-19, transition period of response (the period before fully implementing the response measures), and post-response (the period after complete response). We compared the parameters of the National Emergency Department Information System and information about isolation and COVID-19.The number of daily ED patients was 86.8 ±â€Š15.4 in the pre-COVID-19, 36.3 ±â€Š13.6 in the transition period, and 67.2 ±â€Š10.0 in the post-response period (P < .001). The lengths of stay in the ED were significantly higher in transition period than in the other periods [pre-COVID-19 period, 219.0 (121.0-378.0) min; transition period, 301 (150.0-766.5) min; post-response period, 281.0 (114.0-575.0) min; P < .001]. The ratios of use of an isolation room and fever (≥37.5°C) were highest in the post-response period [use of isolation room: pre-COVID-19 period, 0.6 (0.7%); transition period, 1.2 (3.3%); post-response period, 16.1 (24.0%); P < .001; fever: pre-COVID-19 period, 14.8(17.3%); transition period, 6.8 (19.1%); post-response period, 14.5 (21.9%), P < .001].During an outbreak of a novel infectious disease, increasing the number of isolation rooms in the ED and applying a rapid confirmation test would enable the accommodation of more suspected patients, which could help reduce the risk posed to the community and thus prevent strain on the local emergency medical system.

External validation of multimodal termination of resuscitation rules for out-of-hospital cardiac arrest patients in the COVID-19 era.

BACKGROUND: Futile resuscitation for out-of-hospital cardiac arrest (OHCA) patients in the coronavirus disease (COVID)-19 era can lead to risk of disease transmission and unnecessary transport. Various existing basic or advanced life support (BLS or ALS, respectively) rules for the termination of resuscitation (TOR) have been derived and validated in North America and Asian countries. This study aimed to evaluate the external validation of these rules in predicting the survival outcomes of OHCA patients in the COVID-19 era. METHODS: This was a multicenter observational study using the WinCOVID-19 Daegu registry data collected during February 18-March 31, 2020. The subjects were patients who showed cardiac arrest of presumed cardiac etiology. The outcomes of each rule were compared to the actual patient survival outcomes. The sensitivity, specificity, false positive value (FPV), and positive predictive value (PPV) of each TOR rule were evaluated. RESULTS: In total, 170 of the 184 OHCA patients were eligible and evaluated. TOR was recommended for 122 patients based on the international basic life support termination of resuscitation (BLS-TOR) rule, which showed 85% specificity, 74% sensitivity, 0.8% FPV, and 99% PPV for predicting unfavorable survival outcomes. When the traditional BLS-TOR rules and KoCARC TOR rule II were applied to our registry, one patient met the TOR criteria but survived at hospital discharge. With regard to the FPV (upper limit of 95% confidence interval < 5%), specificity (100%), and PPV (> 99%) criteria, only the KoCARC TOR rule I, which included a combination of three factors including not being witnessed by emergency medical technicians, presenting with an asystole at the scene, and not experiencing prehospital shock delivery or return of spontaneous circulation, was found to be superior to all other TOR rules. CONCLUSION: Among the previous nine BLS and ALS TOR rules, KoCARC TOR rule I was most suitable for predicting poor survival outcomes and showed improved diagnostic performance. Further research on variations in resources and treatment protocols among facilities, regions, and cultures will be useful in determining the feasibility of TOR rules for COVID-19 patients worldwide.

Comparison of the effects of shortening rest intervals on the quality of cardiopulmonary resuscitation, physiological parameters, and hemodynamic parameters in well-trained rescuers: Randomized simulation study.

BACKGROUND: Cardiopulmonary resuscitation (CPR) performance depends on individual ability and training. Well-trained or professional rescuers can maintain high-quality CPR for longer than laypeople. This study aimed to examine the effects of reducing resting intervals on CPR performance, physiological parameters, and hemodynamic parameters during prolonged CPR in well-trained providers. METHODS: The study enrolled 90 volunteers from the paramedic students of our institution. They were randomly divided into 3 groups: 2 minutes, 1 minute 45 seconds, and 1 minute 30 seconds rest groups. Each participant performed 5 cycles of chest compression only CPR (2 min/cycle) with different resting intervals according to grouping. CPR quality, physiological variations, and hemodynamic variations were measured for each cycle and compared across the groups. RESULTS: Of the 90 volunteers, 79 well-trained providers were finally included. The variation of the average chest compression depth across the 5 cycles showed significant differences between the 3 groups: from cycle 1 to 2: 1.2 (3.1) mm, -0.8 (2.0) mm, and -2.0 (3.0) mm in the 2 minutes, 1 minute 45 seconds, and 1 minute 30 seconds groups, respectively (P < .001); from cycle 1 to 3: 0.0 (3.0) mm, -0.7 (3.2) mm, and -2.6 (3.9) mm, respectively (P = .030). However, all 3 groups maintained the recommended rate and chest compression depth for all 5 cycles. Physiological and hemodynamic parameters showed no significant differences between the groups. CONCLUSIONS: Well-trained providers were able to maintain high-quality CPR despite reducing rest intervals. Adjusting the rest interval may help maintain overall CPR quality in special situations or where layperson rescuers are involved.

Impact of the coronavirus disease 2019 outbreak on the transportation of patients requiring emergency care.

The first confirmed community transmission of coronavirus disease 2019 in Daegu Metropolitan City, South Korea, occurred on February 18, 2020. In the following 70-day period, approximately 6000 new cases occurred, severely impacting the medical service system. This study investigated the crisis-impact on the local emergency transport system.Emergency medical service activity reports were retrospectively reviewed to determine patient demographics and initial vital signs. Delay in reaching the patient, transporting the patient to the hospital, and returning to the fire station were assessed and categorized based on patients' initial vital signs. The study period was divided into 4 groups (1/1-2/18, 2/19-3/3, 3/4-3/31, and 4/1-04/30) and intergroup differences were analyzed.When compared to Period 1, the time-difference between the request to attend a scene and arrival at the scene was delayed in Periods 2, 3, and 4 by 4 minute 58 s, 3  minute 24 seconds, and 2 minute 20 seconds, respectively; that between arriving at the scene and at the hospital was delayed by 7  minute 43 seconds, 6 minutes 59 seconds, and 4 minutes 30 seconds, respectively; and that between arriving at the hospital and returning to the fire station was delayed by 29  minute 3 second, 25  minute 55 second, and 18  minute 44 second, respectively. In Period 2, for patients with symptoms of severe illness when compared to patients lacking such symptoms, the time-difference between the request to attend the scene and arrival at a hospital and between arrival at the hospital and returning to the fire station were 6 to 23 minute and 12 to 48 minute longer, respectively. Most of the delays impacted patients with a fever. In terms of condition, the statistical effect size for delay in transport time was from large to small: fever, hypoxia, abnormal respiratory rate, respiratory symptom, and hypotension.Outbreaks of infectious disease cause a paradoxical state in emergency medical transport systems, inducing delays in the transport of severely ill patients. Therefore, maintenance and improvement of the medical service system for both patients with infectious disease and those with other severe illnesses is required.

Preparedness of personal protective equipment and implementation of new CPR strategies for patients with out-of-hospital cardiac arrest in the COVID-19 era.

BACKGROUND: In February and March 2020, healthcare providers and citizens in Daegu, South Korea, experienced the onslaught of a large-scale community epidemic of COVID-19. This had a profound impact on patients who experienced out-of-hospital cardiac arrest (OHCA). METHODS: We conducted a retrospective observational study of 171 OHCA patients based on the multicenter WinCOVID registry. Demographic and clinical characteristics, overall survival, COVID-19 related data, as well as personal protective equipment (PPE) and resuscitation techniques used during the COVID-19 outbreak were evaluated and compared with outcomes from a 2018 historical cohort (n â€‹= â€‹158). RESULTS: Among the interventions, high-level PPE was introduced and standard cardiopulmonary resuscitation was changed to chest compressions using mechanical devices. All OHCA patients were treated as confirmed or suspicious for COVID-19 regardless of symptoms. Furthermore, complete or partial closures of emergency centers and the number of medical personnel requiring self-isolation decreased in response to the introduction of isolated resuscitation units. However, the adjusted odds ratio and 95% confidence intervals for survival discharge and favorable neurologic outcome were 0.51 (0.25-0.97) and 0.45 (0.21-1.07) compared with those in the 2018 historical cohort. CONCLUSIONS: Responses to the COVID-19 pandemic included changes to current PPE strategies and introduction of isolated resuscitation units; the latter intervention reduced the number of unexpected closures and quarantines of emergency resources early on during the COVID-19 outbreak. Given the possibility of future outbreaks, we need to have revised resuscitation strategies and the capacity to commandeer emergency resources for OHCA patients.

Acute dystonic reaction induced by a single dose of clebopride: A case report.

RATIONALE: Clebopride is known as a dopamine antagonist used for alleviating emetic symptoms with minimal side effects. Herein, we report a case of acute dystonic reaction possibly caused by administration of clebopride in a young male. PATIENT CONCERNS: A 19-year-old with no special medical conditions, visited a local clinic complaining of abdominal discomfort, associated with nausea and vomiting. The patient was prescribed with tiropramide, clebopride, simethicone, and mosapride citrate, only to visit the emergency department for abrupt neck pain followed with dystonic reactions upon oral administration of the drugs. The patient suffered involuntary movements of the neck to the right, while maintaining voluntary motor controls of the neck to the left. DIAGNOSIS: Vital signs and neurological exams showed no obscurity and the preliminary blood workup (a complete blood count and measurement of electrolytes, inflammatory marker levels, copper concentration, etc) were all within normal ranges. Additional imagery tests including brain computed tomography (CT), neck contrast-enhanced CT, and magnetic resonance imaging failed to prove any focal lesion pertinent to the condition. Drug screening was done and then clebopride was suspected to be the cause of the dystonic reactions. INTERVENTIONS: Benztropine (1 mg) was administered orally. OUTCOMES: The patient's symptoms improved after 1 hour, and he was observed for 6 more hours for possible recurrences before he was discharged. The patient was referred to an outpatient neurology department for 1 month, during which he had no recurrence or other extrapyramidal symptoms. LESSONS: Although it is uncommon to experience extrapyramidal symptoms by clebopride, its chemical closeness to metoclopramide may induce such symptoms under certain clinical situations. Therefore, physicians should take in consideration of this effect and dwell in caution upon prescribing the drug.