The effect of ulinastatin on acute kidney injury in patients undergoing off-pump cardiac bypass surgery.

BACKGROUND: Ulinastatin, an anti-inflammatory and antioxidant trypsin inhibitor, has shown potential in mitigating acute kidney injury (AKI) and reducing serum creatinine levels after various surgeries. This retrospective study aimed to evaluate the effects of ulinastatin on AKI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. METHODS: We hypothesized that the administration of ulinastatin could prevent AKI in OPCAB. Electrical medical records were reviewed to identify OPCAB patients between January 2015 and June 2020. The utilization of ulinastatin was randomly determined and applied during this period. Acute kidney injury was defined according to the KDIGO guideline, and its incidence was compared between the ulinastatin administration group and the control group. To investigate the effect of ulinastatin on renal function, multivariate logistic regression analysis was used to calculate propensity scores for each group. RESULTS: A total 454 OPCAB were performed, and after following inclusion and exclusion process, 100 patients were identified in the ulinastatin group and 303 patients in the control group. Using 1:2 propensity score matching, we analyzed 100 and 200 patients in the ulinastatin and control groups. The incidence of AKI was similar between the groups (2.5% for the control group, 2.0% for the ulinastatin group, p > 0.999). However, the serum creatinine value on the first post-operative day were significantly lower in the ulinastatin group compared to the control group (0.774 ± 0.179 mg/dL vs 0.823 ± 0.216 mg/dL, P = 0.040), while no significant differences were observed for the other time points (P > 0.05). The length of ICU stay day was significantly shorter in the ulinastatin group (2.91 ± 2.81 day vs 5.22 ± 7.45 day, respectively, P < 0.001). CONCLUSIONS: Ulinastatin did not have a significant effect on the incidence of AKI; it demonstrated the ability to reduce post-operative serum creatine levels at first post-operative day and shorten the length of ICU stay.

Intravenous dexamethasone does not prolong the duration of pudendal nerve block in infants and children undergoing hypospadias surgery: A randomized clinical trial.

BACKGROUND: The administration of intravenous dexamethasone increases the duration of neuraxial block and improves the quality of analgesia. However, little is known about these effects of dexamethasone on peripheral nerve blocks in children. AIMS: In this study, we aimed to investigate the benefit of intravenous dexamethasone for enhancing the effect of pudendal block on postoperative analgesia in children who underwent hypospadias surgery. METHODS: In total, 46 children aged 6-36 months who underwent hypospadias surgery were randomly allocated to either a control group (normal saline, group C) or dexamethasone group (0.5 mg/kg, group D). Pudendal block was performed before the surgery using 0.3 mL/kg of 0.225% ropivacaine on both sides. Parents were instructed to press the patient-controlled analgesia bolus button when their children's pain score was >4 points. The primary outcome measure was the time at which the first patient-controlled analgesia by proxy bolus dose was administered. The secondary outcome measures were pain score, number of patient-controlled analgesia administration by proxy bolus attempts, number of rescue analgesics required, total amount of fentanyl administered, and overall parental satisfaction. RESULTS: The time of first patient-controlled analgesia bolus administration by proxy was not different between the control and dexamethasone groups (5.6 [5.2, 8.8] h versus 6.5 [5.4, 8.1] h, hazard ratio 0.8, 95% confidence intervals 0.43 to 1.47, p = .46). There were no statistically significant differences among the secondary outcomes. CONCLUSIONS: Administration of intravenous dexamethasone did not enhance the duration of pudendal nerve block in infants and children aged 6-36 months who underwent hypospadias surgery.

The relationship between working time mismatch and depression according to actual hours worked.

OBJECTIVES: The effect of the combination of working hours and working time mismatch on depression is unknown. This study was undertaken to confirm the relationship between working time mismatch and depression with respect to hours worked. MATERIAL AND METHODS: The data of 45 514 adult workers that participated in the 6th Korean Working Conditions Survey (KWCS-VI 2020) were reviewed. Depression was defined using the World Health Organization 5 Well-Being Index (WHO-5) cut-off score of 50. Working time mismatch was defined as a difference between actual and desired working hours. To identify associations between working hour mismatch and depression according to weekly hours worked, stratification analysis was conducted by dividing the study subjects into 3 groups based on actual hours worked weekly (<40 h, 40-<52 h, or ≥52 h). Multiple logistic regression analysis adjusted for potential confounders was performed to calculate odds ratios of depression. RESULTS: In the <40 h, 40-<52 h, and ≥52 h groups, the odds ratios (OR) of working more hours than desired were 1.51, 95% CI: 1.20-1.92 (<40 h), 1.70, 95% CI: 1.58-1.84 (40-<52 h), and 1.55, 95% CI: 1.41-1.69 (≥52 h), respectively, compared to a matched actual versus desired working hours group (the matched group). On the other hand, the odds ratios of working fewer hours than desired were 1.17, 95% CI: 1.07-1.27 (<40 h), 1.38, 95% CI: 1.20-1.60 (40-<52 h), and 1.98, 95% CI: 1.24-3.17 (≥52 h), respectively. The risk of depression was found to increase significantly with working time mismatch within all 3 working hour groups. CONCLUSIONS: Working time mismatch increases the risk of worker depression regardless of hours worked. Int J Occup Med Environ Health. 2023;36(6):788-97.

The Impact of Head Elevation on Prevalence and Severity of Emergence Cough in Male Patients during Endotracheal Extubation.

BACKGROUND Emergence cough during endotracheal extubation can lead to complications. This cough is triggered by the deviation of the endotracheal tube from the airway anatomy, causing pressure on the airway mucosal wall. Head elevation has the potential to align the airway passage with the tube's configuration. In this study, we aimed to investigate the impact of head elevation using a pillow on the prevalence and severity of emergence cough in male patients. MATERIAL AND METHODS A total of 71 male patients undergoing laparoscopic cholecystectomy were randomly assigned to either the head elevation group (n=35) or the control group (n=36). The head elevation group maintained a position with a neck flexion angle of 35º using a pillow, while the control group remained in a neutral position after anesthetic induction. The severity of cough was assessed before, during, and after extubation using a 4-point scale, with grades 2 and 3 indicating cough and grade 3 indicating severe cough. RESULTS The characteristics and intraoperative data of the patients were similar between the two groups. There was no significant difference in the incidence of cough and severe cough between the groups. However, the severity of cough was significantly lower in the head elevation group compared to the control group before extubation (cough scale: 0/5/8/23 vs 1/2/17/15 in the control group vs the head elevation group, P=0.039). The time to extubation, respiratory complications, nausea, pain, and the number of patients receiving fentanyl were comparable between the groups. CONCLUSIONS Head elevation using a pillow effectively reduced the severity of cough before endotracheal extubation during anesthesia emergence in male patients. However, it did not significantly reduce the incidence of cough. These findings highlight the potential benefits of head elevation in minimizing the discomfort associated with emergence cough.

Border tissue morphology is associated with macular ganglion cell thickness in open-angle glaucoma.

Externally oblique border tissue (EOBT) configuration is topographically associated with glaucomatous damage in the optic nerve head. We investigated the relationship between the EOBT characteristics and macular retinal ganglion cell (RGC) thickness in patients with open-angle glaucoma (OAG). A total of 149 eyes with OAG that had an EOBT observed on optical coherence tomography exams were included. After determining the maximum EOBT length and angular location of the maximal EOBT length, we analyzed their correlation with macular ganglion cell inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness. The macular GCIPL and pRNFL thickness were compared based on the angular location of the longest EOBT, and their association was assessed using multivariable regression analysis. Maximum EOBT length was significantly correlated with macular GCIPL thickness, but not with pRNFL thickness. Macular GCIPL was thinnest in eyes with EOBT located in a temporal direction to the optic disc. Longer maximum EOBT and temporally elongated EOBT were independently associated with a thinner macular GCIPL in the multivariable regression analysis. These suggest that temporal elongation of the EOBT may increase the stress and strain on the RGCs derived from the macula and make RGCs more susceptible to glaucoma-inducing damage.

The Effect of Ramosetron on Remifentanil in Preventing Emergence Cough from Sevoflurane Anesthesia in Female Patients.

BACKGROUND: Remifentanil reduces cough during extubation. Ramosetron, a 5-HT3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients. METHODS: Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC50) and 95% of patients (EC95) were assessed using Dixon's up-and-down or isotonic regression method with a bootstrapping approach. RESULTS: Using Dixon's up-and-down method, the EC50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL). CONCLUSION: Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil.

Synthesis of Benzoxaphosphole 1-Oxide Heterocycles via a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Ketones.

An efficient and transition-metal-free three-component reaction with benzynes formed in situ from 2-(trimethylsilyl)aryl triflate, phosphites, and ketones was developed for the synthesis of benzoxaphosphole 1-oxides. An array of benzoxaphosphole 1-oxides were prepared from both activated and non-activated ketones in moderate to good yields with a broad functional group tolerance. This reaction is useful for preparing organophosphorus compounds encountered in natural products and materials.

Association between nicotine dependency with occupational injury in Korean men.

BACKGROUND: The relationship between smoking status or second-hand smoking and occupational injuries has been the subject of considerable study, but few have studied the relationship between nicotine dependence and occupational injuries. The objective of this study was to investigate the relationship between nicotine dependence and occupational injury among employees at a range of Korean companies. METHODS: Initially, the personal and occupational characteristics and nicotine dependences of workers were measured, and 12 months later a survey was used to determine whether subjects had experienced any occupational injury. This study was conducted in several workplaces on 6,893 male workers in manufacturing and service industries that received health screening at Inha University Hospital in Incheon. RESULTS: The adjusted odds ratios (ORs) of occupational injury in the low, moderate, and high nicotine dependence groups were 1.38 (95% confidence interval [CI]: 1.04-1.84), 1.52 (95% CI: 1.10-2.10), and 1.71 (95% CI: 0.92-3.19), respectively. For smokers only, adjusted ORs tended to increase linearly (p for trend < 0.05). When only smokers were included, analysis of continuous FTND (Fagerstrom Test of Nicotine Dependence) scores showed that adjusted OR increased by 1.10 (95% CI: 1.03-1.19) per FTND point. After stratifying the data by working type and working hours per week, the non-shift work group maintained this relationship (OR: 1.13, 95% CI: 1.04-1.24) and OR was higher in the group that works more than 60 hours per week with FTND score as a continuous variable (OR: 1.24, 95% CI: 1.07-1.44). CONCLUSIONS: The study shows nicotine dependency might affect occupational injury. From a short-term perspective, addressing worker's nicotine dependence by giving an adequate break time or smoking area might reduce work-related injuries.

Tracheal intubation with or without a neuromuscular blocking agent for a short surgical procedure in children: Prospective, randomized, double-blind trial.

BACKGROUND: Although a neuromuscular blocking agent during induction of anesthesia is the standard of care in adults, some pediatric anesthesiologists remain concerned about their use for several reasons. Therefore, propofol and short-acting opioids with a moderate concentration of sevoflurane have been used as alternatives to a neuromuscular blocking agent. AIMS: This study compared propofol, alfentanil, and rocuronium to determine the optimal anesthetic agent for intubation conditions as well as emergence in a short pediatric procedure. METHODS: In this prospective, randomized, double-blind study, 114 pediatric patients, aged 1-9 years, were randomly assigned to one of three groups receiving either propofol 2 mg kg-1 (propofol group), alfentanil 14 mcg kg-1 (alfentanil group), or rocuronium 0.3 mg kg-1 (rocuronium group). The primary outcome was intubating conditions, which were evaluated 90 s after test drug administration. Vital signs were recorded during the intubation period. Complications during and after emergence, time to recovery, airway-related complications, and severity of emergence agitation were recorded. RESULTS: Compared with the propofol group (60%), significantly more excellent intubating conditions were observed in the alfentanil group (97%, percent difference -37, 95% confidence interval (CI) -54.4--21.0, p < .001) and the rocuronium group (87%, percent difference -27, 95% CI -46.5--8.2, p = .041). Hemodynamic responses were different between the rocuronium and alfentanil groups, although the incidence of adverse events was not different among the three groups. The emergence duration was only statistically different between the rocuronium group [9.9 ± 3.2 min] and the propofol group [11.7 ± 2.2 min] (difference 95% CI 0.667-3.583, p = .001), while that of the alfentanil group [10.9 ± 2.4 min] was comparable with the other groups. CONCLUSIONS: Both 0.3 mg kg-1 rocuronium and 14 µg kg-1 alfentanil are superior adjuncts for tracheal intubation in children undergoing frenulectomy in comparison with 2 mg kg-1 propofol. Hemodynamic adverse events and recovery profiles were comparable among the three groups.

Clinical Utility of Combined Circulating Tumor Cell and Circulating Tumor DNA Assays for Diagnosis of Primary Lung Cancer.

BACKGROUND/AIM: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination. PATIENTS AND METHODS: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing. RESULTS: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type. CONCLUSION: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).

Influence of head and neck position on the performance of supraglottic airway devices: A systematic review and meta-analysis.

BACKGROUND: Changes in head and neck position may significantly affect the performance of supraglottic airway devices (SADs) by altering the pharyngeal structure. PURPOSE: This systematic review and meta-analysis aimed to elucidate the effect of changes in head and neck position on performance of SADs. DATA SOURCE: Bibliographic databases, including PubMed, EMBASE, the Cochrane library, and the Web of Science. STUDY ELIGIBILITY CRITERIA: Prospective studies investigating the effects of head and neck positions on the performance of SADs. METHODS: A random effect model was applied in the all analyses. Subgroup analysis was performed according to the type of device and the age of patient. The oropharyngeal leak pressure was the primary outcome measure. Secondary outcome measures included peak inspiratory pressure, fibreoptic view, and ventilation score (PROSPERO, CRD42017076971). RESULTS: Seventeen studies met the eligibility criteria. Overall, the oropharyngeal leak pressure significantly increased (mean difference 4.07 cmH2O; 95% confidence interval 3.30 to 4.84) during neck flexion with adverse effects on ventilation and fibreoptic view. Conversely, the oropharyngeal leak pressure decreased (mean difference -4.05; 95% confidence interval -4.90 to -3.20) during neck extension with no significant effect on ventilation or fibreoptic view. Rotation of the head and neck did not significantly affect SAD performance. CONCLUSIONS: The reduced oropharyngeal leak pressure in the extended neck position was not associated with impaired ventilation except with the air-Q self-pressurizing airway. The flexed neck position significantly worsens ventilation and the alignment between the SAD and glottis despite improving the seal except with the air-Q self-pressurizing airway and LMA Proseal.

Erratum: Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube.

This corrects the article on p. e43 in vol. 29, PMID: 29770616.

Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube.

OBJECTIVE: The aim of the present study was to assess the frequency of germline mutations in patients with peritoneal carcinoma (PC) or the fallopian tube carcinoma (FTC), using a multi-gene panel. METHODS: Twenty-six patients diagnosed with either PC or FTC between January 2013 and December 2016 were recruited consecutively. Germline DNA was sequenced using a 6-gene next generation sequencing (NGS) panel following genetic counseling. Surgico-medical information was obtained from hospital records. Genetic variations were detected using the panel and were cross-validated by Sanger direct sequencing. RESULTS: Germline BRCA1/2 mutations were identified in 6 patients (23.1%). Four were detected in patients with PC and 2 were in FTC patients. No mutations were detected in TP53, PTEN, CDH1, or PALB2. We identified 11 variant of uncertain significance (VUS) in 9 patients; 2 in BRCA1, 3 in BRCA2, 2 in TP53, and 4 in CDH1. We also detected a CDH1 c.2164+16->A VUS in 3 patients. CONCLUSION: The prevalence of germline BRCA1/2 mutations in patients with PC or FTC is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.

Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal.

The porcine major histocompatibility complex (MHC) is called swine leukocyte antigen (SLA), which controls immune responses and transplantation reactions. The SLA is mapped on pig chromosome 7 (SSC7) near the centromere. In this study, 3 class I (SLA-1, SLA-3, and SLA-2) and 3 class II (DRB1, DQB1, and DQA) genes were used for investigation of SLA haplotypes in Yucatan miniature pigs in Korea. This pig breed is a well-known model organism for biomedical research worldwide. The current study indicated that Korean Yucatan pig population had 3 Class I haplotypes (Lr-4.0, Lr-6.0, and Lr-25.0) and 3 class II haplotypes (Lr-0.5, Lr-0.7, and Lr-0.25). The combinations of SLA class I and II haplotype together, 2 homozygous (Lr-4.5/4.5 and Lr-6.7/6.7) and 3 heterozygous (Lr-4.5/6.7, Lr-4.5/25.25, and Lr-6.7/25.25) haplotypes were identified, including previously unidentified new heterozygous haplotypes (Lr-4.5/4.7). In addition, a new SLA allele typing method using Agilent 2100 bioanalyzer was developed that permitted more rapid identification of SLA haplotypes. These results will facilitate the breeding of SLA homozygous Yucatan pigs and will expedite the possible use of these pigs for the biomedical research, especially xenotransplantation research.

Stiffness of Hydrogels Regulates Cellular Reprogramming Efficiency Through Mesenchymal-to-Epithelial Transition and Stemness Markers.

The stiffness of hydrogels has been reported to direct cell fate. Here, we found that the stiffness of hydrogels promotes the reprogramming of mouse embryonic fibroblasts into induced pluripotent stem cells (iPSCs). We prepared cell culture substrates of various stiffnesses (0.1, 1, 4, 10, and 20 kPa) using a polyacrylamide hydrogel. We found that culture on a soft hydrogel plays an important role in inducing cellular reprogramming into iPSCs via activation of mesenchymal-to-epithelial transition and enhancement of stemness marker expression. These results suggest that physical signals at the interface between cell and substrate can be used as a potent regulator to promote cell fate changes associated with reprogramming into iPSCs, which may lead to effective and reproducible iPSC-production.

Note: Simple leak sealing technique for ultra-high vacuum cryostat by using freezable liquid.

Here we introduce a simple, low-cost, contamination-free, and highly reliable technique for sealing an ultra-high vacuum (UHV) cryostat by using cryogenically freezable liquid. We demonstrate it by sealing an UHV cryostat with dry leaks in the high vacuum range; ethanol was utilized to fill and block the leakage pathways through the subsequent in situ solidification by LN2. The seal is reversible and can be maintained as long as the cryostat is kept at cryogenic temperature.

Proposed Motor Scoring System in a Porcine Model of Parkinson's Disease induced by Chronic Subcutaneous Injection of MPTP.

Destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a common pathophysiology of Parkinson's disease (PD). Characteristics of PD patients include bradykinesia, muscle rigidity, tremor at rest and disturbances in balance. For about four decades, PD animal models have been produced by toxin-induced or gene-modified techniques. However, in mice, none of the gene-modified models showed all 4 major criteria of PD. Moreover, distinguishing between PD model pigs and normal pigs has not been well established. Therefore, we planned to produce a pig model for PD by chronic subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), neurotoxin. Changes in behavioral patterns of pigs were thoroughly evaluated and a new motor scoring system was established for this porcine model that was based on the Unified Parkinson's Disease Rating Scale (UPDRS) in human PD patients. In summary, this motor scoring system could be helpful to analyze the porcine PD model and to confirm the pathology prior to further examinations, such as positron emission tomography-computed tomography (PET-CT), which is expensive, and invasive immunohistochemistry (IHC) of the brain.

Pulse pressure variation is not a valid predictor of fluid responsiveness in patients with elevated left ventricular filling pressure.

PURPOSE: The purpose of this study was to test the hypothesis that the predictive ability of pulse pressure variation (PPV) for fluid responsiveness would be altered in patients with elevated left ventricular (LV) filling pressure. MATERIALS AND METHODS: According to the preoperative echocardiographic assessment of the ratio of early transmitral flow velocity to early diastolic velocity of the mitral annulus (E/E'), patients undergoing surgical coronary revascularization were classified into normal (n=34, E/E'<8) and high (n=34, E/E'>15) LV filling pressure group. After anesthetic induction, PPV and hemodynamic data were measured before and after 6 mL/kg of colloid administration. Fluid responsiveness was defined as 12% or more increase in stroke volume index assessed by pulmonary artery catheter and tested by the area under the receiver operating characteristic curve (AUROC). RESULTS: The AUROCs of PPV in the normal and high filling pressure group were 0.829 (95% confidence interval [CI], 0.661-0.963; P<.001) and 0.583 (95% CI, 0.402-0.749; P=.110), respectively. The AUROCs of cardiac filling pressures and right ventricular end-diastolic volume index did not show statistical significance in both groups. CONCLUSIONS: None of the assessed preload indices including PPV were able to predict fluid responsiveness in patients with elevated LV filling pressure.

Novel antimitotic activity of 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) through the inhibition of tubulin polymerization.

The natural chalcones and their derivatives exhibit many biological activities, such as anti-inflammatory and antitumoral. However, the precise mechanisms of action of benzochalcone derivatives are currently unknown. Here, a set of benzochalcones was synthesized, and the molecular mechanisms underlying inhibition of tumor growth were investigated. Colony-forming assays revealed that among tested compounds, 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) most effectively inhibited the clonogenicity of Capan-1 human pancreatic cancer cells. HymnPro inhibited cell proliferation in several human solid tumor cell lines and suppressed xenografted tumor growth in nude mice. Mechanistically, HymnPro induced cell cycle arrest at the G2/M phase, followed by an increase in apoptotic cell death. These events were associated with the inhibition of tubulin polymerization through binding of HymnPro to tubulin, leading to the formation of abnormal mono- or multipolar mitotic microtubule structures accompanied by spherical arrangement of multinucleated chromosomes. Furthermore, HymnPro activated caspase-2, caspase-9, caspase-3, and caspase-7 and increased the cleavage of poly(ADP-ribose) polymerase (PARP). HymnPro increased the phosphorylation of JNK1/2, Erk1/2, and p38 kinase. Pretreatment with SP600125, U0126, or SB600125 abrogated HymnPro-induced activation of caspases-3 and caspase-7 and the cleavage of PARP, suggesting that MAPK signalings are involved in HymnPro-induced apoptosis. It was concluded that a novel HymnPro compound exerts antitumor activity by disrupting microtubule assembly, which leads to mitotic arrest and sequential activation of the caspase pathway, resulting in apoptosis.

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K.

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine ß-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 µM, and 43.9 µM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 µM, and 42.5 µM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 µM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 µM and this value was higher than that of deprenyl (0.046 µM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 µM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.