Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology.

OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date. METHODS: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models. RESULTS: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown. CONCLUSIONS: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Predictors for emergency readmission in patients with ureteral calculi: a focus on pain management and stone location.

BACKGROUND: The management of patients with ureteral calculi in the emergency department (ED) remains challenging due to high revisit rates. PURPOSE: To identify predictors of revisits among patients with ureteral calculi in the ED. DESIGN, SETTING, AND PARTICIPANTS: Data from patients who presented at a tertiary academic hospital in Seoul, Republic of Korea, between February 2018 and December 2019, were analyzed retrospectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables, including the respiratory rate (RR), estimated glomerular filtration rate (eGFR), duration of pain, number of analgesic doses, location of ureteral calculi, and ED length of stay (LOS) were examined using logistic regression. We also examined some additional variables included in the STONE and CHOKAI scoring systems to examine their association with revisit. RESULTS: Significant predictors of revisits included the number of analgesic doses and the location of ureteral calculi. Patients who required multiple analgesic doses or those with proximal or mid-ureteral calculi were more likely to revisit the ED. Although the STONE and CHOKAI scores could predict uncomplicated ureteral calculi, we found that the CHOKAI score is a valuable tool for predicting the likelihood of patient revisits (p = 0.021). CONCLUSIONS: Effective pain management and consideration of calculi location are important for predicting patient revisits. More research is required to validate findings, develop precise predictive models, and empower tailored care for high-risk patients. In patients with ureteral calculi in the ED, the number of analgesics given and stone location predict return visits. Proximal ureteral calculi on CT may require early urologic intervention to prevent pain-related revisits.

Natural Product-Based Glycolysis Inhibitors as a Therapeutic Strategy for Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Targeted therapy against the epidermal growth factor receptor (EGFR) is a promising treatment approach for NSCLC. However, resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge in its clinical management. EGFR mutation elevates the expression of hypoxia-inducible factor-1 alpha to upregulate the production of glycolytic enzymes, increasing glycolysis and tumor resistance. The inhibition of glycolysis can be a potential strategy for overcoming EGFR-TKI resistance and enhancing the effectiveness of EGFR-TKIs. In this review, we specifically explored the effectiveness of pyruvate dehydrogenase kinase inhibitors and lactate dehydrogenase A inhibitors in combating EGFR-TKI resistance. The aim was to summarize the effects of these natural products in preclinical NSCLC models to provide a comprehensive understanding of the potential therapeutic effects. The study findings suggest that natural products can be promising inhibitors of glycolytic enzymes for the treatment of EGFR-TKI-resistant NSCLC. Further investigations through preclinical and clinical studies are required to validate the efficacy of natural product-based glycolytic inhibitors as innovative therapeutic modalities for NSCLC.

Validation of the Korean Version of the Clinical Frailty Scale-Adjusted Korean Triage and Acuity Scale for Older Patients in the Emergency Department.

Background and Objectives: The Clinical Frailty Scale (CFS), used to screen for prehospital frailty in patients aged >65 years, is simple, time-efficient, and has been validated in emergency departments (EDs). In this study, we analyzed whether the Korean Triage and Acuity Scale (KTAS) classification by level in older patients determined to have frailty based on the Korean version of the CFS increases the triage performance of the current KTAS. Materials and Methods: The primary outcome was 30-day in-hospital mortality, and secondary outcomes were hospital and intensive care unit (ICU) admissions. This study retrospectively analyzed prospectively collected data from three ED centers. Patients with a CFS score ranging from five (mildly frail) to nine (terminally ill) were categorized into the frailty group. We upgraded the KTAS classification of the frailty group by one level of urgency and defined this as the CFS-KTAS. Results: The cutoff values for predicting admission were three and two for the KTAS and CFS-KTAS, respectively. A significant difference was observed in the area under the receiver operating characteristic (AUROC) curve between the KTAS and CFS-KTAS. To predict ICU admission, the cutoff score was two for both scales. A significant difference was observed in the AUROC curve between the KTAS and CFS-KTAS. For predicting in-hospital mortality, the cutoff score was two for both scales. A significant difference was observed in the AUROC curve between the KTAS and CFS-KTAS. Conclusions: This study showed that the CFS-adjusted KTAS has a more useful prognostic value than the KTAS alone for predicting hospital outcomes in older patients.

Comparison of antibiotic resistance rates and outcomes among older adult patients with urinary tract infections living in long- term care hospitals and the community.

OBJECTIVE: In this study, we compared the proportion of antibiotic resistance between patients who visited the emergency department (ED) with urinary tract infection (UTI) from long-term care hospitals (LTCH), which is a type of long-term care facilities (LTCF) and the community. We assessed the resulting difference in prognosis. METHOD: Older adults who visited the ED between January and December 2019 and were diagnosed with UTI were divided into community residents and LTCH residents. We investigated the antibiotics sensitivity rates, end of therapy (EOT), and the patient's outcomes were evaluated. RESULTS: The antibiotic resistance rate was higher in LTCH residents. LTCH residents had a higher in hospital mortality rate compared to community residents. EOT was found to be longer, and admission rate and in-hospital mortality rate were also higher in LTCH residents. CONCLUSION: LTCF residents had a higher rate of antibiotic resistance and a poor prognosis.

Association between type 2 diabetes and skeletal muscle quality assessed by abdominal computed tomography scan.

AIM: To examine the association between type 2 diabetes and the amount and quality of trunk muscle as assessed by computed tomography (CT) scan. MATERIALS AND METHODS: A total of 20,986 subjects (13,007 men and 7979 women) who underwent abdominal CT scan as part of a routine health check-up were included. The total abdominal muscle area (TAMA) measured at the third lumbar vertebrae was classified into skeletal muscle area (SMA), and intermuscular adipose tissue area. SMA was divided into good quality muscles (normal attenuation muscle area [NAMA]) and poor quality muscles (low attenuation muscle area). NAMA/TAMA index was calculated. RESULTS: Subjects with type 2 diabetes had higher values of TAMA and SMA but significantly lower values of NAMA and NAMA/TAMA index. Compared with those in the lowest quartile of NAMA/TAMA index, subjects in the highest quartile had metabolically favourable laboratory findings, a lower prevalence of type 2 diabetes (Q1 vs. Q4: 19.3% vs. 9.5% in men, 12.3% vs. 3.0% in women) and inverse association with type 2 diabetes (odds ratio for Q2, Q3, and Q4: 0.87, 0.78, and 0.75 in men; 0.82, 0.70, and 0.68 in women) after multivariable adjustment. CONCLUSIONS: The amount of good quality muscle on CT scan was associated with a lower prevalence of type 2 diabetes.

Association Between Muscle Quality Measured by Abdominal Computed Tomography and Subclinical Coronary Atherosclerosis.

OBJECTIVE: Low muscle mass was known to be associated with cardiovascular diseases. However, only few studies investigated the association between muscle quality and subclinical coronary atherosclerosis. Thus, we evaluated whether muscle quality measured by abdominal computed tomography is associated with the risk of coronary artery calcification. Approach and Results: We conducted a cross-sectional study on 4068 subjects without cardiovascular disease who underwent abdominal and coronary computed tomography between 2012 and 2013 during health examinations. The cross-sectional area of the skeletal muscle was measured at the L3 level (total abdominal muscle area) and segmented into normal attenuation muscle area, low attenuation muscle area, and intramuscular adipose tissue. We calculated the normal attenuation muscle area/total abdominal muscle area index, of which a higher value reflected a higher proportion of good quality muscle (normal attenuation muscle area) and a lower proportion of myosteatosis (low attenuation muscle area and intramuscular adipose tissue). In women, as the normal attenuation muscle area/total abdominal muscle area quartiles increased, the odds ratios (95% CIs) for significant coronary artery calcification (>100) consistently decreased (0.44 [0.24-0.80], 0.39 [0.19-0.81], 0.34 [0.12-0.98]; P=0.003) after adjusting for cardiovascular risk factors including visceral fat area and insulin resistance. In men, the odds ratios in the Q2 group were significantly lower than those in the Q1, but the association was attenuated in Q3-4 after adjustment. CONCLUSIONS: A higher proportion of good quality muscle was strongly associated with a lower prevalence of significant coronary artery calcification after adjustment, especially in women. Poor skeletal muscle quality may be an important risk factor for subclinical coronary atherosclerosis.

Epidemiology, injury characteristics and clinical outcomes of bicycle and motorcycle accidents in the under 20 population: South Korea.

BACKGROUND: Bicycles and motorcycles are a main means of transportation and leisure for individuals aged under 20 years in South Korea. We aimed to identify the epidemiology of injuries and describe and compare patterns of injury and clinical outcomes of two-wheel vehicle-related accidents in these individuals. METHODS: We analysed data obtained from the National Emergency Department Information System for 401 emergency departments (EDs) from January 2016 to December 2018. We included patients aged < 20 years who experienced injuries while driving or a passenger on two-wheeled vehicles. We analysed patients with a bicycle-related injury and those with a motorcycle-related injury, and then compared two groups and performed a regression analysis for factors predicting severe trauma. RESULTS: This study enrolled 54,342 two-wheel vehicle injury patients (37,410 bicycle and 16,932 motorcycle-related), of which, 86.8% (bicycle) and 94.9% (motorcycle) were males. External injuries were the most common. ED mortality was 9 (0.0%) for bicycles and 53 (0.3%) for motorcycles. Overall, 3,346 (8.9%) patients were hospitalised with bicycle injuries and 4,096 (24.2%) with motorcycle injuries. Among admitted patients with bicycle-related injuries, 48.7% had upper extremity injuries and among those admitted patients with motorcycle-related injuries, 76.0% had lower extremity injuries. Among hospitalised patients, the mean injury severity score (ISS) was 12.0 ± 12.6 in bicycle-related injury and 17.6 ± 15.4 in motorcycle-related injury. The number of patients with ISS ≥ 16 was 27.6% for bicycle related injuries and 45.2% for motorcycle-related injuries. The mean length of hospital stay was 191.5.8 ± 224.2 h for bicycle injury, and 359.6 ± 416.7 h for motorcycles. Hospital mortality cases were 0.2% with bicycle injury and 1.2% with motorcycle injury. Motorcycle-related injuries had more severe injury (ISS ≥ 16), with an adjusted odds ratio of 2.825 (95% confidence interval 2.610-3.059) compared to bicycle-related injuries. CONCLUSIONS: In the population aged under 20 years, two-wheel vehicle-related occurred predominantly in males. When using two-wheeled vehicles, motorcycle injuries were higher in patients aged over 14 years and were associated with higher ISS (≥ 16). Political efforts should be made to educate under 20 years of age for safe driving and to wear protective gear, including helmets to prevent severe injury.

Comparative Analysis of Characteristics of Patients Who Visited the Emergency Department due to Suicide Attempts During Coronavirus Disease-2019 Pandemic.

The coronavirus infection 2019 (COVID-19) pandemic has affected on mental health and contributed to increased depression and anxiety. We assessed the impact of the COVID-19 pandemic on suicide-related the emergency department (ED) visits. We compared the characteristics of suicide-related patients who visited the ED between the "COVID-19 period" and the "pre-COVID-19 period". The mean age of patients was younger after COVID-19 pandemic. In comparison by age group, the proportion of patients during the COVID-19 period increased in their teens and 20s, and the rest of the age groups decreased. The proportion of patients who requested help was higher during the COVID-19. The authenticity of suicide attempts showed a higher proportion of patients during the pre-COVID-19. Therefore, during the pandemic, attention should be paid to worsening mental health problems, such as anxiety or depression, rather than the lethality of suicide attempts.

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance.

Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization and dysbiosis contributes to inflammatory bowel disease (IBD) pathogenesis. However, the molecular factors mediating colonic homeostasis are not well characterized. Here, we found that Ninjurin1 (Ninj1) limits colon inflammation by regulating macrophage polarization and microbiota composition under homeostatic conditions and during colitis development. Ninj1 deletion in mice induced hypersusceptibility to colitis, with increased prevalence of colitogenic Prevotellaceae strains and decreased immunoregulatory Lachnospiraceae strains. Upon co-housing (CoH) with WT mice, Ninj1-/- mice showed increased Lachnospiraceae and decreased Prevotellaceae abundance, with subsequent improvement of colitis. Under homeostatic conditions, M1 macrophage frequency was higher in the Ninj1-/- mouse colons than wild-type (WT) mouse colons, which may contribute to increased basal colonic inflammation and microbial imbalance. Following colitis induction, Ninj1 expression was increased in macrophages; meanwhile Ninj1-/- mice showed severe colitis development and impaired recovery, associated with decreased M2 macrophages and escalated microbial imbalance. In vitro, Ninj1 knockdown in mouse and human macrophages activated M1 polarization and restricted M2 polarization. Finally, the transfer of WT macrophages ameliorated severe colitis in Ninj1-/- mice. These findings suggest that Ninj1 mediates colonic homeostasis by modulating M1/M2 macrophage balance and preventing extensive dysbiosis, with implications for IBD prevention and therapy.

Predictive performance of blood urea nitrogen to serum albumin ratio in elderly patients with gastrointestinal bleeding.

INTRODUCTION: Acute gastrointestinal (GI) bleeding is one of the most important and the common causes of patients visiting the emergency department. Dehydrated state leads to increased blood urea nitrogen (BUN) and decreased albumin level. Many scoring systems had been developed to predict outcomes for patients with GI bleeding. Among the many scoring systems, the AIMS65 score was a simple and accurate risk assessment scoring tool. Therefore, in this study, we evaluated the prognostic performance of the blood urea nitrogen to serum albumin ratio (B/A ratio) compared to the AIMS65 score tool in elderly patients with GI bleeding. MATERIAL AND METHODS: This was a retrospective cohort study of patients with GI bleeding in our institution from February 2018 through May 2020. Baseline characteristic data were obtained. The data were compared with the prevalence of ICU admission and in-hospital mortality. The B/A ratio and the AIMS65 score as predictors of ICU admission and in-hospital mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. RESULTS: In the 596 patients included in the study, of whom 188 (31.5%) were admitted to the ICU and 36 (6.0%) died during hospitalization. Multivariate logistic regression analysis revealed that the B/A ratio was significant predictors of ICU admission and in-hospital mortality. In addition, the B/A ratio was significant higher in ICU admission patients and non-survivors. The AUROC value of the B/A ratio was 0.682 and that of the AIMS65 score was 0.699 for predicting ICU admission. For predicting in-hospital mortality, the AUROC value was 0.770 and 0.763, respectively. CONCLUSION: The B/A ratio is as simple and useful tool for predicting outcomes for old aged GI bleeding patients as the AIMS65 score.

Comparison of IVC diameter ratio, BUN/creatinine ratio and BUN/albumin ratio for risk prediction in emergency department patients.

INTRODUCTION: Early prediction of patients' prognosis in the emergency department (ED) is important. Patients' conditions such as dehydration help predict prognosis. The ratio of serum blood urea nitrogen to creatinine (BUN/Cr ratio) and inferior vena cava (IVC) diameter is often used to determine dehydration. Also, serum albumin levels reflect nutritional conditions such as dehydration. In this study, we evaluated the performance of BUN/Cr ratio, IVC diameter ratio, and BUN/Albumin ratio as predictive markers for in-hospital mortality and ICU admission among various diseases in ED. MATERIAL AND METHODS: This retrospective cohort study utilized data from patients who had abdominal and pelvic computed tomography (APCT) performed at our institution from 2015 to 2018. The measurement of IVC diameter from computed tomography, the BUN/Cr ratio, and the BUN/Albumin ratio were calculated. Differences in the performance among the BUN/Cr ratio, the IVC diameter ratio, and the BUN/Albumin ratio for predicting outcomes were evaluated by the area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 914 patients were enrolled and 78 patients (8.5%) were admitted to the ICU, and 71 patients (7.8%) died during the clinical process. Multivariate logistic regression showed that only the BUN/Albumin ratio was a significant predictor of inhospital mortality and ICU admission. CONCLUSION: Among dehydration markers the BUN/Albumin ratio is a simple and useful tool for predicting the outcomes of patients visiting the ED.

Echinochrome A Treatment Alleviates Fibrosis and Inflammation in Bleomycin-Induced Scleroderma.

Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.

Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil.

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

The Oral Administration of Sanguisorba officinalis Extract Improves Physical Performance through LDHA Modulation.

Muscle fatigue is induced by an acute or chronic physical performance inability after excessive physical activity often associated with lactate accumulation, the end-product of glycolysis. In this study, the water-extracted roots of Sanguisorba officinalis L., a herbal medicine traditionally used for inflammation and diarrhea, reduced the activities of lactate dehydrogenase A (LDHA) in in vitro enzyme assay myoblast C2C12 cells and murine muscle tissue. Physical performance measured by a treadmill test was improved in the S. officinalis-administrated group. The analysis of mouse serum and tissues showed significant changes in lactate levels. Among the proteins related to energy metabolism-related physical performance, phosphorylated-AMP-activated protein kinase alpha (AMPKα) and peroxisome proliferator-activated receptor-coactivator-1 alpha (PGC-1α) levels were enhanced, whereas the amount of LDHA was suppressed. Therefore, S. officinalis might be a candidate for improving physical performance via inhibiting LDHA and glycolysis.

Comparison of the Clinical Process and Outcomes in Patients after Coronavirus Infection 2019 Outbreak.

Background and Objectives: The coronavirus infection 2019 (COVID-19) pandemic has affected emergency department (ED) management. Its viral transmission necessitates the use of isolation rooms and personal protective equipment for treating suspected patients, such as those with fever. This delays the time until the first encounter with the patients, thereby increasing the length of stay (LOS) in the ED. We aimed to compare delays in the ED LOS and clinical processes between the COVID-19 period and pre-COVID-19 period. Moreover, we intended to evaluate if the aforementioned delay affected patient outcomes. Materials and Methods: We conducted a single-center, retrospective study in Korea. Patients with fever were compared between the "COVID-19 period" from March 2020 to August 2020 and the "pre-COVID-19 period" from March 2019 to September 2019. We compared the overall ED LOS and individual time variable, including initial diagnostic tests (laboratory tests, radiography), specific diagnostic test (computed tomography), and treatment processes (antibiotics). A logistic regression analysis was conducted to identify the association between hospital admission and patient data. Results: We enrolled 931 and 749 patients during pre- and COVID-19 periods, respectively. Patients with fever remained in the ED for a longer duration during the COVID-19 period (pre-COVID-19:207.7 ± 102.7 min vs. during COVID-19: 223.5 ± 119.4 min, p = 0.004). The total time for performing laboratory tests and radiography displayed significant differences between the two periods, particularly from the time of patient arrival in the ED to the time of issuing the order. The time until antibiotic administration was delayed in the COVID-19 period (pre-COVID-19:195.8 ± 103.3 min vs. during COVID-19: 216.9 ± 108.4 min, p = 0.003). The logistic regression analysis for hospital admission identified ED LOS as an independent factor in both periods. Conclusions: The delay until encountering patients with fever resulted in longer ED LOS during the COVID-19 period; however, it possibly did not increase the hospital admission rates.

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity.

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

Protective role of skeletal muscle mass against progression from metabolically healthy to unhealthy phenotype.

OBJECTIVE: Metabolically healthy individuals are known to be resistant to cardiovascular disease development. However, a considerable fraction of those individuals shows deteriorated metabolic health over time. Although skeletal muscle is the primary insulin-responsive target organ, a longitudinal investigation of the skeletal muscle mass in relation to the development of metabolically unhealthy phenotype has not been performed. We aimed to evaluate whether greater skeletal muscle mass is an independent protective factor for the development of metabolically unhealthy phenotype. DESIGN, PARTICIPANTS AND MEASUREMENTS: We conducted a retrospective cohort study with 9033 metabolically healthy volunteers who underwent routine health examinations in 2012 and a follow-up examination in 2016. Obesity was defined as Asian-Pacific body mass index criterion ≥25 kg/m2 . Subjects with fewer than two risk factors (elevated blood pressure, triglyceride, glucose, high-sensitivity C-reactive protein, insulin resistance and decreased high-density lipoprotein cholesterol levels) were characterized as metabolically healthy using Wildman criteria. RESULTS: At the 4-year follow-up, approximately one-fourth of the nonobese participants and half of the participants with obesity showed metabolic deterioration. In nonobese men and women, higher appendicular skeletal muscle mass (ASM)/weight at baseline was significantly associated with decreased risk of metabolic deterioration. Compared to the lowest quartile of ASM/weight, the adjusted odds ratios (95% confidence intervals) of the highest quartile were 0.68 (0.52-0.89) in nonobese men and 0.64 (0.46-0.90) in nonobese women. However, this association was not observed in obese subjects. CONCLUSIONS: Greater skeletal muscle mass at baseline is significantly associated with maintenance of metabolically healthy status, especially in nonobese individuals.

Ninjurin1 Assembles Into a Homomeric Protein Complex Maintained by N-linked Glycosylation.

Ninjurin1 (Ninj1) is a cell surface protein known as a homophilic adhesion molecule. Previous studies have shown a trans-interaction of Ninj1 between immune cells and endothelial cells; however, little is known about Ninj1 modification and structure in the cis-interaction. We showed that Ninj1 assembles into a homomeric complex via a cis-interaction mediated by the intracellular region and N-glycosylation at Asn60 . We identified cis-interaction between Ninj1 proteins using CFP- and YFP-tagged Ninj1 by Förster resonance energy transfer using a confocal microscope and fluorescence-activated cell sorter. We further observed the Ninj1 homomeric complexes composed of two to six monomeric Ninj1 molecules by a formaldehyde cross-linking assay. Co-immunoprecipitation assays with epitope-tagged truncated Ninj1 suggested that the intracellular region encompassing Leu101 -Ala110 participates in Ninj1 homomer assembly. Ninj1 N-glycosylation was characterized by treatment of tunicamycin and substitution of Asn to Gln or Ala. Fluorescence-activated cell sorting-based Förster resonance energy transfer assays further demonstrated that N-glycosylation is indispensable for the Ninj1 cis-interaction, and a formaldehyde cross-linking assay confirmed that interruption of N-glycosylation by Asn substitution disrupted Ninj1 homomeric complex formation. In silico analysis revealed that Ninj1 is highly conserved in vertebrates and that the conserved sequence contains an N-glycosylation motif and cis-interacting intracellular region, which participate in Ninj1 homomer assembly. Taken together, these data show that Ninj1 assembles into a homomeric protein complex and that N-glycosylation is a prerequisite for Ninj1 homomer assembly. J. Cell. Biochem. 118: 2219-2230, 2017. © 2017 Wiley Periodicals, Inc.