Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity.

Phenylalanine hydroxylase (PAH) is the key enzyme in phenylalanine metabolism, deficiency of which is associated with the most common metabolic phenotype of phenylketonuria (PKU) and hyperphenylalaninemia (HPA). A bulk of PKU disease-associated missense mutations in the PAH gene have been studied, and the consequence of each PAH variant vary immensely. Prior research established that PKU-associated variants possess defects in protein folding with reduced cellular stability leading to rapid degradation. However, recent evidence revealed that PAH tetramers exist as a mixture of resting state and activated state whose transition depends upon the phenylalanine concentration and certain PAH variants that fail to modulate the structural equilibrium are associated with PKU disease. Collectively, these findings framed our understanding of the complex genotype-phenotype correlation in PKU. In the current study, we substantiate a link between PAH protein stability and its degradation by the ubiquitin-mediated proteasomal degradation system. Here, we provide an evidence that PAH protein undergoes ubiquitination and proteasomal degradation, which can be reversed by deubiquitinating enzymes (DUBs). We identified USP19 as a novel DUB that regulates PAH protein stability. We found that ectopic expression of USP19 increased PAH protein level, whereas depletion of USP19 promoted PAH protein degradation. Our study indicates that USP19 interacts with PAH and prevents polyubiquitination of PAH subsequently extending the half-life of PAH protein. Finally, the increase in the level of PAH protein by the deubiquitinating activity of USP19 resulted in enhanced metabolic function of PAH. In summary, our study identifies the role of USP19 in regulating PAH protein stability and promotes its metabolic activity. Graphical highlights 1. E3 ligase Cdh1 promotes PAH protein degradation leading to insufficient cellular amount of PAH causing PKU. 2. A balance between E3 ligase and DUB is important to regulate the proteostasis of PAH. 3. USP19 deubiquitinates and stabilizes PAH further protecting it from rapid degradation. 4. USP19 increases the enzymatic activity of PAH, thus maintaining normal Phe levels.

MST1R as a potential new target antigen of chimeric antigen receptor T cells to treat solid tumors.

Although chimeric antigen receptor T cell (CAR-T) is a promising immunotherapy in hematological malignancies, there remain many obstacles to CAR-T cell therapy for solid tumors. Identifying appropriate tumor-associated antigens (TAAs) is especially critical for success. Using a bioinformatics approach, we identified common potential TAAs for CAR-T cell immunotherapy in solid tumors. We used the GEO database as a training dataset to find differentially expressed genes (DEGs) and verified candidates using the TCGA database, obtaining seven common DEGs (HM13, SDC1, MST1R, HMMR, MIF, CD24, and PDIA4). Then, we used MERAV to analyze the expression of six genes in normal tissues to determine the ideal target genes. Finally, we analyzed tumor microenvironment factors. The results of major microenvironment factor analyses showed that MDSCs, CXCL1, CXCL12, CXCL5, CCL2, CCL5, TGF-ß, CTLA-4, and IFN-γ were significantly overexpressed in breast cancer. The expression of MST1R was positively correlated with TGF-ß, CTLA-4, and IFN-γ. In lung adenocarcinoma, MDSCs, Tregs, CXCL12, CXCL5, CCL2, PD-L1, CTLA-4, and IFN-γ were significantly overexpressed in tumor tissues. The expression of MST1R was positively correlated with TGF-ß, CTLA-4, and IFN-γ. In bladder cancer, CXCL12, CCL2, and CXCL5 were significantly overexpressed in tumor tissues. MST1R expression was positively correlated with TGF-ß. Our results demonstrate that MST1R has the potential as a new target antigen for treating breast cancer, lung adenocarcinoma, and bladder cancer and may be used as a progression indicator for bladder cancer.

Effect of Porcine Placental Extract Mixture on Alcohol-Induced Hepatotoxicity in Rats.

This study was conducted to examine the effect of porcine placenta extract mixture (pPEM, enzymatic/acidic extract = 1/3) on alcoholic hepatotoxicity after pPEM dosing with alcohol in rats. The experimental groups were normal, control, silymarin, three pPEM (590, 1771, and 2511 mg/kg/day, po), and silymarin (100 mg/kg/day, po) groups (n = 10). Alcoholic hepatotoxicity was caused by a liquid ethanol diet for 4 weeks. The effect of pPEM and silymarin on alcoholic hepatotoxicity was evaluated by serology, hepatic ADH and ALDH activities, and histopathological findings. After oral dosing with alcohol for 4 weeks, ALT and AST were significantly increased to 33.7 → 115.6 and 81.37 → 235.0 in the alcohol group, respectively. These levels were decreased significantly to 83.9 and 126.7 in the silymarin group and dose-dependently to 73.6-56.9 and 139.2-122.8 in all pPEM groups. Hepatic ADH and ALDH might have been increased in the control and not in the silymarin and pPEM groups for hepatic ADH. All pPEM groups exhibited no effects on hepatic ALDH except for the high pPEM group. Mild inflammation and fatty lesions were observed in the alcohol group and were attenuated in the silymarin and pPEM groups. As a results, the pPEM showed protective activities against alcoholic hepatotoxicity on the serological markers, hepatic ADH and ALDH, and pathological findings.

Effect of Single-Dose, Oral Enzymatic Porcine Placental Extract on Pharmacokinetics of Alcohol and Liver Function in Rats.

BACKGROUND: Human placenta extract (HPE) has been used to treat a number of liver diseases. Porcine placenta is relatively safe and has been reported to have similar immune effects to HPE and used as its alternative. This study evaluates the effect of enzymatic porcine placental extract (EPPE, Uni-Placenta®) on alcohol pharmacokinetics in rat. METHODS: This study was designed to determine the effect of single-dose EPPE on the pharmacokinetics of alcohol and liver function. Results were based on serum alcohol and acetaldehyde concentrations and activities of hepatic and gastric ADH and ALDH in rats. RESULTS: The hepatic ADH in alcohol group was significantly increased and it may be enzyme-induction by alcohol. The hepatic ALDH and gastric ADH were not changed, but gastric ALDH was significantly decreased only in the high-dose EPPE group. In the alcohol pharmacokinetics parameters, the AUC was 44.5 mM∙h in the alcohol group. Otherwise, AUCs of low, middle, high, and silymarin groups were significantly decreased. Cmax was reached at 1 hour and then gradually decreased to 63% and 43% in the middle and high groups at 3 hours, respectively, and to 92% in the low groups. The pharmacokinetics and serum concentrations of acetaldehyde showed no differences between EPPE groups except the silymarin group. No histologic changes were seen in any group. CONCLUSIONS: The single-dose EPPE (0.5 to 2.5 g/kg) suppressed absorption of alcohol in the gastrointestinal tract. This may be useful in preventing hangover effects and toxicity after drinking alcohol and may also preserve liver health after alcohol ingestion.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

The potential theragnostic (diagnostic+therapeutic) application of exosomes in diverse biomedical fields.

Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.

Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.

Comparison of the Effects of Pilates and Yoga Exercise on the Dynamic Balancing Ability and Functional Movement of Fencers.

This study was conducted to compare and analyze whether Pilates exercise and yoga exercise help improve the performance of female fencers and prevent injury, and the dynamic balance test (LQ-YBT) and functional movement screening (FMS) test score of the elite adult female fencers were compared and analyzed as evaluation indicators. Participants were randomly classified into Pilates (n = 10) and yoga groups (n = 10), members of which took part in 50 min of exercise (5 min of warm-up, 40 min of main exercise, and 5 min of cool-down) twice weekly for eight weeks. The results obtained from this study were analyzed via independent t-test and 2-way ANOVA. The results were as follows: LQ-YBT measures (reaching distance) increased significantly for both groups, as did FMS scores (deep squat, hurdle step, inline lunge, shoulder mobility, active straight-leg raise, trunk-stability push-up, and rotary stability). These results suggest that Pilates exercise and yoga exercise might be likely effective in improving the performance of adult female fencers and injury prevention by increasing their dynamic balance ability and functional movement.

Anterior operation for unstable thoracolumbar and lumbar burst fractures: tricortical autogenous iliac bone versus titanium mesh cage.

STUDY DESIGN: We retrospectively compared 25 cases that used the autogenous iliac bone grafting with 18 cases that used a titanium mesh cage for reconstruction of the vertebral body. OBJECTIVE: To analyze clinical and radiographic results of the autogenous iliac bone and a titanium mesh cage used to reconstruct the vertebral body. SUMMARY OF BACKGROUND DATA: Grafting of the autogenous iliac bone as a strut bone has been traditionally applied for reconstruction of the spine using anterior approach. Although grafting the autogenous iliac bone as a strut bone achieves a high bone fusion rate, it has reported complications in the donor site. For this reason, bone fusion with a mesh cage has been introduced. METHODS: Between March 2000 and December 2010, 43 cases that underwent decompression and instrumented fusion for unstable burst fractures using the anterior approach were enrolled. Levels of injury were T12 in 8 cases, L1 in 19 cases, L2 in 11 cases, and L3 in 5 cases. The mean follow-up period was 64.5 months (range, 14-129 mo). RESULTS: The local kyphotic angle in the group that used the tricortical autogenous iliac bone (group A) was measured 24.81±2.27 degrees preoperatively and 4.95±0.61 degrees at the last follow-up. The angle in the group that used a titanium mesh cage (group B) was 25.21±1.55 degrees preoperatively and 3.9±0.43 degrees at the last follow-up. Both groups obtained bone fusion of grade I and II by Bridwell fusion criteria. The operation site visual analog scale and Korean Oswestry disability index did not differ significantly between 2 groups. Donor site visual analog scale and the operation time was significantly in favor of group B (P<0.05). CONCLUSIONS: Titanium mesh cage filled with the autogenous cancellous bone shortened operation time and reduced the risk of complications in the donor site compared with the group that used the tricortical iliac bone.

Analyses of the Chemical Composition of Plasma-Activated Water and Its Potential Applications for Vaginal Health.

This study aimed to elucidate the unique chemical compositions of plasma-activated water (PAW) and the potential antibacterial efficacy of PAW as a novel vaginal cleanser. We analyzed the ion compositions (four anions: F-, Cl-, NO3-, SO42-; five cations: Na+, NH4+, K+, Mg2+, Ca2+) of several formulations of PAW generated at different electrical powers (12 and 24 V) at various treatment time points (1, 10, and 20 min), and stay durations (immediate, 30, and 60 min). As treatment duration increased, hypochlorous acid (HOCl), Ca2+, and Mg2+ concentrations increased and Cl- concentration decreased. Higher electrical power and longer treatment duration resulted in increased HOCl levels, which acts to prevent the growth of general microorganisms. Notably, PAW had no antibacterial effects against the probiotic, Lactobacillus reuteri, which produces lactic acid and is important for vaginal health. These findings indicate that PAW contains HOCl and some cations (Ca2+ and Mg2+), which should help protect against pathogens of the vaginal mucosa and have a cleansing effect within the vaginal environment while not harming beneficial bacteria.

Effect of Metformin on Myocardial Injury Induced by Hepatic Ischemia-Reperfusion in Rats.

Background: There is no effective medication for treatment or prevention of hepatic ischemia-reperfusion (HIR) injury caused by liver transplantation and hepatectomy. This study aimed to investigate the therapeutic effects of metformin on HIR injury and related myocardial injury in rats. Methods: Wistar male rats were randomly divided into four groups: sham group, ischemia-reperfusion group, and IR group treated with metformin 150 mg/kg and 100 mg/kg. Wistar male rats were administered metformin 150 mg/kg, 100 mg/kg or saline 30 min pre-operative and underwent 15 min ischemia and 6 h reperfusion (n = 4). Results: Metformin significantly alleviates the injury caused by HIR. Administration of metformin resulted in a significant reduction in the serum levels of alanine transaminase and aspartate transaminase and the activity of malondialdehyde, creatine kinase-MB, and lactate dehydrogenase but maintained high catalase and superoxide dismutase activity. Metformin significantly inhibited the IR-induced elevation of tumor necrosis factor-α in liver and heart tissue. Conclusion: Metformin can alleviate hepatic and myocardial injury induced by IR by inhibiting oxidative stress.

Clinical characteristics and outcome of coronavirus disease 2019 infection in patients with solid organ transplants: A systematic review and meta-analysis.

BACKGROUND: Although many studies have reported cases of COVID-19 infection in transplant recipients, most of them only involve a small number of patients and narrow geographic areas. This study aims to investigate the clinical characteristics, morbidity, severity, and mortality of COVID-19 infection among solid organ transplant (SOT) recipients by meta-analysis. METHOD: We performed a literature search using the databases PubMed, Web of Science, and Google Scholar as of November 26, 2020. We included randomized controlled trials and cohort studies, excluding case reports and small case series (n < 10). The pooled incidence proportion and 95% confidence intervals (CI) were used to estimate the combined results of forty-seven studies were included for the meta-analysis. Heterogeneity was assessed using I2. Freeman-Tukey double arcsine transformation was used to stabilize the specific rate variance. Publication bias was using Egger's test. RESULTS: The morbidity rate of COVID-19 in SOT recipients was 2.10% [95% CI 1.35-3.01], and the proportion of severe infection was 22.46% [95% CI 15.74-29.90]. The mortality rate was 17.38% [95% CI 13.72-21.34]. In the analysis by transplanted organ, the proportion of patients with severe infection was highest in recipients of two or more transplants 48.85% [95% CI 11.88-86.38]. The mortality rate was highest in lung transplant recipients 25.12% [95% CI 16.94-34.00]. The most common symptoms of COVID-19 in SOT recipients were fever (73.39%), cough (58.90%), and respiratory symptoms (45.77%). CONCLUSION: SOT was a risk factor for worse COVID-19 outcomes, although the morbidity of COVID-19 in SOT recipients was not markedly higher than the general population. These results may change when our understanding of the disease progress.

Systemic exposure to propranolol in patients with chronic liver disease and its correlation with portal blood flow.

Propranolol is a beta-blocker used for the prevention of variceal bleeding in cirrhotic patients. We investigated the pharmacokinetics of propranolol in patients with chronic liver disease compared to that in healthy individuals. The relative amount of portal blood flow was measured to investigate the correlation of portal blood flow and the systemic exposure of propranolol. Thirty healthy subjects, 18 patients with chronic active hepatitis (CAH), and 54 patients with cirrhosis were included in this prospective study. Blood samples for pharmacokinetic analysis were taken up to 8 h post-dose. The portal blood flow was estimated by H/L ratio using thallium-201 (201TI) per rectal scintigraphy. A total of 78 subjects completed the study. The area under the concentration-time curve (AUC) to the last measurable time (AUClast, ng⋅h/mL) were 150.2 ± 154.1, 112.2 ± 84.7, and 204.0 ± 137.3 in healthy subjects, CAH patients, and cirrhosis patients, respectively. AUC rmlast showed positive correlation with the H/L ratio in patients with chronic liver disease (r = 0.5817, p < 0.0001). In conclusion, the patients with cirrhosis showed higher systemic exposure to propranolol than healthy subjects or patients with CAH. The increase in systemic exposure to propranolol was correlated with the decrease in portal blood flow.

Human Trial for the Effect of Plasma-Activated Water Spray on Vaginal Cleaning in Patients with Bacterial Vaginosis.

Underwater plasma discharge temporally produces several reactive radicals and/or free chlorine molecules in water, which is responsible for antimicrobial activity. Hence, it can simply sanitize tap water without disinfectant treatment. Additionally, the spraying technique using cleaning water exploits deep application in the narrow and curved vaginal tract of patients. Herein, we attempted a clinical trial to evaluate the vaginal cleaning effect of spraying plasma-activated water (PAW) to patients with vaginitis (46 patients). The efficacy was compared with treatment with betadine antiseptics used to treat bacterial vaginosis (40 patients). To evaluate the cleaning effect, Gram staining of the vaginal secretions was conducted before and after spraying PAW or betadine treatment (BT). Consequently, PAW-sprayed (PAWS) patients (22.3%) showed a better vaginal cleaning effect against Gram-positive and -negative bacteria than BT patients (14.4%). Moreover, 18 patients in the BT group showed worsened vaginal contamination, whereas five patients in the PAWS group showed worsened vaginal contamination. Taken together, the noncontact method of spraying cleaning water to the vagina exhibited a reliable vaginal cleaning effect without further bacterial infection compared with BT. Therefore, we suggest a clinical application of the spraying method using PAW for vaginal cleaning to patients with vaginitis without disinfectants and antibiotics.

Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.

Phenylalanine hydroxylase (PAH) is a key enzyme in mammals that maintains the phenylalanine (Phe) concentration at an appropriate physiological level. Some genetic mutations in the PAH gene lead to destabilization of the PAH enzyme, leading to phenylketonuria (PKU). Destabilized PAH variants can have a certain amount of residual enzymatic activity that is sufficient for metabolism of Phe. However, accelerated degradation of those variants can lead to insufficient amounts of cellular PAH protein. The optimal protein level of PAH in cells is regulated by a balancing act between E3 ligases and deubiquitinating enzymes (DUBs). In this work, we analyzed the protein expression and stability of two PKU-linked PAH protein variants, R241C and R243Q, prevalent in the Asian population. We found that the tested PAH variants were highly ubiquitinated and thus targeted for rapid protein degradation. We demonstrated that USP19, a DUB that interacts with both PAH variants, plays a regulatory role by extending their half-lives. The deubiquitinating activity of USP19 prevents protein degradation and increases the abundance of both PAH protein variants. Thus, our study reveals a novel mechanism by which deubiquitinating activity of USP19 extends the residual enzymatic activity of PAH variants.

Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation.

Although Helicobacter pylori infections of the gastric mucosa are characterized by the infiltration of inflammatory cells such as eosinophils, the responses of eosinophils to H. pylori vacuolating cytotoxin (VacA) have not been fully elucidated. This study investigates the role of VacA in the apoptosis of human eosinophils. We treated human eosinophils with purified H. pylori VacA and observed that induction of apoptosis is a relatively late event. Expression of cellular inhibitor of apoptosis protein (c-IAP)-2 was upregulated during the early period of VacA stimulation, and transfection with c-IAP2 siRNA augmented apoptotic cell death. VacA caused the translocation of cytoplasmic Bax to the mitochondria and increased cytochrome c release from mitochondria in eosinophils. Transfection of an EoL-1 eosinophil cell line with Bax siRNA decreased the release of cytochrome c and DNA fragmentation. Furthermore, apoptosis facilitated by Bax and cytochrome c was primarily regulated by p38 MAPK in VacA-treated eosinophils. These results suggest that the exposure of human eosinophils to H. pylori VacA induces the early upregulation of c-IAP2 and a relatively late apoptotic response, with the apoptosis progressing through a sequential pathway that includes p38 MAPK activation, Bax translocation, and cytochrome c release.

Relationship between Self-Reported Sleep Duration and Risk of Anemia: Data from the Korea National Health and Nutrition Examination Survey 2016-2017.

The importance of sleep has been gaining more and more attention nowadays. It has been widely studied that some major health issues, such as cardiovascular diseases or mortality, are closely related to the extreme ends of sleep durations. Anemia is one of the health problems in modern society. In this study, we aimed to find a relationship between anemia occurrence and sleep duration. Data of 11,131 Korean adults aged 19 years or older were recruited from the 2016-2017 Korea National Health and Nutrition Examination Survey and analyzed in this cross-sectional study. 'Anemia' was defined in this study by hemoglobin level of <13 g/dL in men and <12 g/dL in women. Selected data were sorted into five groups by sleep duration: <5 h, 5 h ~ <6 h, 6 h ~ <8 h, 8 h ~ <9 h, and ≥9 h per day. We performed multivariate logistic regression analysis to assess the relationship between sleep duration and risk of anemia after adjusting for covariates including age, gender, family income level, education level, physical activity, cigarette smoking, and alcohol usage. Other factors were assessed in the analysis, such as depression, hypertension, diabetes, dyslipidemia, stroke, coronary artery disease, malignancy, stress level, and body mass index (BMI). We found that sleep duration of <5 h was related to high risk of anemia (odds ratio = 1.87; 95% confidence interval = 1.01-3.49, sleep duration of 6 h ~ <8 h as the reference group). Also, sleep duration of ≥9 h was related to lower risk of anemia in most premenopausal women after adjusting for covariates (odds ratio = 0.61; 95% confidence interval = 0.38-0.96, sleep duration of 6 h ~ < 8 h as the reference group). Male individuals with sleep durations of <5 h (odds ratio = 2.01; 95% confidence interval =1.05-3.84) and of ≥9 h (odds ratio = 2.48; 95% confidence interval =1.63-3.81) had a significantly higher risk of anemia without covariate adjustment. Postmenopausal women with sleep durations of ≥9 h had a significantly higher risk of anemia (odds ratio =2.02; 95% confidence interval =1.33-3.08) without adjusting for covariates. However, the associations became statistically insignificant after adjusting for age and covariates in both men and postmenopausal women. In conclusion, we found significant associations between extreme ends of sleep duration and risk of anemia in premenopausal Korean women. However, we did not observe strong associations between self-reported sleep duration and anemia risk in men or postmenopausal women.

Cardiac biomarkers and COVID-19: A systematic review and meta-analysis.

OBJECTIVE: To systematically investigate the relationship between cardiac biomarkers and COVID-19 severity and mortality. METHODS: We performed a literature search using PubMed, Web of Science, and Google Scholar. The standardized mean difference (SMD) and 95% confidence interval (CI) were applied to estimate the combined results of 67 studies. A meta-analysis of cardiac biomarkers was used to evaluate disease mortality and severity in COVID-19 patients. RESULTS: A meta-analysis of 7812 patients revealed that patients with high levels of cardiac troponin I (SMD = 0.81 U/L, 95% CI = 0.14-1.48, P = 0.017), cardiac troponin T (SMD = 0.78 U/L, 95% CI = 0.07-1.49, P = 0.032), high-sensitive cardiac troponin I (SMD = 0.66 pg/mL, 95% CI = 0.51-0.81, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.93 U/L, 95% CI = 0.21-1.65, P = 0.012), creatine kinase-MB (SMD = 0.54 U/L, 95% CI = 0.39-0.69, P < 0.001), and myoglobin (SMD = 0.80 U/L, 95% CI = 0.57-1.03, P < 0.001) were associated with prominent disease severity in COVID-19 infection. Moreover, 9532 patients with a higher serum level of cardiac troponin I (SMD = 0.51 U/L, 95% CI = 0.37-0.64, P < 0.001), high-sensitive cardiac troponin (SMD = 0.51 ng/L, 95% CI = 0.29-0.73, P < 0.001), high-sensitive cardiac troponin I (SMD = 0.51 pg/mL, 95% CI = 0.38-0.63, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.85 U/L, 95% CI = 0.63-1.07, P < 0.001), creatine kinase-MB (SMD = 0.48 U/L, 95% CI = 0.32-0.65, P < 0.001), and myoglobin (SMD = 0.55 U/L, 95% CI = 0.45-0.65, P < 0.001) exhibited a prominent level of mortality from COVID-19 infection. CONCLUSION: Cardiac biomarkers (cardiac troponin I, cardiac troponin T, high-sensitive cardiac troponin, high-sensitive cardiac troponin I, high-sensitive cardiac troponin T, creatine kinase-MB, and myoglobin) should be more frequently applied in identifying high-risk COVID-19 patients so that timely treatment can be implemented to reduce severity and mortality in COVID-19 patients.

Bacteroides fragilis enterotoxin induces human beta-defensin-2 expression in intestinal epithelial cells via a mitogen-activated protein kinase/I kappaB kinase/NF-kappaB-dependent pathway.

Enterotoxigenic Bacteroides fragilis (ETBF) produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although spontaneous disappearance of ETBF infection is common, little information is available on regulated expression of antibacterial factors in response to BFT stimulation. This study investigates the role of BFT in human beta-defensin 2 (hBD-2) induction from intestinal epithelial cells. Stimulation of HT-29 and Caco-2 intestinal epithelial cell lines with BFT resulted in the induction of hBD-2. Activation of a reporter gene for hBD-2 was dependent on the presence of NF-kappaB binding sites. In contrast, suppression of AP-1 did not affect hBD-2 expression in BFT-stimulated cells. Inhibition of p38 mitogen-activated protein kinase (MAPK) using SB203580 and small interfering RNA (siRNA) transfection resulted in a significant reduction in BFT-induced I kappaB kinase (IKK)/NF-kappaB activation and hBD-2 expression. Our results suggest that a pathway including p38 MAPK, IKK, and NF-kappaB activation is required for hBD-2 induction in intestinal epithelial cells exposed to BFT, and may be involved in the host defense following infection with ETBF.

The role of nitric oxide in the expression of renal aquaporin 2 in a cirrhotic rat model: does an AVP-independent mechanism exist for the regulation of AQP2 expression?

The aquaporin (AQP) water channel is expected to play a decisive role of hyponatremia and water retention in cirrhotic patients. Despite the importance of the water channel, however, previous findings vary widely when it concerns AQP2 of the kidneys in subjects with cirrhosis. The purpose of this study was to investigate the expression of AQP2 in the distal renal tubule in cirrhosis, and the presence of the nitric oxide-AQP2 signaling pathway as a possible vasopressin-aquaporin-independent pathway. Sixty male Wister rats were assigned to six groups: (1) control; (2) TAA (thioacetamide); (3) TAA with nitric oxide donor; (4) TAA with nitric oxide inhibitor; (5) TAA with HMG CoA reductase inhibitor; (6) TAA with tetrahydrobiopterin. Immunohistochemical staining for AQP2, real-time polymerase chain reaction (PCR) for AQP2 and 3, citrulline assay, and renal cGMP concentration were measured. The AQP2-positivity of cirrhotic rats were higher than the controls (P < 0.05). The AQP2-positivity decreased in the nitric oxide donor group, but the proportion rose back up when the subjects were injected with the nitric oxide inhibitor (P < 0.05). The expression of AQP2 and AQP3 mRNA was also found to show an increase in the cirrhotic group as compared with the normal controls (P < 0.05). The cirrhotic group administered with nitric oxide donor showed a significant decline in the expression of the mRNA. The control group's cGMP concentration was lower than that of the cirrhotic group (P < 0.05), but a comparison of the two groups injected with nitric oxide modulators, such as statin and BH4, did not show significant differences in the cGMP concentration level. The expression of AQP2 of the kidneys increased in the cirrhotic rats. AQP2 had relations to the activity changes of nitric oxide synthetase.