A comparative study of changes in smoking cessation attempt rates and related factors before and during COVID-19.

This study aimed to identify whether smoking cessation attempts (SCA) for health promotion changed during the coronavirus disease 2019 (COVID-19) pandemic and how the characteristics of people who undertook SCA before versus during COVID-19 differed. This was a secondary data analysis of the South Korean 2019-2021 Community Health Survey data for 163,334 smokers that compared sociodemographic factors, health behaviors, and health status by SCA and year using χ2 statistics and multiple logistic regression analysis. The SCA rate significantly decreased from 72.6 % in 2019 to 44.1 % in 2021. In 2019, the rate was high for those over 60 years old but decreased by half by 2021. The ORs for SCA were higher in women than men in all years and were lower in 2019 for all age groups except those in their 70 s; however, in 2021, the ORs for those in their 20 s were higher than those in their 70 s and were slightly higher for non-high-risk drinkers than for high-risk drinkers. ORs were higher among those trying to lose or gain weight than among those who were not. Despite its health benefits, the SCA rate significantly decreased. Issuing public statements encouraging SCA is critical. Measures are necessary to increase the rate of SCA among people in their 70 s and support those seeking to control their weight for successful smoking cessation. In addition, a strategy to maintain the SCA rate in people in their 20 s is required to ensure their future health.

Utilization of End-of-Life Care Rooms by Patients Who Died in a Single Hospice Unit at a National University Hospital in South Korea.

Purpose: For the dignity of patients nearing the end of their lives, it is essential to provide end-of-life (EoL) care in a separate, dedicated space. This study investigated the utilization of specialized rooms for dying patients within a hospice unit. Methods: This retrospective study examined patients who died in a single hospice unit between January 1, 2017, and December 31, 2021. Utilizing medical records, we analyzed the circumstances surrounding death, the employment of specialized rooms for terminally ill patients, and the characteristics of those who received EoL care in a shared room. Results: During the 1,825-day survey period, deaths occurred on 632 days, and 799 patients died. Of these patients, 496 (62.1%) received EoL care in a dedicated room. The average duration of using this dedicated space was 1.08 days. Meanwhile, 188 patients (23.5%) died in a shared room. Logistic regression analysis revealed that a longer stay in the hospice unit was associated with a lower risk of receiving EoL care in a shared room (odds ratio [OR]=0.98, 95% confidence interval [CI] 0.97~0.99; P=0.002). Furthermore, a higher number of deaths on the day a patient died was associated with a greater risk of receiving EoL care in a shared room (OR=1.66, 95% CI 1.33~2.08; P<0.001). Conclusion: To ensure that more patients receive EoL care for an adequate duration in a private setting, additional research is necessary to increase the number of dedicated rooms and incorporate them into the hospice unit at an early stage.

Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.

Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis.

Association between weekend catch-up sleep and hyperuricemia with insufficient sleep in postmenopausal Korean women: a nationwide cross-sectional study.

OBJECTIVE: Hyperuricemia is associated with metabolic and cardiovascular diseases and mortality. Efforts to lower the risk of hyperuricemia in various ways are needed as the prevalence of these diseases increases in postmenopausal women. Studies have shown that one of these methods is associated with adequate sleep duration, which is related to a low risk of hyperuricemia. Considering that it is difficult for people to get enough sleep in modern society, this study hypothesized that weekend catch-up sleep could be an alternative. To our knowledge, no past study has investigated the relation between weekend catch-up sleep and hyperuricemia in postmenopausal women. Hence, the aim of this research was to estimate the relation between weekend catch-up sleep and hyperuricemia with insufficient sleep in postmenopausal women during weekday or workday. METHODS: This study included 1,877 participants extracted from the Korea National Health and Nutrition Examination Survey VII. The study population was divided into weekend catch-up sleep and non-weekend catch-up sleep groups. Odds ratios with 95% confidence intervals were derived using multiple logistic regression analysis. RESULTS: Weekend catch-up sleep had a significantly lower prevalence of hyperuricemia after adjusting for confounders (odds ratio, 0.758 [95% confidence interval, 0.576-0.997]). In a subgroup analysis, weekend catch-up sleep of 1 to 2 hours was significantly correlated with a lower prevalence of hyperuricemia after adjusting for confounders (odds ratio: 0.522 [95% confidence interval, 0.323-0.845]). CONCLUSIONS: Weekend catch-up sleep had a decreased prevalence of hyperuricemia in postmenopausal women with sleep deprivation.

Immunogenicity and Protective Efficacy of Recombinant Protective Antigen Anthrax Vaccine (GC1109) in A/J Mice Model.

A recombinant protective antigen anthrax vaccine (GC1109) is being developed as a new-generation vaccine by the Korea Disease Control and Prevention Agency. In accordance with the ongoing step 2 of phase II clinical trials, the immunogenicity and protective efficacy of the booster dose of GC1109 were evaluated in A/J mice after 3 serial vaccinations at 4-week intervals. The results indicated that the booster dose significantly increased the production of anti-protective antigen (PA) IgG and toxin-neutralizing antibody (TNA) compared with those of the group without booster. An enhanced protective effect of the booster dose was not observed because the TNA titers of the group without booster were high enough to confer protection against spore challenge. Additionally, the correlation between TNA titers and probability of survival was determined for calculating the threshold TNA titer levels associated with protection. The threshold 50 % neutralization factor (NF50) of TNA showing 70 % probability of protection was 0.21 in A/J mice with 1,200 LD50 Sterne spores challenge. These results indicate that GC1109 is a promising candidate as a new-generation anthrax vaccine and that a booster dose might provide enhanced protection by producing toxin-neutralizing antibodies.

Association between Sleep Duration and Presbycusis in Korean Adults: Korea National Health and Nutrition Examination Survey.

BACKGROUND: Sleep duration is associated with hearing loss, especially presbycusis, which is the most common type of hearing loss; however, there is limited evidence regarding this association among the Korean population. We aimed to determine the relationship between sleep duration and high-frequency hearing loss in Korean adults aged ≥40 years. METHODS: We examined 5,547 Korean adults aged ≥40 years who completed audiometric tests and questionnaires regarding sleep duration during the 2010-2012 cycle of the Korea National Health and Nutrition Examination Survey. Mild presbycusis was defined as >25 decibels (dB) and <40 dB, whereas moderate-to-severe presbycusis was defined as >40 dB pure tone averages at high frequencies (3,000, 4,000, and 6,000 Hz) for both ears. Additionally, the sleep duration was divided into quartiles. Odds ratios and 95% confidence intervals were estimated using multivariable logistic regression after adjusting for covariates. RESULTS: The prevalence of presbycusis in South Korean adults was 62.1%, of which 61.4% showed moderate to severe presbycusis. The incidence of moderate-to-severe, but not mild, presbycusis showed a significant positive correlation with sleep duration. CONCLUSION: Our findings suggest that sleep duration is associated with the prevalence of presbycusis.

Pep27 Mutant Immunization Inhibits Caspase-14 Expression to Alleviate Inflammatory Bowel Disease via Treg Upregulation.

Inflammatory bowel disease (IBD) is a highly prevalent gut inflammatory disorder. Complicated clinical outcomes prolong the use of conventional therapy and often lead to compromised immunity followed by adverse events and high relapse rates. Thus, a profound medical intervention is required. Previously, intranasal immunization of pneumococcal pep27 mutant (Δpep27) exhibited long-lasting protection against immune-related disorders. System biology analysis has predicted an inverse correlation between Δpep27 immunization and gastroenteritis. Recently, we established that Δpep27-elicited Tregs repressed Wnt5a expression and enhanced barrier integrity, suggesting the restoration of immunological tolerance. Therefore, we evaluated whether Δpep27 can alleviate IBD. Δpep27 dose-dependent response was analyzed in dextran sulfate sodium-induced mice using transcriptome analysis. Pro- and anti-inflammatory signatures were cross-correlated by quantitative PCR and western blot analyses. To address the hierarchy regulating the activity of caspase-14, an undefined marker in IBD, and regulatory T cells (Tregs), antibody-based neutralization studies were conducted. Fecal microbiome profiles were analyzed by 16S rRNA pyrosequencing. Δpep27 significantly attenuated dextran sulfate sodium-induced oxidative stress parameters, proinflammatory cytokines, caspase-14 expression level, and upregulated tight junction, anti-inflammatory genes IL-10 and TGF-ß1 via upregulation of Tregs to restore healthy gut microbiota. Neutralization studies unveiled that ∆pep27 had a remedial effect via Treg upregulation. Caspase-14, being an important mediator in the pathogenesis of IBD, can be an alternate therapeutic target in IBD. ∆pep27-increased Tregs repressed caspase-14 expression and reversed gut microbial dysbiosis, aiding to re-establish immunological tolerance.

Association between Serum Folic Acid Levels and Asthma in the Korean Population: A Study Based on the 2016-2018 Korea National Health and Nutrition Examination Survey.

BACKGROUND: Folic acid is involved in inflammatory reactions; however, the association between folic acid and allergic diseases, particularly asthma, remains unclear. Thus, this study aimed to evaluate the association between serum folic acid levels and asthma in Koreans. METHODS: This study analyzed the serum folic acid levels of 6,615 individuals included in the 2016-2018 Korea National Health and Nutrition Examination Survey. The prevalence of asthma was determined using a questionnaire that identified cases of physician-diagnosed asthma. The relationship between serum folic acid levels and asthma was analyzed using logistic regression analysis. RESULTS: Multiple logistic regression analysis showed that a 1 ng/mL increase in serum folic acid level significantly reduced the risk of asthma after adjusting for confounding factors including sex, age, household income, current smoking, current alcohol use, and body mass index (odds ratio [OR], 0.930; 95% confidence interval [CI], 0.876- 0.987; P=0.017). The relationship between the adjusted odds of asthma and serum folic acid levels were consistently inverse (OR, 2.266; 95% CI, 1.126-4.420; P for trend=0.038). CONCLUSION: Serum folic acid levels are inversely associated with physician-diagnosed asthma in the Korean population.

Pneumococcal pep27-mutant inhibits Wnt5a expression via the regulation of T helper cells to attenuate colitis.

Inflammatory bowel disease (IBD) is a chronic gut inflammatory disease characterized by extensive colitis and remission of the symptoms. The incidence rate and prevalence of IBD are increasing worldwide; IBD affects millions of people, has poorly defined etiology, and often results in a failure of pharmacological interventions. Regardless of the cause, mucosal healing is indispensable for the regeneration of inflamed mucosa to ensure intestinal homeostasis. Intranasal immunization with the pneumococcal pep27 mutant (Δpep27) has been reported as an avirulent and live vaccine that has been proposed to suppress immune-regulated disorders, eliciting long-lasting immunity. The dose-dependent activity of Δpep27 in the lungs was measured by transcriptome analysis to investigate the long-lasting immunogenic response against IBD. Novel therapeutic targets based on the modulation of Wnt signaling and T regulatory cells interconnected with other signaling cascades in the context of IBD were investigated by qPCR and immunoblotting. M1/M2 macrophages were quantified by FACS analysis. Dextran sulfate sodium-induced colitis induced significant upregulation of Th2 and Th17 as well as noncanonical Wnt5, which subsequently inhibited regulatory T (Treg) expression. In contrast, Δpep27 immunization significantly attenuated the levels of Wnt5, proinflammatory cytokines, oxidative stress parameters, and infiltration of inflammatory cells and enhanced barrier integrity via T helper cell homeostasis and upregulation of M2 macrophages. The data of the present study suggested that Δpep27-elicited Tregs were able to repress Wnt5a expression, assisting with the restoration of immunological tolerance and providing a robust regenerative and antioxidant milieu.

Association between Near Work Time and Depression among Workers in South Korea.

BACKGROUND: The aim of this study was to evaluate the association between near work time and depression. METHODS: Data of 1,551 workers aged 19-49 years from the sixth Korea National Health and Nutrition Examination Survey were examined. The Patient Health Questionaire-9 scores were used to screen for depression. Participants who scored a total of 10 or above, which is suggestive of the presence of depression, were classified as the depression group; the rest were classified as normal. The correlation between daily near work time and depression was analyzed using multivariate logistic analysis after adjusting for other sociodemographic and health behavior-related variables. RESULTS: Multivariate logistic analysis found that workers with 3 or more hours of near work were more likely to report depression compared to the reference group who had 2 or fewer hours per day of near work (adjusted odds ratio, 2.471; 95% confidence interval, 1.062-5.747). CONCLUSION: Longer near work time was associated with depression among South Korea's workers. Therefore, it is necessary to reduce near work time to prevent depression.

Prognosis palliative care study, palliative prognostic index, palliative prognostic score and objective prognostic score in advanced cancer: a prospective comparison.

BACKGROUND: Predicting how long a patient with far advanced cancer has to live is a significant part of hospice and palliative care. Various prognostic models have been developed, but have not been fully compared in South Korea. OBJECTIVES: We aimed to compare the accuracy of the Prognosis in Palliative Care Study (PiPS), Palliative Prognostic Index (PPI), Palliative Prognostic Score (PaP) and Objective Prognostic Score (OPS) for patients with far advanced cancer in a palliative care unit in South Korea. METHODS: This prospective study included patients with far advanced cancer who were admitted to a single palliative care unit at the National University Hospital. Variables for calculating the prognostic models were recorded by a palliative care physician. The survival rate was estimated using the Kaplan-Meier method. The sensitivity, specificity, positive predictive value and negative predictive value of each model were calculated. RESULTS: A total of 160 patients participated. There was a significant difference in survival rates across all groups, each categorised through the five prognostic models. The overall accuracy (OA) of the prognostic models ranged between 54.5% and 77.6%. The OA of clinicians' predictions of survival ranged between 61.9% and 81.3%. CONCLUSION: The PiPS, PPI, PaP and OPS were successfully validated in a palliative care unit of South Korea. There was no difference in accuracy between the prognostic models, and OA tended to be lower than in previous studies.

Growth and Stress Tolerance Comprise Independent Metabolic Strategies Critical for Staphylococcus aureus Infection.

Staphylococcus aureus is an important pathogen that leads to high morbidity and mortality. Although S. aureus produces many factors important for pathogenesis, few have been validated as playing a role in the pathogenesis of S. aureus pneumonia. To gain a better understanding of the genetic elements required for S. aureus pathogenesis in the airway, we performed an unbiased genome-wide transposon sequencing (Tn-seq) screen in a model of acute murine pneumonia. We identified 136 genes important for bacterial survival during infection, with a high proportion involved in metabolic processes. Phenotyping 80 individual deletion mutants through diverse in vitro and in vivo assays demonstrated that metabolism is linked to several processes, which include biofilm formation, growth, and resistance to host stressors. We further validated the importance of 23 mutations in pneumonia. Multivariate and principal-component analyses identified two key metabolic mechanisms enabling infection in the airway, growth (e.g., the ability to replicate and form biofilms) and resistance to host stresses. As deep validation of these hypotheses, we investigated the role of pyruvate carboxylase, which was important across multiple infection models and confirmed a connection between growth and resistance to host cell killing. Pathogenesis is conventionally understood in terms of the host-pathogen interactions that enable a pathogen to neutralize a host's immune response. We demonstrate with the important bacterial pathogen S. aureus that microbial metabolism influences key traits important for in vivo infection, independent from host immunomodulation. IMPORTANCE Staphylococcus aureus is an important bacterial pathogen that causes significant morbidity and mortality, infecting numerous bodily sites, including the respiratory tract. To identify the bacterial requirements for lung infection, we conducted a genome-wide screen in a mouse model of acute pneumonia. We discovered that metabolic genes were overrepresented in those required for lung infection. In contrast to the conventional view of pathogenesis focusing on immunomodulation, we demonstrate through phenotyping of deletion mutants in several functional assays that replicative ability and tolerance against host defenses form two key metabolic dimensions of bacterial infection. These dimensions are independent for most pathways but are coupled in central carbon metabolism and highlight the critical role of bacterial metabolism in survival against host defenses during infection.

The Risk of Osteoporosis and Osteoporotic Fracture Following the Use of Irritable Bowel Syndrome Medical Treatment: An Analysis Using the OMOP CDM Database.

Patients with irritable bowel syndrome (IBS) are at increased risk of osteoporosis and osteoporotic fracture. This study investigated whether IBS medication attenuated the rate of osteoporosis and osteoporotic fracture risk. We conducted a retrospective large-scale multicenter study across eight hospital databases encoded in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The primary outcome was the incidence of osteoporosis, whereas secondary outcomes were osteoporotic fractures. After 1:4 matching, 24,723 IBS patients, 78,318 non-IBS patients, 427,640 non-IBS patients with IBS medication, and 827,954 non-IBS patients without IBS medication were selected. The risk of osteoporosis was significantly increased in the IBS group compared to the non-IBS group (hazard ratio (HR) 1.33; confidence interval (CI) 1.17~1.51). Even in patients who were not diagnosed with IBS, the risk of osteoporosis was significantly increased in those with IBS medication compared to those without (HR 1.77, CI 1.62~1.93). The risk of osteoporotic fracture was significantly increased in the IBS medication group (HR 1.69, CI 1.55~1.84). Patients exposed to IBS treatment even without IBS diagnosis were at increased risk of osteoporosis and osteoporotic fracture. Early diagnosis and treatment of osteoporosis should be considered in patients who have received medication for IBS symptoms.

Evaluation for Parkinsonian Bradykinesia by deep learning modeling of kinematic parameters.

A wearable sensor system is available for monitoring of bradykinesia in patients with Parkinson's disease (PD), however, it remains unclear whether kinematic parameters would reflect clinical severity of PD, or would help clinical diagnosis of physicians. The present study investigated whether the classification model using kinematic parameters from the wearable sensor may show accordance with clinical rating and diagnosis in PD patients. Using the Inertial Measurement Units (IMU) sensor, we measured the movement of finger tapping (FT), hand movements (HM), and rapid alternating movements (RA) in 25 PD patients and 21 healthy controls. Through the analysis of the measured signal, 11 objective features were derived. In addition, a clinician who specializes in movement disorders viewed the test video and evaluated each of the Unified Parkinson's Disease Rating Scale (UPDRS) scores. In all items of FT, HM, RA, the correlation between the linear regression score obtained through objective features (angle, period, coefficient variances for angle and period, change rates of angle and period, angular velocity, total angle, frequency, magnitude, and frequency × magnitude) and the clinician's UPDRS score was analyzed, and there was a significant correlation (rho > 0.7, p < 0.001). PD patients and controls were classified by deep learning using objective features. As a result, it showed a high performance with an area under the curve (AUC) about as high as 0.9 (FT Total = 0.950, HM Total = 0.889, RA Total = 0.888, ALL Total = 0.926. This showed similar performance to the classification result of binary logistic regression and neurologist, and significantly higher than that of family medicine specialists. Our results suggest that the deep learning model using objective features from the IMU sensor can be usefully used to identify and evaluate bradykinesia, especially for general physicians not specializing in neurology.

Staphylococcal DNA Repair Is Required for Infection.

To cause infection, Staphylococcus aureus must withstand damage caused by host immune defenses. However, the mechanisms by which staphylococcal DNA is damaged and repaired during infection are poorly understood. Using a panel of transposon mutants, we identified the rexBA operon as being important for the survival of Staphylococcus aureus in whole human blood. Mutants lacking rexB were also attenuated for virulence in murine models of both systemic and skin infections. We then demonstrated that RexAB is a member of the AddAB family of helicase/nuclease complexes responsible for initiating the repair of DNA double-strand breaks. Using a fluorescent reporter system, we were able to show that neutrophils cause staphylococcal DNA double-strand breaks through reactive oxygen species (ROS) generated by the respiratory burst, which are repaired by RexAB, leading to the induction of the mutagenic SOS response. We found that RexAB homologues in Enterococcus faecalis and Streptococcus gordonii also promoted the survival of these pathogens in human blood, suggesting that DNA double-strand break repair is required for Gram-positive bacteria to survive in host tissues. Together, these data demonstrate that DNA is a target of host immune cells, leading to double-strand breaks, and that the repair of this damage by an AddAB-family enzyme enables the survival of Gram-positive pathogens during infection.IMPORTANCE To cause infection, bacteria must survive attack by the host immune system. For many bacteria, including the major human pathogen Staphylococcus aureus, the greatest threat is posed by neutrophils. These immune cells ingest the invading organisms and try to kill them with a cocktail of chemicals that includes reactive oxygen species (ROS). The ability of S. aureus to survive this attack is crucial for the progression of infection. However, it was not clear how the ROS damaged S. aureus and how the bacterium repaired this damage. In this work, we show that ROS cause breaks in the staphylococcal DNA, which must be repaired by a two-protein complex known as RexAB; otherwise, the bacterium is killed, and it cannot sustain infection. This provides information on the type of damage that neutrophils cause S. aureus and the mechanism by which this damage is repaired, enabling infection.

The ClpXP Protease Contributes to Staphylococcus aureus Pneumonia.

Staphylococcus aureus is a leading cause of pneumonia. We show here that the ClpXP protease involved in protein turnover is important for pathogenesis in a murine model of acute pneumonia. Staphylococcus aureus lacking this protease is attenuated in vivo, being rapidly cleared from the airway and leading to decreased immune cell influx and inflammation. Characterization of defined mutations in vitro identified defects in intracellular survival and protection against neutrophil killing. Our results further expand on what is known about ClpXP in the pathogenesis of S. aureus to include the respiratory tract.

The Association of Body Fat and Arterial Stiffness Using the Brachial-Ankle Pulse Wave Velocity.

BACKGROUND: BMI alone may not serve as an index of obesity because it does not reflect body composition. The present study aimed to compare arterial stiffness as assessed by the brachial-ankle pulse wave velocity (ba-PWV) among groups defined by body fat percentage (pBF) and BMI. METHODS: This cross-sectional study was based on 1,700 participants (1,044 men and 656 women) who completed a health screening examination at a national hospital between January 2011 and February 2016. Participants were divided into four groups according to BMI and pBF: normal fat and normal weight (NFNW); excessive fat and normal weight (EFNW); normal fat and obese (NFO); and excessive fat and obese (EFO). The ba-PWV and other cardiometabolic factors were compared among the four groups in men and women separately. RESULTS: For both sexes, the NFNW group had a lower metabolic risk compared to that in the other groups (EFNW, NFO, and EFO). After adjusting for multiple variables, the NFO males had a significantly lower ba-PWV compared to those in the other groups, including NFNW males. The NFO group had significantly more skeletal muscle mass and muscle mass compared the other groups (P<0.05). Among women, the NFNW group had a significantly lower ba-PWV compared the other groups, even after adjusting for multiple variables. CONCLUSION: Lower pBF in obese men may be associated with improved cardiovascular risk.

Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia.

Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development. However, the role of pep27 gene, belonging to the vancomycin-resistance locus (vncRS operon), in virulence, is largely unknown. This study demonstrates that transferrin in the host serum reduces the survival of the host during S. pneumoniae infections in mice. The exposure of the pneumococcal D39 strain to lactoferrin induced the vncRS operon, lysis, and subsequent in vivo cytokine production, resulting in lung inflammation. However, these responses were significantly attenuated in pneumococci harboring a mutation in pep27. Mechanistically, the VncS ligand, identified as lactoferrin, induced the vncRS operon and increased the in vivo mortality rates. Thus, serum-induced activation of vncRS plays an essential role in inducing pneumonia.

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1ß Activation During Streptococcus pneumoniae Infection.

Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1ß secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mice but were lower than in WT mice treated with isotype control, indicating that ATF3 positively regulated IL-17A production. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1ß production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca2+ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in γδ T cells to rapidly induce host defenses during early S. pneumoniae infection.

Effect of Korean Red Ginseng extracts on drug-drug interactions.

BACKGROUND: Ginseng has been the subject of many experimental and clinical studies to uncover the diverse biological activities of its constituent compounds. It is a traditional medicine that has been used for its immunostimulatory, antithrombotic, antioxidative, anti-inflammatory, and anticancer effects. Ginseng may interact with concomitant medications and alter metabolism and/or drug transport, which may alter the known efficacy and safety of a drug; thus, the role of ginseng may be controversial when taken with other medications. METHODS: We extensively assessed the effects of Korean Red Ginseng (KRG) in rats on the expression of enzymes responsible for drug metabolism [cytochrome p450 (CYP)] and transporters [multiple drug resistance (MDR) and organic anion transporter (OAT)] in vitro and on the pharmacokinetics of two probe drugs, midazolam and fexofenadine, after a 2-wk repeated administration of KRG at different doses. RESULTS: The results showed that 30 mg/kg KRG significantly increased the expression level of CYP3A11 protein in the liver and 100 mg/kg KRG increased both the mRNA and protein expression of OAT1 in the kidney. Additionally, KRG significantly increased the mRNA and protein expression of OAT1, OAT3, and MDR1 in the liver. Although there were no significant changes in the metabolism of midazolam to its major metabolite, 1'-hydroxymidazolam, KRG significantly decreased the systemic exposure of fexofenadine in a dose-dependent manner. CONCLUSION: Because KRG is used as a health supplement, there is a risk of KRG overdose; thus, a clinical trial of high doses would be useful. The use of KRG in combination with P-glycoprotein substrate drugs should also be carefully monitored.