Enhanced anaerobic co-digestion of cattle manure with food waste and pig manure: Statistical optimization of pretreatment condition and substrate mixture ratio.

This study investigated the optimal pretreatment condition and mixture ratio of cattle manure (CM) for its efficient anaerobic co-digestion (AcoD) with food waste (FW) and pig manure (PM). The pretreatment performances of thermal (TM), microwave (MW), and ultrasound (US) technologies and the AcoD performance were statistically and experimentally evaluated at various mixture ratios of CM, FW, and PM. The results revealed that the most effective pretreatment condition with the TM, MW, and US pretreatments was 129.3 °C for 49.6 min, 824.2 W for 7.3 min, and 418.0 W for 36.3 min, respectively. The best AcoD performance of optimally pretreated CM (PCM) was achieved when 30.5 % PCM was mixed with 42.5 % FW and 27.0 % PM. A long-term evaluation showed that the start-up rate for the anaerobic mono-digestion of PCM was 2.3 times faster than that of CM and the amount of methane produced was 4.7 times higher; process stability was thus preferentially maintained under a higher organic loading rate (OLR) (2.0 kg-VS/m3∙d). The start-up rate for the AcoD of PCM with FW and PM was 1.2 times higher than that of the AcoD of CM with FW and PM. Although the performance gap between the AcoD reactors after steady state was not significantly different, the PCM AcoD reactor provided a more stable operation under a higher OLR (5.0 kg-VS/m3∙d). This study demonstrates that the pretreatment and co-digestion of CM could significantly enhance the production of biogas and improve process stability.

Maternal PFOS exposure affects offspring development in Nrf2-dependent and independent ways in zebrafish (Danio rerio).

Perfluorooctanesulfonic acid (PFOS) is a ubiquitous legacy environmental contaminant detected broadly in human samples and water supplies. PFOS can cross the placenta and has been detected in cord blood and breastmilk samples, underscoring the importance of understanding the impacts of maternal PFOS exposure during early development. This study aimed to investigate the effects of a preconception exposure to PFOS on developmental endpoints in offspring, as well as examine the role of the transcription factor Nuclear factor erythroid-2-related factor (Nrf2a) in mediating these effects. This transcription factor regulates the expression of several genes that protect cells against oxidative stress including during embryonic development. Adult female zebrafish were exposed to 0.02, 0.08 or 0.14 mg/L PFOS for 1 week (duration of one cycle of oocyte maturation) and then paired with unexposed males from Nrf2a mutant or wildtype strains. Embryos were collected for two weeks or until completion of 5 breeding events. PFOS was maternally transferred to offspring independent of genotype throughout all breeding events in a dose-dependent manner, ranging from 2.77 to 23.72 ng/embryo in Nrf2a wildtype and 2.40 to 15.80 ng/embryo in Nrf2a mutants. Although embryo viability at collection was not impacted by maternal PFOS exposure, developmental effects related to nutrient uptake, growth and pancreatic ß-cell morphology were observed and differed based on genotype. Triglyceride levels were increased in Nrf2a wildtype eggs from the highest PFOS group. In Nrf2a wildtype larvae there was a decrease in yolk sac uptake while in Nrf2a mutants there was an increase. Additionally, there was a significant decrease in pancreatic ß-cell (islet) area in wildtype larvae from the 0.14 mg/L PFOS accompanied by an increase in the prevalence of abnormal islet morphologies compared to controls. Abnormal morphology was also observed in the 0.02 and 0.08 mg/L PFOS groups. Interestingly, in Nrf2a mutants there was a significant increase in the pancreatic ß-cell area in the 0.02 and 0.08 mg/L PFOS groups and no changes in the prevalence of abnormal islet morphologies. These results suggest that the regulation of processes like nutrient consumption, growth and pancreatic ß-cell development are at least partially modulated by the presence of a functional Nrf2a transcriptomic response. Overall, preconception exposure to environmental pollutants, such as PFOS, may impact the maturing oocyte and cause subtle changes that can ultimately impact offspring health and development.

Nuclear lipid droplets in Caco2 cells originate from nascent precursors and in situ at the nuclear envelope.

Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid droplets (nLDs) are present in intestinal cells but their origin and relationship to cytoplasmic TAG synthesis and secretion is unknown. nLDs and related lipid-associated promyelocytic leukemia structures (LAPS) were abundant in oleate-treated Caco2 but less frequent in other human colorectal cancer cell lines and mouse intestinal organoids. nLDs and LAPS in undifferentiated oleate-treated Caco2 cells harbored the phosphatidate phosphatase Lipin1, its product diacylglycerol, and CTP:phosphocholine cytidylyltransferase (CCT)α. CCTα knockout Caco2 cells had fewer but larger nLDs, indicating a reliance on de novo PC synthesis for assembly. Differentiation of Caco2 cells caused large nLDs and LAPS to form regardless of oleate treatment or CCTα expression. nLDs and LAPS in Caco2 cells did not associate with apoCIII and apoAI and formed dependently of microsomal triglyceride transfer protein expression and activity, indicating they are not derived from endoplasmic reticulum luminal LDs precursors. Instead, undifferentiated Caco2 cells harbored a constitutive pool of nLDs and LAPS in proximity to the nuclear envelope that expanded in size and number with oleate treatment. Inhibition of TAG synthesis did affect the number of nascent nLDs and LAPS but prevented their association with promyelocytic leukemia protein, Lipin1α, and diacylglycerol, which instead accumulated on the nuclear membranes. Thus, nLD and LAPS biogenesis in Caco2 cells is not linked to lipoprotein secretion but involves biogenesis and/or expansion of nascent nLDs by de novo lipid synthesis.

Psychosocial and Environmental Correlates of Physical Activity in Korean Adults.

Using hypothesized structural equation modeling, we investigated contributions to physical activity (PA) from psychological, social, and environmental variables. Participants were 768 adults aged 30 years or older (men = 353, women = 415; Mage = 42.51, SD = 10.21 years) living in Jungrang-gu, Seoul. To assess psychological, social, and environmental variables, respondents completed scales measuring self-efficacy, decisional balance, social support, physical environment, and leisure time exercise. We found that psychological, social, and environmental variables had a statistically significant effect on PA, with psychological variables mediating the effects of social and physical environmental variables on PA. These findings lend support to the assumed internal and external validity of the social ecological model (SEM) as an explanation for PA.

A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment.

Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies. The diverse range of experimental models and techniques has significantly contributed to the examination of potential DDIs. Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of many drugs on the market, making them frequently implicated in drug metabolism and DDIs. Consequently, there has been a growing focus on the assessment of DDI risk for CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction and an overview of the in vitro assessment of CYP-mediated DDIs.

Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy.

Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.

LC-MS-Based Direct Quantification of MicroRNAs in Rat Blood.

MicroRNA (miRNA) has recently garnered significant research attention, owing to its potential as a diagnostic biomarker and therapeutic target. Liquid chromatography-mass spectrometry (LC-MS) offers accurate quantification, multiplexing capacity, and high compatibility with various matrices. These advantages establish it as a preferred technique for detecting miRNA in biological samples. In this study, we presented an LC-MS method for directly quantifying seven miRNAs (rno-miR-150, 146a, 21, 155, 223, 181a, and 125a) associated with immune and inflammatory responses in rat whole blood. To ensure miRNA stability in the samples and efficiently purify target analytes, we compared Trizol- and proteinase K-based extraction methods, and the Trizol extraction proved to be superior in terms of analytical sensitivity and convenience. Chromatographic separation was carried out using an oligonucleotide C18 column with a mobile phase composed of N-butyldimethylamine, 1,1,1,3,3,3-hexafluoro-2-propanol, and methanol. For MS detection, we performed high-resolution full scan analysis using an orbitrap mass analyzer with negative electrospray ionization. The established method was validated by assessing its selectivity, linearity, limit of quantification, accuracy, precision, recovery, matrix effect, carry-over, and stability. The proposed assay was then applied to simultaneously monitor target miRNAs in lipopolysaccharide-treated rats. Although potentially less sensitive than conventional methods, such as qPCR and microarray, this direct-detection-based LC-MS method can accurately and precisely quantify miRNA. Given these promising results, this method could be effectively deployed in various miRNA-related applications.

Potential of nitrite-absent anaerobic ammonium oxidation by mixed culture ANAMMOX granules in a single chamber bio-electrochemical system.

Nitrogen (N) removal from wastewater is essential, but it a process that demands a substantial amount of energy. Therefore, there is an urgent need to develop treatment processes that can conserve and use energy effectively. This study investigated the potential of a single chamber bio-electrochemical system (BES) for ammonium (NH4+) removal. Various NH4+:NO2- ratios (1:1, 1:0.5, and 1:0) were tested at an applied potential of 0.4 V vs. Ag/AgCl. Potential in the reactors (R-1, R-2, and R-3) significantly improved NH4+ removal efficiencies. Specifically, R-1, R-2, and R-3 exhibited removal efficiencies of 68.12%, 64.22%, and 57.86%, respectively. NH4+ oxidation in R-3 involved using a carbon brush electrode as an electron acceptor. Significant electric charge generation was observed in all reactors (R-1, R-2, and R-3) during NH4+ removal. Particularly, the use of a carbon brush as an electron acceptor in R-3 resulted in higher electric charge generation compared to those in R-1 and R-2, where NO2- served as an electron acceptor. Upon NH4+ removal and concurrent electric charge generation, nitrate (NO3-) accumulation was observed in reactors with applied potential (R-1, R-2, and R-3), demonstrating greater accumulation compared to reactors without potential (R-7, R-8, and R-9). The mechanism involves ammonium oxidizing bacteria (AOB) oxidizing NH4+ to NO2-, which is then further oxidized by nitrite-oxidizing bacteria (NOB) to NO3-. ANAMMOX bacteria could directly produce N2 from NH4+ and NO2- or NH4+ could be oxidized to N2 through extracellular electron transfer (EET). A carbon brush electron acceptor reduces NO2- requirement by 1.65 g while enhancing NH4+ oxidation efficiency. This study demonstrates the potential of mixed culture ANAMMOX granules for efficient NO2-free NH4+ removal.

Bioelectrochemical system for nitrogen removal: Fundamentals, current status, trends, and challenges.

Biological nitrogen removal (BNR) is essential for the treatment of nitrogen-containing wastewater. However, the requirement for aeration and the addition of external carbon sources, resulting in greenhouse gas emissions and additional costs, are disadvantages of the traditional BNR process. Alternative technologies have been devised to overcome these drawbacks. Bioelectrochemical nitrogen removal (BENR) has been proposed for efficient nitrogen removal, demonstrating flexibility and versatility. BENR can be performed by combining nitrification, denitrification, anaerobic ammonium oxidation (ANAMMOX), or organic carbon oxidation. Bioelectrochemical-ANAMMOX (BE-ANAMMOX) is the most promising method for nitrogen removal, as it can directly convert NH4+ to N2 and H2 in one step when the electrode is arranged as an electron acceptor. High-value-added hydrogen can potentially be recovered with efficient nitrogen removal using this concept, maximizing the benefits of BENR. Using alternative electron acceptors, such as electrodes and metal ions, for complete total nitrogen removal is a promising technology to substitute NO2- production from NH4+ oxidation by aeration. However, the requirement of electron donors for NO3- reduction, low NH4+ removal efficiency, and low competitiveness of exoelectrogenic bacteria still remain the main obstacles. The future direction for successful BENR should aim to achieve complete anaerobic NH4+ oxidation without any electron acceptor and to maximize selectivity in H2 production. Therefore, the bioelectrochemical pathways and balances between efficient nitrogen removal and high-value-added chemical production should be further studied for carbon and energy neutralities.

Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine.

Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual's drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, nongenetic factors are also known to influence drug metabolism phenotypes. This minireview discusses approaches beyond pharmacogenetic testing to phenotype DMEs-particularly the cytochrome P450 enzymes-in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating noncoding RNAs and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity, 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies, and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. SIGNIFICANCE STATEMENT: This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. It highlights the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic strategy for patient characterization and precision dosing.

Cut-Off Value of Voluntary Peak Cough Flow in Patients with Parkinson's Disease and Its Association with Severe Dysphagia: A Retrospective Pilot Study.

Background and Objectives. Swallowing and coughing reflexes are both closely associated with airway protection. Peak cough flow (PCF) is associated with dysphagia in several neurogenic diseases. In this study, we aimed to analyze the relationship between PCF and aspiration in Parkinson's disease (PD) and determine the cut-off value of PCF. Materials and Methods. We retrospectively analyzed the records of patients with PD who underwent a videofluoroscopic swallowing study and checked for PCF. A total of 219 patients were divided into an aspiration group (n = 125) and a non-aspiration group (n = 94). Results. Significantly lower PCF values were observed in the aspiration group compared to the non-aspiration group (132.63 ± 83.62 vs. 181.38 ± 103.92 L/min, p < 0.001). Receiver operating characteristic curve analysis revealed that a PCF cut-off value of 153 L/min (area under the receiver operating characteristic curve, 0.648; sensitivity, 73.06%; specificity, 51.06%) was associated with aspiration in PD. Additionally, a univariate analysis showed that the male sex, lower body mass indexes, higher Hoehn and Yahr scales, and PCF values of ≤153 L/min indicated an increased risk of aspiration. Conclusions. Through a multivariate analysis, we demonstrated that a PCF value ≤153 L/min was associated with an increased risk of aspiration (odds ratio 3.648; 1.797-7.407), highlighting that a low PCF is a risk factor for aspiration in patients with PD.

Ellagic Acid Prevents Particulate Matter-Induced Pulmonary Inflammation and Hyperactivity in Mice: A Pilot Study.

The inhalation of fine particulate matter (PM) is a significant health-related environmental issue. Previously, we demonstrated that repeated PM exposure causes hyperlocomotive activity in mice, as well as inflammatory and hypoxic responses in their lungs. In this study, we evaluated the potential efficacy of ellagic acid (EA), a natural polyphenolic compound, against PM-induced pulmonary and behavioral abnormalities in mice. Four treatment groups were assigned in this study (n = 8): control (CON), particulate-matter-instilled (PMI), low-dose EA with PMI (EL + PMI), and high-dose EA with PMI (EH + PMI). EA (20 and 100 mg/kg body weight for low dose and high dose, respectively) was orally administered for 14 days in C57BL/6 mice, and after the eighth day, PM (5 mg/kg) was intratracheally instilled for 7 consecutive days. PM exposure induced inflammatory cell infiltration in the lungs following EA pretreatment. Moreover, PM exposure induced inflammatory protein expression in the bronchoalveolar lavage fluid and the expression of inflammatory (tumor necrosis factor alpha (Tnfα), interleukin (Il)-1b, and Il-6) and hypoxic (vascular endothelial growth factor alpha (Vegfα), ankyrin repeat domain 37 (Ankrd37)) response genes. However, EA pretreatment markedly prevented the induction of expression of inflammatory and hypoxic response genes in the lungs. Furthermore, PM exposure significantly triggered hyperactivity by increasing the total moving distance with an increase in moving speed in the open field test. On the contrary, EA pretreatment significantly prevented PM-induced hyperactivity. In conclusion, dietary intervention with EA may be a potential strategy to prevent PM-induced pathology and activity.

Particulate Matter Elevates Ocular Inflammation and Endoplasmic Reticulum Stress in Human Retinal Pigmented Epithelium Cells.

Because of their exposure to air, eyes can come into contact with air pollutants such as particulate matter (PM), which may cause severe ocular pathologies. Prolonged ocular PM exposure may increase inflammation and endoplasmic reticulum stress in the retina. Herein, we investigated whether PM exposure induces ocular inflammation and endoplasmic reticulum (ER) stress-related cellular responses in human retinal epithelium-19 (ARPE-19) cells. To understand how PM promotes ocular inflammation, we monitored the activation of the mitogen-activated protein kinase (MAPK)/nuclear factor kappa beta (NFκB) axis and the expression of key inflammatory mRNAs. We also measured the upregulation of signature components for the ER-related unfolded protein response (UPR) pathways, as well as intracellular calcium ([Ca2+]i) levels, as readouts for ER stress induction following PM exposure. Ocular PM exposure significantly elevated the expression of multiple cytokine mRNAs and increased phosphorylation levels of NFκB-MAPK axis in a PM dose-dependent manner. Moreover, incubation with PM significantly increased [Ca2+]i levels and the expression of UPR-related proteins, which indicated ER stress resulting from cell hypoxia, and upregulation of hypoxic adaptation mechanisms such as the ER-associated UPR pathways. Our study demonstrated that ocular PM exposure increased inflammation in ARPE-19 cells, by activating the MAPK/NFκB axis and cytokine mRNA expression, while also inducing ER stress and stress adaptation responses. These findings may provide helpful insight into clinical and non-clinical research examining the role of PM exposure in ocular pathophysiology and delineating its underlying molecular mechanisms.

Dietary Intervention with Quercetin Attenuates Diesel Exhaust Particle-Instilled Pulmonary Inflammation and Behavioral Abnormalities in Mice.

Exposure to diesel exhaust particles (DEPs) is inevitable and closely linked with increased health hazards, causing pulmonary abnormalities by increasing inflammation, hypoxia, and so on. Moreover, long-term exposure to DEPs may trigger whole-body toxicity with behavioral alterations. Therefore, nutritional intervention with natural components may be desirable to prevent and/or ameliorate DEP-inducible pathophysiology in mammals. Quercetin has been demonstrated to reduce metabolic complications by possessing antioxidative, anti-inflammatory, and antimutagenic effects. In this study, we investigated the effects of quercetin on pulmonary inflammation and behavioral alteration in male C57BL/6 mice against DEP instillation. The experimental mice were separated into four treatment groups (n = 8 per group), which include: vehicle control, DEP instillation, dietary intervention with a low dose of quercetin (20 mg/kg) for 14 days with DEP instillation for 7 days, or dietary intervention with a high dose of quercetin (100 mg/kg) for 14 days with DEP instillation for 7 days. Compared with the DEP-instilled group, dietary intervention with quercetin significantly attenuated eosinophils in the bronchoalveolar lavage fluid analysis, pulmonary cytokine, and hypoxic mRNA expressions regardless of quercetin concentrations. DEP instillation triggered hyperactivities in the experimental mice, while quercetin pretreatment successfully normalized DEP-inducible abnormalities regardless of the dosage. Therefore, dietary intervention with quercetin may be an applicable means to prevent DEP-triggered pulmonary and behavioral abnormalities.

Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4ß-hydroxycholesterol/cholesterol ratio.

Ibrutinib is an orally administered Bruton's tyrosine kinase inhibitor approved for the treatment of B-cell malignancies, including chronic lymphocytic leukemia. Ibrutinib is metabolized primarily via oxidation by cytochrome P450 (CYP) 3A4/5 to M37 (the primary active metabolite), M34, and M25. The objectives of this study were to assess the relationship between formation of the major CYP3A-specific ibrutinib metabolites in vitro and hepatic CYP3A activity and protein abundance, and to evaluate the utility of the endogenous CYP3A biomarker, plasma 4ß-hydroxycholesterol (4ß-HC) to cholesterol ratio, to predict ibrutinib metabolite formation in individual cadaveric donors with matching hepatocytes. Ibrutinib (5 µM) was incubated with single-donor human liver microsomes (n = 20) and primary human hepatocytes (n = 15), and metabolites (M37, M34, and M25) were measured by liquid chromatography-tandem mass spectrometry analysis. CYP3A4/5 protein concentrations were measured by quantitative targeted absolute proteomics, and CYP3A activity was measured by midazolam 1'-hydroxylation. Ibrutinib metabolite formation positively correlated with midazolam 1'-hydroxylation in human liver microsomes and hepatocytes. Plasma 4ß-HC and cholesterol concentrations were measured in plasma samples obtained at the time of liver harvest from the same 15 donors with matching hepatocytes. Midazolam 1'-hydroxylation in hepatocytes correlated with plasma 4ß-HC/cholesterol ratio. When an infant donor (1 year old) was excluded based on previous ontogeny studies, M37 and M25 formation correlated with plasma 4ß-HC/cholesterol ratio in the remaining 14 donors (Spearman correlation coefficients [r] 0.62 and 0.67, respectively). Collectively, these data indicate a positive association among formation of CYP3A-specific ibrutinib metabolites in human hepatocytes, hepatic CYP3A activity, and plasma 4ß-HC/cholesterol ratio in the same non-infant donors.

Long-Term Effects of Extracorporeal Shock Wave Therapy on Breast Cancer-Related Lymphedema.

Extracorporeal shock wave therapy (ESWT) can reduce breast cancer-related lymphedema (BCRL). However, evidence of the long-term effectiveness of ESWT on BCRL is sparse. The aim of the study was to investigate whether ESWT has long-term effects on BCRL. We enrolled patients with stage 2 lymphedema. The 28 female patients were randomly divided into the ESWT group (n = 14) and the control group (n = 14). ESWT was applied thrice a week for a total of 3 weeks with an intensity of 0.056 to 0.068 mJ/mm2 and a frequency of 4 Hz. Complex decongestive therapy (CDT) was applied in both groups. The arm circumference, fluid volume, ratio of water content, and skin thickness were measured. Patients were evaluated at before treatment, 3 weeks after ESWT completion, and 3 months post-ESWT completion. The ESWT group, the circumference of the whole arm, volume, ratio of water content, QuickDASH score, and skin thickness showed statistically significant improvement at 3 weeks and 3 months post-treatment. When comparing the changes in measurement between the two groups at 3 weeks and 3 months post-treatment, ESWT group showed statistically significant improvement in circumference (cm) below the elbow, ratio of water content and skin thickness at 3 weeks and 3 months post treatment. Overall, ESWT improved lymphedema in patients with stage 2 BCRL, and the effects persisted for at least 3 months. Therefore, ESWT may be an additional treatment method for patients with lymphedema.

Application of physiologically-based pharmacokinetic model approach to predict pharmacokinetics and drug-drug interaction of rivaroxaban: A case study of rivaroxaban and carbamazepine.

Rivaroxaban (RIV; Xarelto; Janssen Pharmaceuticals, Beerse, Belgium) is one of the direct oral anticoagulants. The drug is a strong substrate of cytochrome P450 (CYP) enzymes and efflux transporters. This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for RIV. It contained three hepatic metabolizing enzyme reactions (CYP3A4, CYP2J2, and CYP-independent) and two active transporter-mediated transfers (P-gp and BCRP transporters). To illustrate the performance of the developed RIV PBPK model on the prediction of drug-drug interactions (DDIs), carbamazepine (CBZ) was selected as a case study due to the high DDI potential. Our study results showed that CBZ significantly reduces the exposure of RIV. The area under the concentration-time curve from zero to infinity (AUCinf ) of RIV was reduced by 35.2% (from 2221.3 to 1438.7 ng*h/ml) and by 25.5% (from 2467.3 to 1838.4 ng*h/ml) after the first dose and at the steady-state, respectively, whereas the maximum plasma concentration (Cmax ) of RIV was reduced by 37.7% (from 266.3 to 166.1 ng/ml) and 36.4% (from 282.3 to 179.5 ng/ml), respectively. The developed PBPK model of RIV could be paired with PBPK models of other interested perpetrators to predict DDI profiles. Further studies investigating the extent of DDI between CBZ and RIV should be conducted in humans to gain a full understanding of their safety and effects.

A Meta-Analysis of Social Ecological Correlates of Physical Activity Among Koreans.

From the viewpoint of behavioral medicine, analyzing various factors that determine physical activity (PA) is necessary to promote PA participation. In this study we aimed to identify the impact of constructs within the social ecological model (SEM) on PA within the Korean population. We reviewed journal articles and dissertations published between February 2012 and May 2022 in this meta-analysis. We searched the Korean Education Research Information Service (KERIS), Korean Information Service System (KISS), National Digital Library (NDL), PubMed Central (PMC), SCOPUS, and Web of Sciences; and we located 13 studies to include in this review. Collectively, these studies indicated that most SEM constructs were significantly correlated with PA. Self-efficacy was most strongly correlated (0.67), followed by perceived benefits (0.48), quality of exercise facilities (0.37), accessibility of exercise facilities (0.33), friend support (0.29), and family support (0.23). These data provide practical information for basing a PA promotion strategy on SEM to enhance community health through behavioral psychology.

Effect of the SNS-Based Physical Activity-Related Psychological Intervention on Physical Activity and Psychological Constructs among Inactive University Students.

Background/Objective: The current study investigated the effects of the physical activity-related psychological intervention via social network service (SNS) on physical activity and psychological constructs in inactive university students. Method: Thirty inactive university students participated in the 12-week intervention and received the physical activity-related psychological strategy via SNS. The physical activity levels, stages of physical activity, self-efficacy, pros, and cons were measured at the three time points (baseline, after 6 weeks, and after 12 weeks). Data analyses included frequency analysis, McNemar chi-square (χ2) test, and a repeated measures ANOVA were conducted. Results: Results indicated that the number of inactive university students gradually decreased across the three different time points, and that a total physical activity of inactive university students significantly increased over the 12-week intervention. In addition, pros and self-efficacy significantly increased but cons gradually decreased over the intervention. Conclusions: The current study suggests that the SNS-based physical activity-related psychological strategies have positive effects on promoting physical activity and its related psychological constructs for inactive university students.

Resumen Antecedentes/Objetivo: Se investigaron los efectos de la intervención psicológica relacionada con la actividad física a través del servicio de red social (SRS) sobre la actividad física y los constructos psicológicos en estudiantes universitarios inactivos. Método: Treinta estudiantes universitarios inactivos participaron en la intervención de 12 semanas y recibieron la estrategia psicológica relacionada con la actividad física a través del SRS. Niveles de actividad física, etapas de la actividad física, autoeficacia, pros y contras se midieron en tres puntos temporales (línea base, después de 6 semanas y después de 12 semanas). Los análisis de datos incluyeron análisis de frecuencia, prueba de chi-cuadrado (χ2) de McNemar y un ANOVA de medidas repetidas. Resultados: Los resultados indicaron que el número de estudiantes universitarios inactivos disminuyó gradualmente en los tres puntos de tiempo diferentes, y que la actividad física total de los estudiantes universitarios inactivos aumentó significativamente durante la intervención de 12 semanas. Además, los pros y la autoeficacia aumentaron significativamente, pero los contras disminuyeron gradualmente durante la intervención. Conclusiones: Se sugiere que las estrategias psicológicas relacionadas con la actividad física basadas en el SNS tienen efectos positivos en la promoción de la actividad física y sus constructos psicológicos relacionados para estudiantes universitarios inactivos.

Interindividual Variability in Cytochrome P450 3A and 1A Activity Influences Sunitinib Metabolism and Bioactivation.

Sunitinib is an orally administered tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity; however, the mechanisms of this toxicity remain unclear. We have previously shown that cytochromes P450 1A2 and 3A4 catalyze sunitinib metabolic activation via oxidative defluorination leading to a chemically reactive, potentially toxic quinoneimine, trapped as a glutathione (GSH) conjugate (M5). The goals of this study were to determine the impact of interindividual variability in P450 1A and 3A activity on sunitinib bioactivation to the reactive quinoneimine and sunitinib N-dealkylation to the primary active metabolite N-desethylsunitinib (M1). Experiments were conducted in vitro using single-donor human liver microsomes and human hepatocytes. Relative sunitinib metabolite levels were measured by liquid chromatography-tandem mass spectrometry. In human liver microsomes, the P450 3A inhibitor ketoconazole significantly reduced M1 formation compared to the control. The P450 1A2 inhibitor furafylline significantly reduced defluorosunitinib (M3) and M5 formation compared to the control but had minimal effect on M1. In CYP3A5-genotyped human liver microsomes from 12 individual donors, M1 formation was highly correlated with P450 3A activity measured by midazolam 1'-hydroxylation, and M3 and M5 formation was correlated with P450 1A2 activity estimated by phenacetin O-deethylation. M3 and M5 formation was also associated with P450 3A5-selective activity. In sandwich-cultured human hepatocytes, the P450 3A inducer rifampicin significantly increased M1 levels. P450 1A induction by omeprazole markedly increased M3 formation and the generation of a quinoneimine-cysteine conjugate (M6) identified as a downstream metabolite of M5. The nonselective P450 inhibitor 1-aminobenzotriazole reduced each of these metabolites (M1, M3, and M6). Collectively, these findings indicate that P450 3A activity is a key determinant of sunitinib N-dealkylation to the active metabolite M1, and P450 1A (and potentially 3A5) activity influences sunitinib bioactivation to the reactive quinoneimine metabolite. Accordingly, modulation of P450 activity due to genetic and/or nongenetic factors may impact the risk of sunitinib-associated toxicities.