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Objectives: To explore the risk factors and clinical outcomes of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection and establish nomograms to predict the probability of CRKP infection and mortality in adult patients., Methods: Patients infected with KP from August 2019 to April 2021 in a tertiary hospital in Shanghai were enrolled. Risk factors associated with CRKP and 30-day mortality were identified using multivariate logistic regression analysis and Cox regression analysis., Results: Overall, 467 patients with KP infection were enrolled, wherein 210 (45.0%) patients were infected with CRKP and 257 (55.0%) patients with carbapenem-susceptible K. pneumoniae (CSKP). Five factors, namely Charlson's Comorbidity Index (CCI) ≥ 3, the use of central venous catheterization, prior hospitalization during the 3 months before infection, and previous exposure to carbapenems and broad-spectrum β-lactams, were found to be independently associated with CRKP infection. Based on these parameters, the nomogram showed a better performance as indicated by C-index of 0.94 (95% confidence interval [CI]: 0.92-0.96) and well-fitted calibration curves. CRKP was independently associated with 30-day mortality. Multivariate Cox regression analysis revealed that age ≥65 years, higher CCI scores, higher Sequential Organ Failure Assessment scores, the presence of respiratory failure, albumin levels ≤30 g/L, and non-appropriate treatments in 3 days, were associated with 30-day mortality., Conclusion: The predictive nomogram established in this study can facilitate the clinicians to make better clinical decisions when treating patients with KP infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yao, Yang, Yao, Bu, Li, Wang, Zhang and Chen.)

Background: Polymyxin B (PMB)-based combination therapies are used to treat severe carbapenem-resistant gram-negative bacterial (CR-GNB) infections. This observational study investigated the relationship between clinical factors, including PMB concentration, and clinical efficacy and safety., Patients and Methods: Polymyxin B regimens were optimized through therapeutic drug monitoring (TDM) and area under the concentration-time curve (AUC). In all, 382 samples were tested from 130 patients. Logistic regression was used to analyze the relationships between variables with clinical efficacy and 30-day mortality factors were analyzed by Cox regression. The sensitivity and specificity of C min and AUC for the occurrence of acute kidney injury (AKI) were determined by ROC curve analysis., Results: The clinical effectiveness of PMB was 65.4%. Multivariate logistic regression analysis revealed that lung infection, continuous renal replacement therapy, and C-reactive protein were independent factors significantly associated with efficacy. AKI occurred in 14.6% of the patients during treatment; age > 73 years (OR: 3.63; 95% CI: 1.035-12.727; P = 0.044), C min greater than 2.3 µg/mL (OR: 7.37; 95% CI: 1.571-34.580; P = 0.011), combined vancomycin (OR: 9.47; 95% CI: 1.732-51.731; P = 0.009), and combined piperacillin-tazobactam (OR: 21.87; 95% CI: 3.139-152.324; P = 0.002) were independent risk factors. The identified PMB cut-offs for predicting AKI were C min = 2.3 µg/mL and AUC = 82.0 mg h/L., Conclusion: Polymyxin B-based combination regimens are effective in treating CR-GNB infections, particularly bloodstream infections, but have shown unsatisfactory for lung infections. C min ≥ 2.3 µg /mL and AUC ≥ 82.0 mg h/L may increase PMB-associated AKI incidence. PMB dose should be adjusted based on TDM to ensure efficacy., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Li et al.)

This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 μmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy., Methods: From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined., Results: This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children., Conclusions: To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-615/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

In Inertial Confinement Fusion (ICF), the asymmetry of a hot spot is an important influence factor in implosion performance. Neutron penumbral imaging, which serves as an encoded-aperture imaging technique, is one of the most important diagnostic methods for detecting the shape of a hot spot. The detector image is a uniformly bright range surrounded by a penumbral area, which presents the strength distribution of hot spots. The present diagnostic modality employs an indirect imaging technique, necessitating the reconstruction process to be a pivotal aspect of the imaging protocol. The accuracy of imaging and the applicable range are significantly influenced by the reconstruction algorithm employed. We develop a neural network named Fast Fourier transform Neural Network (FFTNN) to reconstruct two-dimensional neutron emission images from the penumbral area of the detector images. The FFTNN architecture consists of 16 layers that include a FFT layer, convolution layer, fully connected layer, dropout layer, and reshape layer. Due to the limitations in experimental data, we propose a phenomenological method for describing hot spots to generate datasets for training neural networks. The reconstruction performance of the trained FFTNN is better than that of the traditional Wiener filtering and Lucy-Richardson algorithm on the simulated dataset, especially when the noise level is high as indicated by the evaluation metrics, such as mean squared error and structure similar index measure. This proposed neural network provides a new perspective, paving the way for integrating neutron imaging diagnosis into ICF., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Background: ShuGan-QieZhi capsule (SGQZC) is a traditional Chinese preparation used to treat hyperlipidemia and obesity, even non-alcoholic fatty liver disease (NAFLD). However, its therapeutic effects, main bioactive ingredients, as well as potential mechanisms for NAFLD are still unclear., Purpose: To investigate the pharmacological effect, main active ingredients, and mechanisms of SGQZC against high-fat diet (HFD)-induced NAFLD in mice., Methods: NAFLD models were established by feeding C57BL/6 J mice an HFD for 24 weeks. From the 12th week, HFD-fed mice received daily gavage of either SGQZC or silibinin for 12 weeks. Hepatic hypertrophy parameters, along with hepatic and systemic lipid metabolism changes in NAFLD mice, were assessed. Oil red O and histopathological staining techniques determined lipid accumulation and liver injury severity. qRT-PCR analysis measured the expression of genes tied to liver lipid metabolism and inflammation. HPLC-MS/MS identified the primary components of SGQZC in the serum. Human normal hepatocytes (LO2) and hepatic stellate cells (LX-2) were used to screen SGQZC's bioactive ingredients. Network pharmacological analysis, transcriptomics, and western blotting delved into SGQZC's synergistic mechanisms against NAFLD., Results: SGQZC ameliorated abnormal lipid metabolism and liver hypertrophy in mice with HFD-induced NAFLD, consequently reducing hepatic lipid accumulation, inflammatory cell infiltration, and liver impairment. Eight crucial components of SGQZC were detected in serum using HPLC-MS/MS and were found to effectively attenuate lipid accumulation and inflammation in liver cells. Further investigation indicated that SGQZC modulates MAPK pathway and AKT/NF-κB pathway, subsequently improving lipid metabolism and inflammation., Conclusion: SGQZC alleviates NAFLD by synergistically modulating the MAPK-mediated lipid metabolism and inhibiting AKT/NF-κB pathways-mediated inflammation. Our findings reveal the enormous potential of SGQZC for the treatment of NAFLD, providing a possible new clinical therapeutic strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective: Shengmai injection is a common treatment for coronary heart disease. The accurate dose regimen is important to maximize effectiveness and minimize adverse reactions. We aim to explore the effect of Shengmai injection in patients with coronary heart disease based on real-world data and establish a personalized medicine model using machine learning and deep learning techniques. Methods: 211 patients were enrolled. The length of hospital stay was used to explore the effect of Shengmai injection in a case-control study. We applied propensity score matching to reduce bias and Wilcoxon rank sum test to compare results between the experimental group and the control group. Important variables influencing the dose regimen of Shengmai injection were screened by XGBoost. A personalized medicine model of Shengmai injection was established by XGBoost selected from nine algorithm models. SHapley Additive exPlanations and confusion matrix were used to interpret the results clinically. Results: Patients using Shengmai injection had shorter length of hospital stay than those not using Shengmai injection (median 10.00 days vs. 11.00 days, p = 0.006). The personalized medicine model established via XGBoost shows accuracy = 0.81 and AUC = 0.87 in test cohort and accuracy = 0.84 and AUC = 0.84 in external verification. The important variables influencing the dose regimen of Shengmai injection include lipid-lowering drugs, platelet-lowering drugs, levels of GGT, hemoglobin, prealbumin, and cholesterol at admission. Finally, the personalized model shows precision = 75%, recall rate = 83% and F1-score = 79% for predicting 40 mg of Shengmai injection; and precision = 86%, recall rate = 79% and F1-score = 83% for predicting 60 mg of Shengmai injection. Conclusion: This study provides evidence supporting the clinical effectiveness of Shengmai injection, and established its personalized medicine model, which may help clinicians make better decisions., Competing Interests: Authors XH and SW were employed by Dalian Medicinovo Technology Co., Ltd. and Authors JYZ and FG were employed by Beijing Medicinovo Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ma, Yu, Chen, Li, Liu, Chen, Lyu, Hao, Zhang, Wang, Gao, Zhang and Bu.)

The stoichiometry of senesced leaves is pivotal in nutrient cycling and can be significantly influenced by soil salinization, a rising global issue threatening the functionality of ecosystems. However, the impacts of soil salinization on senesced leaf stoichiometry are not fully understood. In this study, we conducted a pot experiment with varying soil salt concentrations to examine their influence on the concentrations and stoichiometric ratios of nitrogen (N), phosphorus (P), sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), and zinc (Zn) in the senesced leaves of Suaeda glauca (Bunge). Compared to the control group, salt treatments significantly enhanced Na concentration while diminishing the concentrations of K, Ca, Mg, Zn, N, and P. Interestingly, as salinity levels escalated, N concentration maintained stability, whereas P concentration exhibited an increasing trend. Moreover, K, Ca, and Mg significantly declined as salt levels rose. Salt treatments brought about significant changes in stoichiometric ratios, with the N:P, K:Na, N:Na, N:Mg, and Ca : Mg ratios dropping and the N:Ca and N:K ratios rising, illustrating the varying nutrient coupling cycles under different salt conditions. These findings shed light on the plasticity of stoichiometric traits in S. glauca senesced leaves in response to soil salinization shifts, which could potentially offer insights into nutrient cycling reactions to soil salinization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Liu, Qian, Wang and Chen.)

We present a Fresnel zone plate (FZP) mask-based system for single-shot lensless confocal imaging. The system uses an FZP as coded aperture, which allows each point source to cast a unique pattern onto the sensor, representing their horizontal and axial positions. This results in a 2D sensor measurement comprising a series of FZP patterns, which records the spatial intensity distribution of the incoherent illuminant. The reconstruction process is facilitated by an algorithm based on compress sensing (CS) theory and the use of the nuclear norm of gradient scanning and hologram segmentation technology for autofocusing. The simulative and experimental results of this study align well with the expectation that every layered scene can be accurately recovered at the corresponding depth, without undesirable signals from other layers. Additionally, we analyze the deviation of the reconstruction results in the experiment, which emphasizes the need to consider the thickness of the FZP for a precise forward propagation model.

Objectives: To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines., Patients and Methods: We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650., Results: We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment., Conclusions: We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Soil acidification induced by reactive nitrogen (N) inputs can alter the structure and function of terrestrial ecosystems. Because different N-transformation processes contribute to the production and consumption of H + , the magnitude of acidification likely depends on the relative amounts of organic N (ON) and inorganic N (IN) inputs. However, few studies have explicitly measured the effects of N composition on soil acidification. In this study, we first conducted a meta-analysis to test the effects of ON or IN inputs on soil acidification across 53 studies in grasslands. We then compared soil acidification across five different ON:IN ratios and two input rates based on long-term field N addition experiments. The meta-analysis showed that ON had weaker effects on soil acidification than IN when the N addition rate was above 20 g N m -2  year -1 . The field experiment confirmed the findings from meta-analysis: N addition with proportions of ON ≥ 20% caused less soil acidification, especially at a high input rate (30 g N m -2  year -1 ). Structural equation model analysis showed that this result was largely due to a relatively low rate of H + production from ON as NH 3 volatilization and uptake of ON and NH 4 + by the dominant grass species Leymus chinensis (which are both lower net contributors to H + production) result in less NH 4 + available for nitrification (which is a higher net contributor to H + production). These results indicate that the evaluation of soil acidification induced by N inputs should consider N forms and manipulations of relative composition of N inputs may provide an effective approach to alleviate the N-induced soil acidification., (© 2023 John Wiley & Sons Ltd.)

Schisandrin B (Sch.B) shows antineoplastic activity in colorectal cancer, but the mechanism is still obscure. The intracellular spatial distribution may be helpful in elucidating the mechanism. To investigate the intracellular drug distribution of Sch.B in cancer cells, a simple, rapid, and sensitive ultra-highperformance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was established for the determination of Sch.B in colorectal cancer cells. Warfarin was utilized as an internal standard. The sample pretreatment was carried out with protein precipitation using methanol. The analyte was separated on an Atlantis T3-C 18 column (3  μ m, 2.1 ∗ 100 mm) using gradient elution with a mobile phase comprised of methanol and 0.2% formic acid in water. The flow rate was 0.4 mL/min. The linear range of Sch.B was 20.0-1000.0 ng/mL with a correlation coefficient ( R ) more than 0.99. The matrix effect and recovery ranged from 88.01% to 94.59% and from 85.25% to 91.71%; the interday and intraday precision and accuracy, stability, specificity, carryover, matrix effect, and recovery all conformed to the requirements of pharmacopoeia. Cell viability and apoptosis assays demonstrated that Sch.B has an inhibitory effect in a dose-dependent way on HCT116 proliferation and achieved significant suppression at 75  μ M (IC 50 ). It was found that in HCT116 cell, nucleus, and mitochondria, exposure levels of Sch.B peaked at 36 h and then decreased, and mitochondria possessed more Sch.B than nucleus. These results may help to elucidate the antitumor effect of Sch.B., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Bosu Meng et al.)

Objective: This study was developed to assess the in vivo antimicrobial activity of specific drugs using a model system consisting of Caenorhabditis elegans ( C. elegans ) infected with Carbapenem-resistant Klebsiella pneumoniae (CRKP) in an effort to identify promising drugs for CRKP-infected patient treatment. Methods: A C. elegans -CRKP liquid assay platform was developed and used to conduct limited in vivo screening for antimicrobial agents with potential activity against CRKP. Time curves for 10 different concentrations of tested antimicrobial agents were tested in this model system at 0, 2, 6, 8, and 12 h after treatment. The protective effects of these different antimicrobial agents were compared at different time points. Furthermore, ten CRKP strains samples were isolated from clinical specimens to demonstrate the applicability of the nematode model method, and two typical clinical cases are presented. Results: CRKP bacteria were sufficient to induce C. elegans death in a dose- and time-dependent fashion, while effective antimicrobial agents improved the survival of these nematodes in a dose-dependent manner. Notably, PB and TGC exhibited robust antibacterial protection within 12 h even at low tested concentrations, and clear efficacy remained evident for high doses of CAZ at this same time point as mediators of improved nematode survival. The results of C. elegans model method were well consistent with that using the Kirby-Bauer method in 10 CRKP strains samples, and two typical clinical cases showed applicability, reliability and efficacy of C. elegans model method. Conclusion: Overall, nematode models in drug sensitivity testing have shown advantages in clinical settings. Our results highlight the value of C. elegans model systems as tools for the simultaneous screening of different agents for in vivo antibacterial efficacy and are deserved further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yao, Xu, Liu, Wang, Yao and Chen.)

Podocyte lipid accumulation is a potential therapeutic target for diabetic nephropathy (DN). This study was aimed at clarifying the mechanism of Gandi capsule (GDC) ameliorating DN by regulating the lipid metabolism of podocytes. Network pharmacology methods were performed to screen the key molecules and potential targets of GDC for constructing the molecular-protein interaction network of GDC and conducting signal pathway enrichment analysis. GDC was predicted to ameliorate DN through SIRT1/AMPK/HNF4A pathway. Our results showed that GDC improved renal function in db/db mice. Besides, GDC exhibited effectiveness in relieving kidney tissue damage and renal lipid accumulation in db/db mice, and same effects were present in GDC-active ingredient baicalin. We further proved the new role of HNF4A in the lipid metabolism of DN mediated by SIRT1 and AMPK signaling pathways. The results suggested decreased expression of SIRT1 and p-AMPK α in the kidney tissue and increased expression of HNF4A of db/db mice compared with the control group. GDC and baicalin could reverse these expression changes. Furthermore, similar expression changes were observed in the murine podocyte cell line (MPC-5) treated with different concentrations of GDC and baicalin. Our research suggested that GDC and its active ingredient baicalin could alleviate the abnormal lipid metabolism in the kidney of db/db mice and might exert renal protection through the SIRT1/AMPK/HNF4A pathway., Competing Interests: There are no conflicts of interest among the authors., (Copyright © 2022 Ying Zhang et al.)

Objective: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with poor patient outcomes. We aimed to analyze the clinical information of adult patients with CRKP infection in order to establish a nomogram for mortality risk as well as to determine the treatment effectiveness of different antimicrobial regimens., Methods: Adult patients diagnosed with CRKP infection in a tertiary hospital in Shanghai between September 2019 and March 2021 were included. The clinical characteristics and clinical outcomes of these patients were analyzed., Results: A total of 199 cases of CRKP infection were examined. Five factors, namely age ≥65 years, respiratory failure, Sequential Organ Failure Assessment score, serum procalcitonin ≥5 ng/mL, and appropriate treatments in 3 days, were found to be associated with 30-day mortality. Upon incorporating these factors, the nomogram achieved good concordance indexes of 0.85 (95% confidence interval [CI]: 0.80-0.90) and well-fitted calibration curves. Receiver-operating characteristic curves for 7-, 15-, and 30-day survival had areas under the curve of 0.90, 0.87, and 0.88, respectively. Three-drug combination therapy was observed to be associated with lower mortality in the high-risk group (adjusted hazard ratio = 0.24, 95% CI: 0.06-0.99) but not in the low-risk group. Ceftazidime-avibactam, fosfomycin, and amikacin were effective against infections caused by CRKP. Tigecycline improved the treatment efficiency in 7 days, but a trend toward increased mortality was seen (HR, 1.69; 95% CI: 0.98-2.94; P = 0.061)., Conclusion: The antimicrobial regimen efficacy data and the predictive nomogram established in this study can help clinicians in identifying high-risk adult patients with CRKP infection, improving the therapeutic effect, and reducing mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Yang, Yao, Bu, Li, Wang, Chen and Yao.)

To assess the pharmacokinetic parameters of vancomycin in Chinese critically ill pediatric patients, children treated with vancomycin, hospitalized in the intensive care unit were included. Samples to determine peak and trough serum concentrations were obtained on the third day of treatment. Half-life was significantly longer in neonates and showed a decreasing trend in infants and children. In patients aged ≥1 month, AUC 24 /MIC ≥400 was achieved in 31.8% at the dose of 40 mg/kg/d, and in 48.7% at the dose of 60 mg/kg/d with an assumed MIC of 1 mg/L. Augmented renal clearance (ARC) was present in 27.3% of children, which was associated with higher vancomycin clearance and lower AUC values. A good correlation was observed between trough concentration and AUC 24 , and the trough concentration that correlated with AUC 24 of 400 were varied according to the dosage regimens, 8.42 mg/L for 6-hintervals, and 6.63 mg/L for 8-h intervals. To conclude, vancomycin trough concentration that related to the AUC 24 of 400 was much lower in critically ill children than that in adults. The dosage of 60 mg/kg/day did not enough for producing AUC 24 in the range of 400-600 mg h/L in critically ill children, especially in those with ARC., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Oxidation of Al-Sn bearing alloy occurs during production, processing and use, which reduces both alloy performance and performance of coatings applied to the alloy surface. Therefore, the oxidation mechanism of Al-Sn bearing alloy is studied at 25, 180, 300, and 500 °C. The oxidation morphologies of the alloy were observed by scanning electron microscopy (SEM), and the oxidation products were determined by X-ray diffraction (XRD). The oxidation weight gain curves were obtained by thermogravimetric analysis. The experimental results show that: Al-Sn bearing alloy is oxidized quickly to form Al 2 O 3 . As the oxidation temperature increases, Sn phase start to precipitate along the grain boundary and form networked spheroids of Sn on the alloy surface. The amount of precipitation increases with further increase of the oxidation temperature. Cracks and holes are left in the alloy. The oxide layer is mainly composed of Sn, SnO 2 , and Al 2 O 3 . At 25 °C, oxidation rate of Al-Sn alloy approach zero. At 180, 300, and 500 °C, the oxidation rate increases quickly conforming to a power function, and eventually remains stable at about 3 × 10 -6 mg·mm -2 ·s -1 .

Objectives: Despite therapeutic vancomycin is regularly monitored, its dose requirements vary considerably between individuals. Various innovative vancomycin dosing strategies have been developed for dose optimization; however, the utilization of individual factors and extensibility is insufficient. We aimed to develop an optimal dosing algorithm for vancomycin based on the high-dimensional data using the proposed variable engineering and machine-learning methods., Methods: This study proposed a variable engineering process that automatically generates second-order variable interactions. We performed an initial examination of independent variables and interactive variables using eXtreme Gradient Boosting. The vancomycin dose prediction model was established based on the derived variables., Results: Based on the evaluation of the model performance in the validation cohort, our algorithm accounted for 67.5% of variations in the vancomycin doses. Subgroup analysis showed better performance in patients with medium and high body weight (with the ideal predictive percentage of 72.7% and 73.7%), and low and medium levels of serum creatinine (with the ideal predictive percentage of 77.8% and 73.1%) than in other groups., Conclusion: The new vancomycin dose prediction model is potentially useful for patients whose population profiles are similar to those of our patients and yielded desired reference of clinical indicators with specific breakpoints.

There is insufficient evidence concerning the efficacy of wet silver-containing dressings for wound healing in pemphigus vulgaris (PV). In this randomized, controlled clinical trial, 58 patients with PV skin erosions (10%-70% body surface area) were assigned to receive either wet silver-containing dressings (n = 28) or wet to dry povidone-iodine dressings as a control (n = 30). The patients in the treatment group demonstrated a significant improvement in the number of dressing changes, wound healing time, and duration of hospital stay compared with the control group. Patients treated with wet silver dressings had significantly lower NRS pain scores and reported better subjective satisfaction compared with the control group. The only adverse reactions were an occasional abnormal discharge or infection, but there was no difference between the two groups. In our study the wet silver-containing dressings were safe and effective for the treatment of wound healing in PV patients., (© 2021 Wiley Periodicals LLC.)

Purpose: This study aimed to establish an optimal model to predict vancomycin trough concentrations by using machine learning., Patients and Methods: We enrolled 407 pediatric patients (age < 18 years) who received vancomycin intravenously and underwent therapeutic drug monitoring from June 2013 to April 2020 at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. The median (interquartile range) age and weight of the patients were 2 (0.63-5) years and 12 (7.8-19) kg. Vancomycin trough concentrations were considered as the target variable, and eight different algorithms were used for predictive performance comparison. The whole dataset (407 cases) was divided into training group and testing group at the ratio of 80%: 20%, which were 325 and 82 cases, respectively., Results: Ultimately, five algorithms (XGBoost, GBRT, Bagging, ExtraTree and decision tree) with high R 2 (0.657, 0.514, 0.468, 0.425 and 0.450, respectively) were selected and further ensembled to establish the final model and achieve an optimal result. For missing data, through filling the missing values and model ensemble, we obtained R 2 =0.614, MAE=3.32, MSE=24.39, RMSE=4.94 and a prediction accuracy of 51.22% (predicted trough concentration within ±30% of the actual trough concentration). In comparison with the pharmacokinetic models ( R 2 =0.3), the machine learning model works better in model fitting and has better prediction accuracy., Conclusion: Therefore, the ensemble model is useful for the vancomycin concentration prediction, especially in the population of children with great individual variation. As machine learning methods evolve, the clinical value of the ensemble model will be demonstrated in the clinical practice., Competing Interests: Ze Yu, Wenjun He, Peng Yu, Zeyuan Wang, and Fei Gao are affiliated with Beijing Medicinovo Technology Co. Ltd. Xin Hao is affiliated with Dalian Medicinovo Technology Co. Ltd. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 Huang et al.)

Motivation: Warfarin is a widely used oral anticoagulant, but it is challenging to select the optimal maintenance dose due to its narrow therapeutic window and complex individual factor relationships. In recent years, machine learning techniques have been widely applied for warfarin dose prediction. However, the model performance always meets the upper limit due to the ignoration of exploring the variable interactions sufficiently. More importantly, there is no efficient way to resolve missing values when predicting the optimal warfarin maintenance dose., Methods: Using an observational cohort from the Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, we propose a novel method for warfarin maintenance dose prediction, which is capable of assessing variable interactions and dealing with missing values naturally. Specifically, we examine single variables by univariate analysis initially, and only statistically significant variables are included. We then propose a novel feature engineering method on them to generate the cross-over variables automatically. Their impacts are evaluated by stepwise regression, and only the significant ones are selected. Lastly, we implement an ensemble learning based approach, LightGBM, to learn from incomplete data directly on the selected single and cross-over variables for dosing prediction., Results: 377 unique patients with eligible and time-independent 1173 warfarin order events are included in this study. Through the comprehensive experimental results in 5-fold cross-validation, our proposed method demonstrates the efficiency of exploring the variable interactions and modeling on incomplete data. The R 2 can achieve 75.0% on average. Moreover, the subgroup analysis results reveal that our method performs much better than other baseline methods, especially in the medium-dose and high-dose subgroups. Lastly, the IWPC dosing prediction model is used for further comparison, and our approach outperforms it by a significant margin., Conclusion: In summary, our proposed method is capable of exploring the variable interactions and learning from incomplete data directly for warfarin maintenance dose prediction, which has a great premise and is worthy of further research., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: The objective of this study is to identify the potential risk factors for progression from subclinical to clinical psoriatic arthritis (PsA)., Methods: A retrospective, longitudinal, case-control study was conducted at a single hospital, including 25 patients with clinically confirmed PsA in the case group and 137 controls without confirmed PsA. All patients in both groups had a medical history of subclinical PsA. Various baseline covariates were collected from all patients when they had a status of subclinical PsA. Univariate, multivariate, stratified, and interaction analyses were employed to identify potential risk factors of transiting to clinical PsA from subclinical PsA., Results: In multivariate logistic regression analysis, older age (OR 10.15, 95% CI 2.79-36.91, p = 0.00), alcohol drinking (OR 3.43, 95% CI 1.17-10.12, p = 0.03), elevated high-sensitivity C-reactive protein (hs-CRP) (OR 1.05, 95% CI 1.01-1.09, p = 0.03) were identified as risk factors for transition from subclinical to clinical PsA. Stratified and logistic regression analyses suggest a significant interaction between age and fatty liver. For patients aged less than 45 years old, the association between fatty liver and clinical PsA was statistically significant., Conclusions: Older age, alcohol drinking, elevated hs-CRP, and the presence of fatty liver at less than 45 years old appear to increase the risk of transition from subclinical to clinical PsA. These findings call for a need to manage these risk factors.

Aim: Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen., Methods: First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer., Results: The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC 50 , r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC 50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold)., Conclusions: Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

Understanding future climate change requires accurate estimates of the impacts of atmospheric nitrogen (N) deposition, composed of both inorganic and organic compounds, on greenhouse gas (GHG) fluxes in grassland ecosystems. However, previous studies have focused on inorganic compounds and have not considered the potential effects of organic N sources. Here, we conducted a grassland experiment that included organic, inorganic N, and a mix of them at a ratio of 4:6, with two input rates, to study N inputs induced CO 2 , CH 4, and N 2 O fluxes, as well as the potential abiotic and biotic mechanisms driving the fluxes. We found that N compositions significantly affected fluxes each of the three GHGs. Greater organic N decreased the impacts of N addition on CO 2 and N 2 O emissions, caused primarily by low rates of increase in substrates (soil available N) for production of CO 2 and N 2 O resulting from high ammonia volatilization rather than changes in microbial activity. Also, greater organic N slightly stimulated CH 4 uptake. Nitrogen composition effects on CO 2 emissions and CH 4 uptake were independent of N input rates and measurement dates, but N 2 O emissions showed stronger responses to inorganic N under high N addition and in June. These results suggest that future studies should consider the source of N to improve our prediction of future climate impact of N deposition, and that management of N fertilization can help mitigate GHG emissions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We propose and theoretically analyze a single-order diffractive optical element, termed binary sinusoidal multilayer grating (BSMG), to effectively suppress high-order diffractions while retaining high diffraction efficiency in the first order. The key idea is to integrate sinusoidal-shaped microstructures with high-reflectivity multilayer coatings. The dependence of the high-order diffraction property on the microstructure shape and multilayer coatings is investigated. Theoretical calculation reveals that the second-, third-, fourth-, and fifth-order diffraction efficiencies are as low as 0.01%. Strikingly, we show that first-order relative diffraction efficiency (the ratio between the intensity of the first diffraction order versus that of the reflected light) as high as 97.7% can be achieved. Thus, the proposed BSMG should be highly advantageous in future development and application of tender x-ray spectroscopy.

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo We found that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found that these effects were not mediated by tubacin's inhibitory effect on HDAC6 activity, but rather were due to its ability to stabilize eNOS mRNA transcripts. Consistent with these findings, tubacin also inhibited proinflammatory cytokine-induced degradation of eNOS transcripts and impairment of endothelium-dependent relaxation in the mouse aorta. Furthermore, we found that tubacin-induced up-regulation in eNOS expression in vivo is associated with improved endothelial function in diabetic db / db mice and with a marked attenuation of ischemic brain injury in a murine stroke model. Our findings indicate that tubacin exhibits potent eNOS-inducing effects and suggest that this compound might be useful for the prevention or management of endothelial dysfunction-associated cardiovascular diseases., (© 2019 Chen et al.)

Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure.

Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR) in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) liposomes (liposomal pemetrexed) were developed as a strategy to overcome MDR to pemetrexed in breast cancer., Materials and Methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated., Results: Liposomal pemetrexed was small in size (160.77 nm), with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC 50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5) was 2.6-fold more effective than pemetrexed. The in vivo biodistribution study showed that the liposomes significantly accumulated in tumors 24 h after injection. The antitumor assay in mice bearing MDR breast cancer xenograft tumors confirmed the superior antitumor activity of liposomal pemetrexed over pemetrexed. It was also found that the improved therapeutic effect of liposomal pemetrexed may be attributed to apoptosis through both extrinsic and intrinsic pathways., Conclusion: Liposomal pemetrexed represents a potential therapeutic approach for overcoming breast cancer MDR., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Magnesium (Mg) is important for both plant photosynthesis and protein synthesis. Nevertheless, latent Mg deficiencies are common, and Mg addition has shown an improved yield. Might such an increasing yield cause "hidden" hunger for microelements and protein, and if so, what is the mechanism? We conducted two greenhouse experiments using low-Mg soil to investigate (i) effects of five levels of Mg fertilizer (20-400 mg kg -1 ) on eight elements and crude protein concentrations in annual ryegrass and white clover and (ii) if any protein effects of the Mg fertilizer depend upon soil nitrogen (N). Mg addition significantly increased the yield in both species, simultaneously decreasing concentrations of crude protein, calcium (Ca), sodium, manganese, and potassium/Mg and Ca/Mg ratios caused by increased biomass dilution effects and increased [Mg]. Other mineral dilution effects of the Mg fertilizer depended upon species: the concentration of phosphorus decreased only in ryegrass, and the concentration of zinc decreased only in white clover. Mg addition in soil rich with available N (from N fertilizer in ryegrass or biological fixation in white clover) showed an increased crude protein content as well as increased yield in the forage of both species. These results suggest that the Mg fertilizer can affect the protein content positively or negatively depending upon available N in soil and that sufficiently available N must be ensured along with Mg addition in low Mg soils.

Magnesium (Mg) plays important roles in photosynthesis and protein synthesis; however, latent Mg deficiencies are common phenomena that can influence food quality. Nevertheless, the effects of Mg fertilizer additions on plant carbon (C):nitrogen (N):phosphorus (P) stoichiometry, an important index of food quality, are unclear and the underlying mechanisms unexplored. We conducted a greenhouse experiment using low-Mg in situ soil without and with a gradient of Mg additions to investigate the effect of Mg fertilizer on growth and stoichiometry of maize and soybean and also measure these plants' main symbiotic microorganisms: arbuscular mycorrhizal fungi (AMF) and rhizobium, respectively. Our results showed that Mg addition significantly improved both plant species' growth and also increased N and P concentrations in soybean and maize, respectively, resulting in low C:N ratio and high N:P ratio in soybean and low C:P and N:P ratios in maize. These results presumably stemmed from the increase of nutrients supplied by activation-enhanced plant symbiotic microorganisms, an explanation supported by statistically significant positive correlations between plant stoichiometry and plants' symbiotic microorganisms' increased growth with Mg addition. We conclude that Mg supply can improve plant growth and alter plant stoichiometry via enhanced activity of plant symbiotic microorganisms. Possible mechanisms underlying this positive plant-soil feedback include an enhanced photosynthetic product flow to roots caused by adequate Mg supply.

Tetratricopeptide repeat domain 36 (Ttc36), whose coding protein belongs to tetratricopeptide repeat (TPR) motif family, has not been studied extensively. We for the first time showed that Ttc36 is evolutionarily conserved across mammals by bioinformatics. Rabbit anti-mouse Ttc36 polyclonal antibody was generated by injecting synthetic full-length peptides through "antigen intersection" strategy. Subsequently, we characterized Ttc36 expression profile in mouse, showing its expression in liver and kidney both from embryonic day 15.5 (E15.5) until adult, as well as in testis. Immunofluorescence staining showed that Ttc36 is diffusely expressed in liver, however, specifically in kidney cortex. Thus, we further compare Ttc36 with proximal tubules (PT) marker Lotus Tetragonolobus Lectin (LTL) and distal tubules (DT) marker Calbindin-D28k respectively by double immunofluorescence staining. Results showed the co-localization of Ttc36 with LTL rather than Calbindin-D28k. Collectively, on the basis of the expression pattern, Ttc36 is specifically expressed in proximal distal tubules., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: Subcortical ischemic vascular dementia (SIVD) induced by chronic hypoperfusion is a common cause of vascular dementia. The aim of this study was to determine whether the protective effect of carnosine on white matter lesion after chronic cerebral hypoperfusion through suppressing astrocyte activation., Methods: Adult male mice (C57BL/6 strain) were subjected to permanent occlusion of the right unilateral common carotid arteries (rUCCAO) and treated with carnosine or histidine. Open field test, freezing test, Klüver-Barrera staining, immunohistochemical analyses and western blot were performed after rUCCAO., Results: We found that carnosine ameliorated white matter lesion and cognitive impairment after rUCCAO. Carnosine suppressed the activation of astrocyte in both wide type mice and histidine decarboxylase knockout mice. However, administration of histidine did not show the same effect. We found that there were no differences between rUCCAO group and sham group for the expression of glutamate transporter-1 (GLT-1) and glutamate/aspartate transporter (GLAST). Furthermore, carnosine significantly attenuated the increase of inflammatory cytokine interferon gama., Conclusion: These data suggest carnosine induced neuroprotection during SIVD in mice is not dependent on the histaminergic pathway or the regulation of the expression of GLT-1 and GLAST, but may be due to a suppression of astrocyte activation and inflammatory cytokine release.

Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes and may lead to end-stage renal disease (ESRD) and chronic renal failure. The aim of this study was to determine whether low-molecular-weight fucoidan (LMWF) can reduce harmful transforming growth factor-β (TGF-β)-mediated renal fibrosis in DN using in vitro and in vivo experimental models. The experimental results showed that LMWF significantly reversed TGF-β1-induced epithelial-mesenchymal transition and dose-dependently inhibited accumulation of extracellular matrix proteins, including connective tissue growth factor and fibronectin. It was found that LMWF significantly reduced blood urea nitrogen and blood creatinine in both type 1 and type 2 diabetic rat models. H&E, PAS and Masson's trichrome staining of kidney tissue showed LMWF significantly reduced renal interstitial fibrosis. Treatment with LMWF significantly increased E-cadherin expression and reduced α-SMA, CTGF and fibronectin expression in both type 1 and type 2 diabetic models. LMWF also decreased the phosphorylation of Akt, ERK1/2, p38 and Smad3 in vitro and in vivo. These data suggest that LMWF may protect kidney from dysfunction and fibrogenesis by inhibiting TGF-β pathway and have the potential benefit to slow down the progression of DN.

Background: Previous studies found that urea transporter UT-B is abundantly expressed in bladder urothelium. However, the dynamic role of UT-B in bladder urothelial cells remains unclear. The objective of this study is to evaluate the physiological roles of UT-B in bladder urothelium using UT-B knockout mouse model and T24 cell line., Methodology/principal Findings: Urea and NO measurement, mRNA expression micro-array analysis, light and transmission electron microscopy, apoptosis assays, DNA damage and repair determination, and intracellular signaling examination were performed in UT-B null bladders vs wild-type bladders and in vitro T24 epithelial cells. UT-B was highly expressed in mouse bladder urothelium. The genes, Dcaf11, MCM2-4, Uch-L1, Bnip3 and 45 S pre rRNA, related to DNA damage and apoptosis were significantly regulated in UT-B null urothelium. DNA damage and apoptosis highly occurred in UT-B null urothelium. Urea and NO levels were significantly higher in UT-B null urothelium than that in wild-type, which may affect L-arginine metabolism and the intracellular signals related to DNA damage and apoptosis. These findings were consistent with the in vitro study in T24 cells that, after urea loading, exhibited cell cycle delay and apoptosis., Conclusions/significance: UT-B may play an important role in protecting bladder urothelium by balancing intracellular urea concentration. Disruption of UT-B function induces DNA damage and apoptosis in bladder, which can result in bladder disorders.

Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small-molecule library for inhibitors of UT-facilitated urea transport. A novel class of thienoquinolin UT-B inhibitors were identified, of which PU-14 had potent inhibition activity on human, rabbit, rat, and mouse UT-B. The half-maximal inhibitory concentration of PU-14 on rat UT-B-mediated urea transport was ∼0.8 μmol/l, and it did not affect urea transport in mouse erythrocytes lacking UT-B but inhibited UT-A-type urea transporters, with 36% inhibition at 4 μmol/l. PU-14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 μmol/l. Subcutaneous delivery of PU-14 (at 12.5, 50, and 100 mg/kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU-14 has a diuretic effect by urea-selective diuresis. Thus, PU-14 or its analogs might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance. PU-14 may establish 'chemical knockout' animal models to study the physiological functions of UTs.

Background: Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) in both native and transplanted kidneys. The objective of the present study was to evaluate whether low-molecular-weight fucoidan (LMWF) could attenuate renal IRI in an animal model and in vitro cell models and study the mechanisms in which LMWF protected from IRI., Methodology/principal Findings: Male mice were subjected to right renal ischemia for 30 min and reperfusion for 24 h, or to a sham operation with left kidney removed. Kidneys undergone IR showed characteristic morphological changes, such as tubular dilatation, and brush border loss. However, LMWF significantly corrected the renal dysfunction and the abnormal levels of MPO, MDA and SOD induced by IR. LMWF also inhibited the activation of MAPK pathways, which consequently resulted in a significant decrease in the release of cytochrome c from mitochondria, ratios of Bax/Bcl-2 and cleaved caspase-3/caspase-3, and phosphorylation of p53. LMWF alleviated hypoxia-reoxygenation or CoCl(2) induced cell viability loss and ΔΨm dissipation in HK2 renal tubular epithelial cells, which indicates LMWF may result in an inhibition of the apoptosis pathway through reducing activity of MAPK pathways in a dose-dependent manner., Conclusions/significance: Our in vivo and in vitro studies show that LMWF ameliorates acute renal IRI via inhibiting MAPK signaling pathways. The data provide evidence that LMWF may serve as a potential therapeutic agent for acute renal IRI.