Enhanced photocatalytic U(VI) reduction via double internal electric field in CoWO4/covalent organic frameworks p-n heterojunction.

Photoreduction of highly toxic U(VI) to less toxic U(IV) is crucial for mitigating radioactive contamination. Herein, a CoWO4/TpDD p-n heterojunction is synthesized, with TpDD serving as the n-type semiconductor substrate and CoWO4 as the p-type semiconductor grown in situ on its surface. The Fermi energy difference between TpDD and CoWO4 provides the electrochemical potential for charge-hole separation. Moreover, the Coulombic forces from the distinct carrier types between the two materials synergistically facilitate the transfer of electrons and holes. Hence, an internal electric field directed from TpDD to CoWO4 is established. Under photoexcitation conditions, charges and holes migrate efficiently along the curved band and internal electric field, further enhancing charge-hole separation. As a result, the removal capacity of CoWO4/TpDD increases from 515.2 mg/g in the dark to 1754.6 mg/g under light conditions. Thus, constructing a p-n heterojunction proves to be an effective strategy for remediating uranium-contaminated environments.

[Platelet Transfusion Strategies for MASPAT-Matched Platelet Transfusion Failed Patient with Allogeneic Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To investigate the causes of ineffectiveness of platelet transfusion with monoclonal antibody solid phase platelet antibody test (MASPAT) matching in patients with allogeneic hematopoietic stem cell transplantation and explore the strategies of platelet transfusion. METHODS: A case of donor-specific HLA antibodies (DSA) induced by transfusion which ultimately resulted in transplantation failure and ineffective platelet transfusion with MASPAT matching was selected, and the causes of ineffective platelet transfusion and platelet transfusion strategy were retrospectively analyzed. RESULTS: The 32-year-old female patient was diagnosed as acute myeloid leukemia (high risk) in another hospital with the main symptoms of fever and leukopenia, who should be admitted for hematopoietic stem cell transplantation after remission by chemotherapy. In the course of chemotherapy, DSA was generated due to platelet transfusion, and had HLA gene loci incompatible with the donor of the first transplant, leading to the failure of the first transplant. The patient received platelet transfusion for several times before and after transplantation, and the results showed that the effective rate of MASPAT matched platelet transfusion was only 35.3%. Further analysis showed that the reason for the ineffective platelet transfusion was due to the missed detection of antibodies by MASPAT method. During the second hematopoietic stem cell transplantation, the DSA-negative donor was selected, and the matching platelets but ineffective transfusion during the primary transplantation were avoided. Finally, the patient was successfully transplanted and discharged from hospital. CONCLUSIONS: DSA can cause graft failure or render the graft ineffective. For the platelet transfusion of patients with DSA, the platelet transfusion strategy with matching type only using MASPAT method will miss the detection of antibodies, resulting in invalid platelet transfusion.

Simultaneous determination of multiple constituents of Qi-Lin pill by UPLC-MS/MS: Applications to pharmacokinetics and testicular tissue distribution in rats.

Qi-Lin pill (QLP) is an effective traditional Chinese medicine prescription (TCMP) that has been used for the treatment of the oligoasthenozoospermia in China. Recently, some articles described the pharmacological effects of QLP and multiple ingredients in QLP contribute to its effects. However, the pharmacokinetic and target tissue distribution data of QLP are still unknown. In the present study, according to the Bioanalytical Method Validation Guidance of FDA, a sensitive and selective UPLC-MS/MS method was developed and validated for simultaneous determination of multiple constituents in rat plasma and testicular tissue, including morusimic acid A, codonopyrridium B, magnoflorine, emodin, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), ecliptasaponin A, paeoniflorin, albiflorin, gallic acid, danshensu, salvianolic acid A, catechin, isosinensetin, nobiletin, formononetin, calycosin, icariside II, icariin and epimedin C. For 19 analytes, the LLOQs reached 0.01-4 ng/mL. And all calibration curves showed favorable linearity (r ≥ 0.9903) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.92 %, and the accuracies (as relative error) were in the range of - 6.44 % to 6.22 %. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The method was successfully applied for the pharmacokinetics and testis distribution of multiple chemical constituents in QLP after a single oral dose. As a result, high exposure of danshensu, gallic acid, paeoniflorin and albiflorin were observed in rat plasma and testicular tissue. Among the flavonoids, isosinensetin and nobiletin had high exposure in testicular tissue. Moreover, alleviation of progesterone reduction was evaluated in H2O2-induced R2C leydig cells, and danshensu, gallic acid, paeoniflorin, albiflorin and nobiletin showed potent activity. Therefore, these five components were considered to be the effective components of QLP due to their relatively high exposure in vivo and biological activity. This finding also provided relevant information on action mechanism of QLP in the treatment of oligoasthenozoospermia.

Chemical and metabolic profiling of Codonopsis Radix extract with an integrated strategy using ultra-high-performance liquid chromatography coupled with mass spectrometry.

Codonopsis radix was commonly used as food materials or herbal medicines in many countries. However, the comprehensive analysis of chemical constituents, and in vivo xenobiotics of Codonopsis radix remain unclear. In the present study, an integrated strategy with feature-based molecular networking using ultra-high-performance liquid chromatography coupled with mass spectrometry was established to systematically screen the chemical constituents and the in vivo xenobiotics of Codonopsis radix. A step-by-step manner based on a composition database, visual structure classification, discriminant ions, and metabolite software prediction was proposed to overcome the complexities due to the similar structure of chemical constituents and metabolites of Codonopsis radix. As a result, 103 compounds were tentatively characterized, 20 of which were identified by reference standards. Besides, a total of 50 xenobiotics were detected in vivo, including 26 prototypes and 24 metabolites, while the metabolic features of the pyrrolidine alkaloids were elucidated for the first time. The metabolism reactions of pyrrolidine alkaloids and sesquiterpene lactones included oxidation, methylation, hydration, hydrogenation, demethylation, glucuronidation, and sulfation. This study provided a generally applicable approach to the comprehensive investigation of the chemical and metabolic profile of traditional Chinese medicine and offered reasonable guidelines for further screening of quality control indicators and pharmacodynamics mechanism of Codonopsis radix.

Buchwald-Hartwig coupled conjugated microporous polymer for efficient removal COVID-19 antiviral drug famciclovir from waters: Adsorption behavior and mechanism.

The consumption of famciclovir (FCV) has been increased dramatically since the outbreak of coronavirus in 2019, and the pollution and harm of FCV in waters are concerned. Here, by utilizing aryl halides on 2, 4, 6-tris(4-bromophenyl)- 1, 3, 5-triazine (BPT) and primary amine groups on benzidine (BZ), a novel conjugated microporous polymer, namely BPT-BZ-CMP, was synthesized by Buchwald-Hartwig coupling reaction and applied in the removal of FCV from aqueous solution firstly. The synthesized BPT-BZ-CMP were characterized by various methods, including FTIR, SEM, BET, and Zeta-potential. Due to the micropore structure and high specific surface area, it took only 30 min for BPT-BZ-CMP to adsorb FCV to reach an equilibrium, and the maximum adsorption capacity was 347.8 mg·g-1. The Liu and pseudo-second-order kinetic models properly fit the adsorption equilibrium and kinetic data, respectively. The adsorption process was a spontaneous process, and the hydrogen bonding, π-π interaction and C-H···π interaction enhanced the adsorption of FCV on BPT-BZ-CMP. BPT-BZ-CMP maintained a good adsorption capacity after four consecutive adsorption-desorption cycle experiments. This study confirmed the potential of BPT-BZ-CMP as efficient sorbent to remove FCV from aqueous solutions.

Nitrogen-rich based conjugated microporous polymers for highly efficient adsorption and removal of COVID-19 antiviral drug chloroquine phosphate from environmental waters.

Chloroquine phosphate (CQP) has been suggested as an important and effective clinical reliever medication for the 2019 coronavirus (COVID-19). Nevertheless, its excessive use will inevitably cause irreparable damage to the entire ecosystem, thereby posing a considerable environmental safety concern. Hence, the development of highly-efficient methods of removing CQP from water pollution sources, e.g., effluents from hospitals and pharmaceutical factories is significant. This study reported the fabrication of novel C-N bond linked conjugated microporous polymers (CMPs) (BPT-DMB-CMP) with multiple nitrogen-rich anchoring sites for the quick and efficient removal of CQP from aqueous solutions. The irreversible covalent C-N bond linked in the internal framework of BPT-DMB-CMP endowed it with good chemical stability and excellent adsorbent regeneration. With its predesigned functional groups (i.e., rich N-H bonds, triazine rings, and benzene rings) and large area surface (1,019.89 m2·g-1), BPT-DMB-CMP demonstrated rapid adsorption kinetics (25 min) and an extraordinary adsorption capacity (334.70 mg·g-1) for CQP, which is relatively higher than that of other adsorbents. The adsorption behavior of CQP on BPT-DMB-CMP corresponded with Liu model and mixed-order model. Based on the density functional theory (DFT) calculations, X-ray photoelectron spectroscopy (XPS), and adsorption comparisons test, the halogen bonding, and hydrogen bonding cooperates with π - π, C - H···π interactions and size-matching effect in the CQP adsorption system on BPT-DMB-CMP. The excellent practicability for the removal of CQP from real wastewater samples verified the prospect of practical application of BPT-DMB-CMP. BPT-DMB-CMP exhibited the application potentials for the adsorption of other antiviral drugs. This work opens up an efficient, simple, and high adsorption capacity way for removal CQP.

Cationic covalent organic nanosheets for rapid and effective detection of phenoxy carboxylic acid herbicides residue emitted from water and rice samples.

Development of efficient and sensitive adsorbent for capturing phenoxy carboxylic acids (PCAs) from environmental and food samples is necessary because PCAs could threaten human health. Designing nanoparticle with multiple functional groups is beneficial to achieve the strong adsorption interaction and the specific recognition for target compound. In this paper, TpTGCl as an ionic covalent organic framework (ICOF), that could offer plenty of positive charges and hydrogen-bonding sites, was fabricated. TpTGCl achieved quicker, more sensitive enrichment for anionic PCAs. The analysis of binding affinity by density functional theory (DFT) demonstrated that PCAs bonded to TpTGCl primarily via electrostatic attraction, N  H···O and O  H···O, and C  H···π interaction. The quantitative approach indicated low limits of detection (0.016-0.036 ng·g-1 for rice and 0.43-0.78 ng·L-1 for water). Furthermore, successfully determining PCAs emitted from real samples indicated the applicability of TpTGCl.

Biomass-Based Carbon-Supported Sulfate Catalyst for Efficient Synthesis of Dimethoxymethane from Direct Oxidation of Dimethyl Ether.

The synthesis of dimethoxymethane (DMM) from direct oxidation of dimethyl ether (DME) is a green and competitive route with good atomic economy and low carbon emission and is also an urgent need. In this work, biomass-based carbon-supported sulfate catalysts were designed and prepared for the efficient synthesis of DMM from DME oxidation. The prepared carbon support from cellulose displayed much larger specific surface area and a developed microporous structure, which effectively benefited a high dispersion of sulfate components, leading to mainly weak acid sites and more oxygen functional groups on the catalyst surface. The Ti(SO4)2/PC-H2SO4 catalyst exhibits excellent performance for DME oxidation with DMM1-2 selectivity up to 96.7%, and DMM selectivity reaches 89.1%, notably higher than that of previously reported results. The distinctive surface structure and chemical properties of the carbon support have important impacts on the dispersion state of sulfate species, affecting the acidic and redox properties of the catalysts.

High crystalline magnetic covalent organic framework with three-dimensional grapevine structure for ultrasensitive extraction of nitro-polycyclic aromatic hydrocarbons in food and environmental samples.

Developing and establishing an efficient pre-treatment approach for the precise extraction of nitrated-polycyclic aromatic hydrocarbons (N-PAHs) from real-life samples is critical for ensuring their safety. In this study, a novel crystalline magnetic covalent organic framework with a grapevine structure not a single core-shell, Fe3O4@TAPT-DMTA-COF, was fabricated via chemical bonding. Unchanging the reticulated structure and high crystallinity of TAPT-DMTA-COF, the combination made this material possess not only simple operation via magnetic decantation but also remarkable chemical stability. Fe3O4@TAPT-DMTA-COF had a large surface area (1578.45 m2/g), and rich electronegative triazine-groups, which makes it become a superior magnetic enrichment material for trace N-PAHs. For N-PAHs analysis, low limits of detection (LODs) (1.43-17.24 ng/L), excellent relative standard deviations (RSDs ≤ 11.52%), and wide linearity (10-5000 ng/L) were obtained. Real-life applications based on this composite have been successfully explored by capturing the N-PAHs emitted from food and environmental samples.

[Role of fecal calprotectin in the diagnosis of neonatal necrotizing enterocolitis: a Meta analysis].

OBJECTIVE: To study the value of fecal calprotectin (FC) in the diagnosis of neonatal necrotizing enterocolitis (NEC) through a Meta analysis. METHODS: Web of Science, Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, Weipu Periodical Database, Wanfang Data, Chinese Biomedical Literature Database were searched for related studies published up to May 2020, with manual search as supplementation. The QUADAS criteria were used to evaluate the quality of the articles included. Meta-DiSc 1.4 and Stata 15.0 software were used to perform the Meta analysis, including the evaluation of specificity, sensitivity, likelihood ratio, and diagnostic odds ratio. The sensitivity analysis and heterogeneity testing were performed, and the summary receiver operating characteristic (SROC) curve and Fagan diagram were plotted. RESULTS: A total of 15 articles were enrolled, involving 1 719 neonates. Among these articles, 4 had low quality, 2 had high quality, and the rest had medium quality. There was high heterogeneity between studies, and there was no threshold effect or publication bias. The random effects model analysis showed that FC had a pooled specificity of 0.80 (95%CI:0.78-0.82) and a sensitivity of 0.86 (95%CI:0.83-0.89) in the diagnosis of NEC, with a negative likelihood ratio of 0.19 (95%CI:0.14-0.26), a positive likelihood ratio of 4.71 (95%CI:3.57-6.23), and a diagnostic odds ratio of 29.56 (95%CI:17.98-48.61). The area under the SROC curve was 0.9131 and the Q* index was 0.8456. The Fagan diagram showed that the post-test probability of NEC indicated by negative FC was 13%, while that indicated by positive FC was 86%. The Meta regression analysis showed that the heterogeneity came from other non-threshold factors. CONCLUSIONS: FC has high potential and efficiency in the early diagnosis of NEC. FC measurement can be used for the diagnosis of NEC, but it should be combined with clinical manifestations and other related laboratory examinations.

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality.

OBJECTIVES: Acute kidney injury (AKI) is a common complication after lung transplantation (LTx) which is closely related to the poor prognosis of patients. We aimed to explore potential risk factors and outcomes associated with early post-operative AKI after LTx. METHODS: A retrospective study was conducted in 136 patients who underwent LTx at our institution from 2017 to 2019. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Univariate and multivariate analyses were conducted to identify risk factors related to AKI. The primary outcome was the incidence of AKI after LTx. Secondary outcomes were associations between AKI and short-term clinical outcomes and mortality. RESULTS: Of the 136 patients analyzed, 110 developed AKI (80.9%). AKI was associated with higher baseline eGFR (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00-1.03)) and median tacrolimus (TAC) concentration (OR 1.15 (95% CI: 1.02-1.30)). Patients with AKI suffered longer mechanical ventilation days (p = .015) and ICU stay days (p = .011). AKI stage 2-3 patients had higher risk of 1-year mortality (HR 16.98 (95% CI: 2.25-128.45)) compared with no-AKI and stage 1 patients. CONCLUSIONS: Our results suggested early post-operative AKI may be associated with higher baseline eGFR and TAC concentrations. AKI stage 1 may have no influence on survival rate, whereas AKI stage 2-3 may be associated with increased mortality at 1-year.

Triazine-cored covalent organic framework for ultrasensitive detection of polybrominated diphenyl ethers from real samples: Experimental and DFT study.

Food and environmental safety issues attributable to the polybrominated diphenyl ethers (PBDEs) are gaining increasing attention, and these urge us to establish a high-performance sample-handling technique. In this study, an outstanding adsorption performance with short adsorption time (10 min) was achieved for PBDEs using a novel synthesized dispersive solid-phase extraction adsorbent, a reticulated covalent organic framework with N/O functional groups (i.e., imine linkage, triazine, and methoxy) (TAPT-DMTA-COF). By conducting sufficient experimentation and theoretical simulation on adsorption mechanism, the halogen bond between electronegative N/O atoms of TAPT-DMTA-COF and the electropositive Br atoms of PBDEs were observed to play a more pivotal role than π-π, C-H…π interactions, and hydrophobic effects. Furthermore, the positive linear relation between calculated adsorption energy and Br content directly clarified that enrichment behavior of PBDEs can be attributed to halogen bonding. These data implied that integrated nanostructure (i.e., N/O functional groups and reticulated architecture) effectively enhanced adsorption capacity. In case of PBDE analysis, this approach achieved excellent results with low limits of detection (0.03-0.13 ng L-1). Finally, the promising potential applications of aforementioned method were verified by spiking water, fish, and milk samples with PBDEs; good PBDEs recoveries were obtained.

Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. METHODS: L-[14C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. RESULTS: The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (Vmax = 0.051 nmoL/min and Km = 34.94 µM). CONCLUSIONS: A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.

A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice.

PHT1 (SLC15A4) is responsible for translocating l-histidine (l-His), di/tripeptides and peptide-like drugs across biological membranes. Previous studies have indicated that PHT1 is located in brain parenchyma, however, its role and significance in brain along with effect on the biodistribution of substrates is unknown. In this study, adult gender-matched Pht1-competent (wildtype) and Pht1-deficient (null) mice were used to investigate the effect of PHT1 on l-His brain disposition via in vitro slice and in vivo pharmacokinetic approaches. We also evaluated the serum clinical chemistry and expression levels of select transporters and enzymes in the two genotypes. No significant differences were observed between genotypes in serum chemistry, body weight, viability and fertility. PCR analyses indicated that Pept2 had a compensatory up-regulation in Pht1 null mice (about 2-fold) as compared to wildtype animals, which was consistent in different brain regions and confirmed by immunoblots. The uptake of l-His was reduced in brain slices by 50% during PHT1 ablation. The l-amino acid transporters accounted for 30% of the uptake, and passive (other) pathways for 20% of the uptake. During the in vivo pharmacokinetic studies, plasma concentration-time profiles of l-His were comparable between the two genotypes after intravenous administration. Still, biodistribution studies revealed that, when sampled 5min after dosing, l-His values were 28-48% lower in Pht1 null mice, as compared to wildtype animals, in brain parenchyma but not cerebrospinal fluid. These findings suggest that PHT1 may play an important role in histidine transport in brain, and resultant effects on histidine/histamine homeostasis and neuropeptide regulation.

Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis.

1. Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF). 2. A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95 L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12 L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition. 3. The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.

Context- and time-dependent neurobiological and behavioral sensitization induced by a single morphine exposure in mice.

RATIONALE: Drug-induced sensitization in the mesocorticolimbic systems is thought to play an important role in certain aspects of drug addiction, including the involvement of drug-associated cues and environments in mediating drug-seeking behaviors. Our previous studies have identified the significance of heat shock protein 70 (Hsp70) in the development of a single morphine exposure-induced behavioral sensitization. OBJECTIVES: The present study expands upon these findings by investigating the effect of environment on the expression of behavioral sensitization induced by a single morphine exposure, and the potential involvement of Hsp70 protein levels in these effects. METHODS: Mice were pretreated with a single morphine injection in test chambers (morphine-paired) or home cages (morphine-unpaired) on day 1 and challenged on day 2 or 8, in test chambers. Hsp70 expression in the nucleus accumbens (NAc) was analyzed after the challenge. RESULTS: The expression of single morphine exposure-induced behavioral sensitization was accompanied by a significant increase in Hsp70 expression in NAc. In contrast, the unpaired morphine-treated group failed to exhibit behavioral sensitization or higher Hsp70 expression. Additionally, by adding a habituation process prior to the challenge, we demonstrated that conditioned hyperactivity, which was not accompanied by an increased expression of Hsp70, is not essential for behavioral sensitization. CONCLUSIONS: Behavioral sensitization induced by a single morphine exposure in mice exhibits context and time dependency, with environmental context likely functioning via an inhibitory conditioning mechanism. Furthermore, alterations in Hsp70 expression in the NAc may represent a neurobiological sensitization mechanism mediating context- and time-dependent behavioral sensitization.

[Prediction of total nitrogen and alkali hydrolysable nitrogen content in loess using hyperspectral data based on correlation analysis and partial least squares regression].

Wuqi County of Shaanxi Province, where the vegetation recovering measures have been carried out for years, was taken as the study area. A total of 100 loess samples from 24 different profiles were collected. Total nitrogen (TN) and alkali hydrolysable nitrogen (AHN) contents of the soil samples were analyzed, and the soil samples were scanned in the visible/near-infrared (VNIR) region of 350-2500 nm in the laboratory. The calibration models were developed between TN and AHN contents and VNIR values based on correlation analysis (CA) and partial least squares regression (PLS). Independent samples validated the calibration models. The results indicated that the optimum model for predicting TN of loess was established by using first derivative of reflectance. The best model for predicting AHN of loess was established by using normal derivative spectra. The optimum TN model could effectively predict TN in loess from 0 to 40 cm, but the optimum AHN model could only roughly predict AHN at the same depth. This study provided a good method for rapidly predicting TN of loess where vegetation recovering measures have been adopted, but prediction of AHN needs to be further studied.

Population pharmacokinetics of mycophenolic acid in lung transplant recipients with and without cystic fibrosis.

PURPOSE: The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant. METHODS: Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed. RESULTS: For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CF patients had a slower absorption rate (Ka), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates. CONCLUSIONS: The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V2/F and V3/F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.

Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice.

AIM: Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis. METHODS: Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined. RESULTS: Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice. CONCLUSION: The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.