A Patient Similarity Network (CHDmap) to Predict Outcomes After Congenital Heart Surgery: Development and Validation Study.

Background: Although evidence-based medicine proposes personalized care that considers the best evidence, it still fails to address personal treatment in many real clinical scenarios where the complexity of the situation makes none of the available evidence applicable. "Medicine-based evidence" (MBE), in which big data and machine learning techniques are embraced to derive treatment responses from appropriately matched patients in real-world clinical practice, was proposed. However, many challenges remain in translating this conceptual framework into practice. Objective: This study aimed to technically translate the MBE conceptual framework into practice and evaluate its performance in providing general decision support services for outcomes after congenital heart disease (CHD) surgery. Methods: Data from 4774 CHD surgeries were collected. A total of 66 indicators and all diagnoses were extracted from each echocardiographic report using natural language processing technology. Combined with some basic clinical and surgical information, the distances between each patient were measured by a series of calculation formulas. Inspired by structure-mapping theory, the fusion of distances between different dimensions can be modulated by clinical experts. In addition to supporting direct analogical reasoning, a machine learning model can be constructed based on similar patients to provide personalized prediction. A user-operable patient similarity network (PSN) of CHD called CHDmap was proposed and developed to provide general decision support services based on the MBE approach. Results: Using 256 CHD cases, CHDmap was evaluated on 2 different types of postoperative prognostic prediction tasks: a binary classification task to predict postoperative complications and a multiple classification task to predict mechanical ventilation duration. A simple poll of the k-most similar patients provided by the PSN can achieve better prediction results than the average performance of 3 clinicians. Constructing logistic regression models for prediction using similar patients obtained from the PSN can further improve the performance of the 2 tasks (best area under the receiver operating characteristic curve=0.810 and 0.926, respectively). With the support of CHDmap, clinicians substantially improved their predictive capabilities. Conclusions: Without individual optimization, CHDmap demonstrates competitive performance compared to clinical experts. In addition, CHDmap has the advantage of enabling clinicians to use their superior cognitive abilities in conjunction with it to make decisions that are sometimes even superior to those made using artificial intelligence models. The MBE approach can be embraced in clinical practice, and its full potential can be realized.

Identification of molecular characteristics of FUT8 and alteration of core fucosylation in kidney renal clear cell cancer.

BACKGROUND: Kidney renal clear cell cancer (KIRC) is a type of urological cancer that occurs worldwide. Core fucosylation (CF), as the most common post-translational modification, is involved in the tumorigenesis. METHODS: The alterations of CF-related genes were summarized in pan-cancer. The "ConsensusClusterPlus" package was utilized to identify two CF-related KIRC subtypes. The "ssgsea" function was chosen to estimate the CF score, signaling pathways and cell deaths. Multiple algorithms were applied to assess immune responses. The "oncoPredict" was utilized to estimate the drug sensitivity. The IHC and subgroup analysis was performed to reveal the molecular features of FUT8. Single-cell RNA sequencing (scRNA-seq) data were scrutinized to evaluate the CF state. RESULTS: In pan-cancer, there was a noticeable alteration in the expression of CF-related genes. In KIRC, two CF-related subtypes (i.e., C1, C2) were obtained. In comparison to C2, C1 exhibited a higher CF score and correlated with poorer overall survival. Additionally, the TME of C2 demonstrated increased activity in neutrophils, macrophages, myeloid dendritic cells, and B cells, alongside a higher presence of silent mast cells, NK cells, and endothelial cells. Compared to normal samples, higher expression of FUT8 is observed in KIRC. The mutation of SETD2 was more frequent in low-FUT8 samples while the mutation of DNAH9 was more frequent in high-FUT8 samples. scRNA-seq analyses revealed that the CF score was predominantly higher in endothelial cells and fibroblast cells. CONCLUSIONS: Two CF-related subtypes with distinct prognosis and TME were identified in KIRC. FUT8 exhibited elevated expression in KIRC samples.

Functional Analyses of Three Targeted DNA Antimicrobial Peptides Derived from Goats.

With the increase in drug-resistant bacteria, new antibacterial drugs have emerged as a prominent area of research and development. Antimicrobial peptides (AMPs), as innate immune agents, have garnered significant attention due to their potent, rapid, and broad-spectrum antibacterial activity. This study focused on investigating the functionality of three AMPs (CATH 1, CATH 2, and MAP34-B) derived from goat submandibular glands. Among these AMPs, CATH 2 and MAP34-B exhibited direct antibacterial activity against both Gram-negative and Gram-positive bacteria, primarily targeting the bacterial membrane. Additionally, these two AMPs were found to have the potential to induce reactive oxygen species (ROS) production in bacterial cells and interact with bacterial genome DNA, which may play a crucial role in their mechanisms of action. Furthermore, both CATH 1 and CATH 2 demonstrated significant antioxidant activity, and all three AMPs exhibited potential anti-inflammatory activity. Importantly, the cytotoxic activity of these AMPs against mammalian cells was found to be weak, and their hemolytic activity was extremely low. Overall, the characteristics of these three AMPs found in goat submandibular glands offer new insights for the study of host protection from an immunological perspective. They hold promise as potential candidates for the development of novel antibacterial agents, particularly in the context of combating drug-resistant bacteria.

HUWE1 Amplifies Ubiquitin Modifications to Broadly Stimulate Clearance of Proteins and Aggregates.

Selective breakdown of proteins and aggregates is crucial for maintaining normal cellular activities and is involved in the pathogenesis of diverse diseases. How the cell recognizes and tags these targets in different structural states for degradation by the proteasome and autophagy pathways has not been well understood. Here, we discovered that a HECT-family ubiquitin ligase HUWE1 is broadly required for the efficient degradation of soluble factors and for the clearance of protein aggregates/condensates. Underlying this capacity of HUWE1 is a novel Ubiquitin-Directed ubiquitin Ligase (UDL) activity which recognizes both soluble substrates and aggregates that carry a high density of ubiquitin chains and rapidly expand the ubiquitin modifications on these targets. Ubiquitin signal amplification by HUWE1 recruits the ubiquitin-dependent segregase p97/VCP to process these targets for subsequent degradation or clearance. HUWE1 controls the cytotoxicity of protein aggregates, mediates Targeted Protein Degradation and regulates cell-cycle transitions with its UDL activity.

[M8L4]8+-Type Squares Self-Assembled by Dipalladium Corners and Bridging Aromatic Dipyrazole Ligands for Iodine Capture.

Square-like metallamacrocyclic palladium(II) complexes [M8L4]8+ (1-7) were synthesized by reacting aromatic dipyrazole ligands (H2L1-H2L3 with pyromellitic arylimide-, 1,4,5,8-naphthalenetetracarboxylic arylimide-, and anthracene-based aromatic groups, respectively) with dipalladium corners ([(bpy)2Pd2(NO3)2](NO3)2, [(dmbpy)2Pd2(NO3)2](NO3)2, or [(phen)2Pd2(NO3)2](NO3)2, where bpy = 2,2'-bipyridine, dmbpy = 4,4'-dimethyl-2,2'-bipyridine, and phen = 1,10-phenanthroline) in aqueous solutions via metal-directed self-assembly. Metallamacrocycles 1-7 were fully characterized by 1H and 13C nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry, and the square structure of 7·8NO3- was further confirmed via single crystal X-ray diffraction. These square-like metallamacrocycles exhibit effective performance for iodine adsorption.

Field measures of strengthen plant-microbial remediation of PAHs-FQs compound pollution.

In this study, five PAHs (benzo [b] fluoranthene (BbF), phenanthrene (Phe), fluoranthene (Flu), fluorene (Fl), benzo [A] pyrene (Bap)), and five FQs (ofloxacin (OFL), enrofloxacin (ENR), ciprofloxacin (CIP), norfloxacin (NOR), lomefloxacin (LOM)) were selected as ligands; peroxidase (1NML) was selected as receptor degrading protein. In the plant-microbial degradation, the factors with significant inhibitory effects are NOR, Bap, CIP, ENR, OFL, Flu, LOM, Phe, Fl, and BbF by the fractional factorial design experiment and molecular docking-assisted molecular dynamics methods. Using Taguchi experiment and molecular dynamics simulation methods, the main external field measures were designed and screened to effectively promote the degradation of PAHs-FQs under the combined pollution scenarios of Bap-CIP and BbF-NOR, respectively. The peroxidase mutation design plans with enhanced substrate affinity were then designed and screened using the DS software by predicting the virtual key amino acid of peroxidase. The novel biodegradable enzymes 2YCD-1, 2YCD-4, 2YCD-5, 2YCD-7, and 2YCD-9 had better structures and showed excellent degradability for PAHs and FQs. This study explored the degradation rules of the composite pollutants in the coexistence systems of multiple PAHs and FQs, providing the best external field measures for the control and treatment of the combined pollution effects of different PAHs and FQs. Overall, the current study has important practical significance for promoting the plant-microbial joint remediation of PAHs-FQs pollution and for reducing the combined pollution of PAHs and FQs in farmland systems.

Site-directed modification of multifunctional lignocellulose-degrading enzymes of straw based on homologous modeling.

Studying the straw lignocellulose strengthening mechanism during simultaneous degradation has important practical significance for improving resource utilization and reducing environmental pollution. In this paper, the degradation ability of four straw lignocellulose-degrading enzymes was evaluated by molecular docking and molecular dynamics. Using the significantly binds to straw lignocellulose-degrading enzyme as a template, a multifunctional lignocellulose-degrading enzyme 3CBH-1KS5-4XQD-1B85 was constructed based on amino acid recombination and homologous modeling. Five efficient degrading enzymes (3CBH-1, 3CBH-2, 3CBH-3, 3CBH-4, and 3CBH-5) were designed by site-directed mutagenesis of 3CBH-1KS5-4XQD-1B85 amino acid at position 346. Molecular dynamics showed that the degradation ability of 3CBH-1 was significant and it was 1.45 times higher than 3CBH-1KS5-4XQD-1B85. Moreover, the mechanism of enhanced degradability and the stability of the enzymes were explored. With the aid of Taguchi experiments, the suitable external environment for degrading straw was determined. In the presence of inhibitors (organic acids and phenolic compounds), the binding energy of 3CBH-1 (238.46 ± 30.96 kJ/mol) is 36.42% higher than that of 3CBH-1KS5-4XQD-1B85 (174.79 ± 20.35 kJ/mol) without external environmental stimulation. Based on homology modeling, this paper constructed a site-directed mutagenesis scheme of multifunctional enzymes, and the aim was to obtain multifunctional and efficient straw lignocellulose-degrading enzymes through protein engineering, which provided a feasible scheme for straw biodegradation.

Application of mind map can promote the health education effect of children with vasovagal syncope.

Objective: To explore the effect of mind map on health education in children with vasovagal syncope (VVS). Methods: In this prospective controlled study, 66 children with VVS (29 males, 10.38 ± 1.80 years) and their parents (12 males, 39.27 ± 3.74 years) who were hospitalized in the Department of Pediatrics, The Second Xiangya Hospital, Central South University from April 2020 to March 2021 were set as the control group. 66 children with VVS (26 males, 10.29 ± 1.90 years) and their parents (9 males, 38.65 ± 1.99 years) who were hospitalized in the same hospital from April 2021 to March 2022 were set as the research group. Traditional oral propaganda method was applied in the control group, and the health education method based on mind map was applied in the research group. The self-designed VVS health education satisfaction questionnaire and comprehensive health knowledge questionnaire were used to conduct on-site return visits to the children and their parents who had been discharged from the hospital for 1 month. Results: There was no significant difference in age, sex, hemodynamic type of VVS, and the parental age, sex, education level between the control group and the research group (P > 0.05). Health education satisfaction score, health education knowledge mastery score, compliance score, subjective efficacy and objective efficacy in the research group were higher than those in the control group (P < 0.05). If the satisfaction score, knowledge mastery score, and compliance score increase by 1 point, the risk of poor subjective efficacy is reduced by 48, 91, and 99%, respectively, and the risk of poor objective efficacy is reduced by 44, 92, and 93%, respectively. Conclusions: Application of mind map can improve the health education effect of children with VVS.

MAGE-A3 regulates tumor stemness in gastric cancer through the PI3K/AKT pathway.

Gastric cancer remains a malignant disease of the digestive tract with high mortality and morbidity worldwide. However, due to its complex pathological mechanisms and lack of effective clinical therapies, the survival rate of patients after receiving treatment is not satisfactory. A increasing number of studies have focused on cancer stem cells and their regulatory properties. In this study, we first constructed a co-expression network based on the WGCNA algorithm to identify modules with different degrees of association with tumor stemness indices. After selecting the most positively correlated modules of the stemness index, we performed a consensus clustering analysis on gastric cancer samples and constructed the co-expression network again. We then selected the modules of interest and applied univariate COX regression analysis to the genes in this module for preliminary screening. The results of the screening were then used in LASSO regression analysis to construct a risk prognostic model and subsequently a sixteen-gene model was obtained. Finally, after verifying the accuracy of the module and screening for risk genes, we identified MAGE-A3 as the final study subject. We then performed in vivo and in vitro experiments to verify its effect on tumor stemness and tumour proliferation. Our data supports that MAGE-A3 is a tumor stemness regulator and a potent prognostic biomarker which can help the prediction and treatment of gastric cancer patients.

Potential Toxicity Risk Assessment and Priority Control Strategy for PAHs Metabolism and Transformation Behaviors in the Environment.

In this study, 16 PAHs were selected as the priority control pollutants to summarize their environmental metabolism and transformation processes, including photolysis, plant degradation, bacterial degradation, fungal degradation, microalgae degradation, and human metabolic transformation. Meanwhile, a total of 473 PAHs by-products generated during their transformation and degradation in different environmental media were considered. Then, a comprehensive system was established for evaluating the PAHs by-products' neurotoxicity, immunotoxicity, phytotoxicity, developmental toxicity, genotoxicity, carcinogenicity, and endocrine-disrupting effect through molecular docking, molecular dynamics simulation, 3D-QSAR model, TOPKAT method, and VEGA platform. Finally, the potential environmental risk (phytotoxicity) and human health risks (neurotoxicity, immunotoxicity, genotoxicity, carcinogenicity, developmental toxicity, and endocrine-disrupting toxicity) during PAHs metabolism and transformation were comprehensively evaluated. Among the 473 PAH's metabolized and transformed products, all PAHs by-products excluding ACY, CHR, and DahA had higher neurotoxicity, 152 PAHs by-products had higher immunotoxicity, and 222 PAHs by-products had higher phytotoxicity than their precursors during biological metabolism and environmental transformation. Based on the TOPKAT model, 152 PAH by-products possessed potential developmental toxicity, and 138 PAH by-products had higher genotoxicity than their precursors. VEGA predicted that 247 kinds of PAH derivatives had carcinogenic activity, and only the natural transformation products of ACY did not have carcinogenicity. In addition to ACY, 15 PAHs produced 123 endocrine-disrupting substances during metabolism and transformation. Finally, the potential environmental and human health risks of PAHs metabolism and transformation products were evaluated using metabolic and transformation pathway probability and degree of toxic risk as indicators. Accordingly, the priority control strategy for PAHs was constructed based on the risk entropy method by screening the priority control pathways. This paper assesses the potential human health and environmental risks of PAHs in different environmental media with the help of models and toxicological modules for the toxicity prediction of PAHs by-products, and thus designs a risk priority control evaluation system for PAHs.

The emerging roles and mechanism of m6a in breast cancer progression.

Breast cancer (BC) has continued to be the leading cause of cancer deaths in women, accompanied by highly molecular heterogeneity. N6-methyladenosine (m6A), a methylation that happens on adenosine N6, is the most abundant internal mRNA modification type in eukaryotic cells. Functionally, m6A methylation is a reversible modification process and is regulated by 3 enzymes with different functions, namely "writer", "reader", and "eraser". Abnormal m6A modifications trigger the expression, activation, or inhibition of key signaling molecules in critical signaling pathways and the regulatory factors acting on them in BC. These m6A-related enzymes can not only be used as markers for accurate diagnosis, prediction of prognosis, and risk model construction, but also as effective targets for BC treatment. Here, we have emphasized the roles of different types of m6A-related enzymes reported in BC proliferation, invasion, and metastasis, as well as immune regulation. The comprehensive and in-depth exploration of the molecular mechanisms related to m6A will benefit in finding effective potential targets and effective stratified management of BC.

miR-497-5p-RSPO2 axis inhibits cell growth and metastasis in glioblastoma.

Numerous studies have found a relationship between cancer formation and aberrant microRNA expression, however the biological significance of miR-497-5p in glioblastoma (GBM) is still unknown. Compared to normal brain glial cells, miR-497-5p expression in GBM tissues was substantially lower in our study. The microRNA miR-497-5p targets R-spondin 2 (RSPO2) only when it is present. RSPO2 silencing has the same effect on GBM cells as miR-497-5p silencing, as demonstrated before. Additional mechanistic investigations have shown that miR-497-5p suppresses the Wnt/ß-catenin signaling pathway by targeting RSPO2 to reduce cell proliferation, migration, and invasion. A negative correlation was discovered between MiR-497-5p and RSPO2 in 37 of the GBM tumors studied. MiR-497-5p-RSPO2 axis controls Wnt/ß-catenin signaling and plays a function in GBM carcinogenesis, suggesting that it may be a therapeutic target to reduce GBM growth, as shown by our research findings.

Core fucosylation involvement in the paracrine regulation of proteinuria-induced renal interstitial fibrosis evaluated with the use of a microfluidic chip.

Proteinuria is a clinical manifestation of chronic kidney disease that aggravates renal interstitial fibrosis (RIF), in which injury of peritubular microvessels is an important event. However, the changes in peritubular microvessels induced by proteinuria and their molecular mechanisms remain unclear. Thus, we aimed to develop a co-culture microfluidic device that contains renal tubules and peritubular microvessels to create a proteinuria model. We found that protein overload in the renal tubule induced trans-differentiation and apoptosis of endothelial cells (ECs) and pericytes. Moreover, profiling of secreted proteins in this model revealed that a paracrine network between tubules and microvessels was activated in proteinuria-induced microvascular injury. Multiple cytokine receptors in this paracrine network were core-fucosylated. Inhibition of core fucosylation significantly reduced ligand-receptor binding ability and blocked downstream pathways, alleviating trans-differentiation and apoptosis of ECs and pericytes. Furthermore, the protective effect of genetic FUT8 deficiency on proteinuria overload-induced RIF and pericyte-myofibroblast trans-differentiation was validated in FUT8 knockout heterozygous mice. In conclusion, we constructed and used a multiple-unit integrated microfluidic device to uncover the mechanism of proteinuria-induced RIF. Furthermore, FUT8 may serve as a hub-like therapeutic target to alleviate peritubular microvascular injury in RIF. STATEMENT OF SIGNIFICANCE: In this study, we constructed a multiple-unit integrated renal tubule-vascular chip. We reproduced human proteinuria on the chip and found that multiple receptors were modified by FUT8-catalyzed core fucosylation (CF) involved in the cross-talk between renal tubules and peritubular microvessels in proteinuria-induced RIF, and inhibiting the FUT8 of receptors could block the tubule-microvessel paracrine network and reverse the damage of peritubular microvessels and renal interstitial fibrosis. This tubule-vascular chip may provide a prospective platform to facilitate future investigations into the mechanisms of kidney diseases, and target-FUT8 inhibition may be an innovative and potential therapeutic strategy for RIF induced by proteinuria.

An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation.

The ring-like ATPase complexes in the AAA+ family perform diverse cellular functions that require coordination between the conformational transitions of their individual ATPase subunits (Erzberger and Berger, 2006; Puchades et al., 2020). How the energy from ATP hydrolysis is captured to perform mechanical work by these coordinated movements is unknown. In this study, we developed a novel approach for delineating the nucleotide-dependent free-energy landscape (FEL) of the proteasome's heterohexameric ATPase complex based on complementary structural and kinetic measurements. We used the FEL to simulate the dynamics of the proteasome and quantitatively evaluated the predicted structural and kinetic properties. The FEL model predictions are consistent with a wide range of experimental observations in this and previous studies and suggested novel mechanistic features of the proteasomal ATPases. We find that the cooperative movements of the ATPase subunits result from the design of the ATPase hexamer entailing a unique free-energy minimum for each nucleotide-binding status. ATP hydrolysis dictates the direction of substrate translocation by triggering an energy-dissipating conformational transition of the ATPase complex.

In cells, many biological processes are carried out by large complexes made up of different proteins. These macromolecules act like miniature machines, flexing and moving their various parts to perform their cellular roles. One such complex is the 26S proteasome, which is responsible for recycling other proteins in the cell. The proteasome consists of approximately 31 subunits, including a ring of six ATPase enzymes that provide the complex with the energy it needs to mechanically unfold proteins. To understand how the proteasome and other large complexes work, researchers need to be able to monitor how their structure changes over time. These dynamics are challenging to probe directly with experiments, but can be assessed using computer simulations which track the movement of individual molecules and atoms. However, currently available computer systems do not have enough power to simulate the dynamics of large protein assemblies, like the 26S proteasome: for example, it would take longer than a thousand years to model how each atom in the complex moves over a timescale in which a biological change would happen (roughly 100ms). Here, Fang, Hon et al. have developed a new approach to simulate the structural dynamics of the proteasome's ring of ATPase enzymes. Different known structures of the proteasome were used to identify the range of possible movements and shapes the complex can make. Fang, Hon et al. then used this data to calculate the energy level of each structure ­ also known as the 'free energy landscape' ­ and the rate of transition between them. This made it possible to simulate how the different ATPase enzymes move within the ring under a wide range of conditions. The simulated ATPase movements predicted how the proteasome machine would behave during various tasks, including degrading other proteins. Fan, Hon et al. carefully examined these predictions and found that they were consistent with experimental observations, validating their new simulation method. This work demonstrates the feasibility of simulating the actions of a large protein complex based on its free energy landscape. The results offer important insights into the functional mechanics of the 26S proteasome and related protein machines. Further work may help to simplify this process so the approach can be used to investigate the dynamics of other protein assemblies.

A model for phthalic acid esters' biodegradability and biotoxicity multi-effect pharmacophore and its application in molecular modification.

The objective of this study was to investigate 13 phthalic acid esters (PAEs) with medium or long straight-alkyl-chain, branching or unsaturated side chains, because their structural characteristics make them difficult to biodegrade or highly toxic. A biodegradability and biotoxicity multi-effect pharmacophore model was built using comprehensive evaluation method. The results suggested that introducing hydrophobic groups to the side chains of the PAEs could improve the molecules' biodegradability and biotoxicity effects simultaneously. Thus, 40 target PAE (HEHP, DNOP, DUP) derivatives were designed. Two environmentally friendly PAE derivatives (HEHP-Anthryl and HEHP-Naphthyl) were screened via the test of environmental friendliness and functionality. In addition, the biodegradation and biotoxicity of derivatives were found to have improved as a result of the change in van der Waals forces between molecules and their corresponding proteins. Moreover, the environmental safety of the screened PAE derivatives was confirmed by predicting the toxicity of their intermediates and calculating the energy barrier values for biodegradation and metabolic pathways. This study could provide theoretical guidance for the practical development of environmentally friendly plasticizer.

Heavy metal pollution caused by cyanide gold leaching: a case study of gold tailings in central China.

It is known that the tailings of gold mines have brought serious heavy metal pollution; however, the heavy metal pollution caused by gold tailings in specific geological environments and extraction processes still must be studied. This study investigated the distribution, speciation, bioaccumulation, and pollution of heavy metals in soils from the Yueliangbao gold tailings area in central China, where gold was extracted by cyanidation. The results show that the concentrations of Cu, Pb, Zn, Mn, Mo, and Cd in the soils of the tailings pond were higher than those in the local background. The concentrations of heavy metals related to mineralization activities, such as Cu, Pb, Zn, and Mo, varied with the distance to the tailings pond center. There was a decreasing trend of tailings pond center > tailings pond entrance > surrounding environment. This study's gold tailings pond differed from those of other regions because of its high content of unextracted Cu remaining in the pond. The proportion of non-residual Cu in the tailing pond soil was much higher than that of residual Cu, indicating it was likely to migrate to the surrounding environment. The pollution assessment indicated that the tailings pond soils were heavily polluted by Cu, and the level of heavy metal pollution in soils was positively correlated with the distance to the tailings pond center. Consequently, this tailings pond may become a source of Cu pollution in the surrounding environment, thus endangering environmental safety and human health. The study of heavy metal concentrations in the dominant plants showed that Chinese brake (Pteris vittata L.), Ramose scouring rush (Equisetum ramosissimum), and Manyflower silvergrass (Miscanthus floridulus) had the potential to be used for the phytostabilization of Cu.

An adjusted 3D-QSAR model for the combined activity of fluoroquinolones photodegradation and microbial degradation assisted by dynamic simulation and its application in molecular modification.

This study developed a comprehensive characterization method for the combined degradation effect of modified fluoroquinolones (FQs) photodegradation and microbial degradation. A combination of revised 3D-QSAR model, molecular docking, path simulation inference, pharmacokinetics, molecular dynamics (MD) simulation and toxicokinetics simulation was used to construct a systematic environment-friendly drug screening system. Five derivatives were screened with significantly improved combined degradation effect (over 20%) and functional characteristics and human health parameters through combined model verification, functional and human health risk assessment. The simulation path of photo- and microbial-degradation of gatifloxacin and new gatifloxacin molecules was derived, and the reaction energy barrier was also calculated. The ratio of the total rate-determining steps change rate of the decreased energy barrier (14.10%:26.30%) was consistent with the ratio of the increased degradation performance predicted by the model (22.87%:19.77%), demonstrating the reliability of revised 3D-QSAR model and it could be applied in molecular modification. MD and toxicokinetics simulation were used to predict the binding energy and aquatic toxicity between photo- and microbial-degradation products and the degradation enzymes, which further to screen the degradation pathways with low potential environmental risks. The findings will be helpful to screen environment-friendly drug and develop appropriate strategies for its risk management.

Simultaneous Determination of Three Coumarins in Rat Plasma by HPLC-MS/MS for Pharmacokinetic Studies Following Oral Administration of Chimonanthi Radix Extract.

Chimonanthi Radix (CR) is widely used in the treatment of influenza in China. Extensive studies revealed that the major bioactive constituents of CR were coumarins. However, pharmacokinetic study of coumarins in CR has not been fully studied. The purpose of this study was to establish a convenient and effective high-performance liquid chromatography-tandem mass spectrometry method that was used to simultaneously determine scopoletin, scopolin and isofraxidin in rat plasma after oral administration of CR extract using xanthotoxin as the internal standard. The chromatographic separation was carried out on a COSMOCORE C18 column (100 × 2 mm, 2.6 µm), using gradient elution with the mobile phase consisting of 0.1% formic acid (A) and acetonitrile (B). Three coumarins and IS were quantified by positive ion electrospray ionization in multiple reaction monitoring mode. The method was fully validated in terms of specificity, accuracy, precision (intra- and inter-day), matrix effect, recovery as well as the stability of the analytes under various conditions. The results could provide further research foundation for anti-influenza mechanism of three coumarins in CR.

Calcium-Polystyrene Sulfonate Decreases Inter-Dialytic Hyperkalemia in Patients Undergoing Maintenance Hemodialysis: A Prospective, Randomized, Crossover Study.

Hyperkalemia is a life-threatening emergency in maintenance hemodialysis (MHD) patients. This clinical trial investigated the efficacy and safety of calcium-polystyrene sulfonate (Ca-PS) in MHD patients with interdialytic hyperkalemia. A total of 58 hemodialysis patients with hyperkalemia (≥5.5 mol/L) were selected and administered either a 3-week Ca-PS (3 × 5 g/day) or a blank control following the model of a prospective, randomized, crossover clinical trial with a 1-week washout period. All patients were followed up for another 3 weeks for safety evaluations. The primary outcome was the magnitude of the change in serum potassium levels. The secondary outcomes were electrocardiography (ECG) changes and treatment safety (volume overload, electrolyte imbalance). Compared with the control group, Ca-PS treatment significantly reduced serum potassium levels (P <0.01). More patients in the Ca-PS group had lower serum potassium levels than the safety level of <5.5 mmol/L (32% for control vs. 61% for Ca-PS, P <0.01). Peaked T-wave occurred less frequently in patients in the Ca-PS group (13.8% for Ca-PS vs. 31.03% for control, P <0.01). In addition, Ca-PS reduced serum phosphorus levels with no effects on serum levels of calcium and sodium, fluid volume, blood pressure, or interdialytic weight gain. Ca-PS treatment decreases serum levels of potassium and phosphorus in MHD patients with interdialytic hyperkalemia. Ca-PS does not induce volume overload or disrupt electrolyte balance.

A Sample and Sensitive HPLC-MS/MS Method for Simultaneous Determination of Ziyuglycoside I and Its Metabolite Ziyuglycoside II in Rat Pharmacokinetics.

Ziyuglycoside I (ZGS1) is a promising drug candidate for the treatment of leucopenia. Currently, information on ZGS1 and its in vivo metabolite ziyuglycoside II (ZGS2) is limited. The objective of this study was to investigate the pharmacokinetics, tissue distribution, and excretion of ziyuglycoside I (ZGS1) and its metabolite ziyuglycoside II (ZGS2) in rats. In our study, a simple and sensitive high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was established for simultaneous determination of ZGS1 and its metabolite for Sprague-Dawley rat pharmacokinetics studies. The method was validated following internationally-approved guidelines. The results presented in this study indicated that subcutaneous administration of ZGS1 prolonged its extension time and increased the area under the curve (AUC0-t) of ZGS2 during 0 to t minutes. In summary, in this study, the pharmacokinetic characteristics of ZGS1 and its metabolite ZGS2 were defined and its tissue distribution, and excretion in rats were described. Our finding may be beneficial for leucopenia drug that focus on ZGS1.