Sodium Carbazolide and Derivatives as Solid-State Electrolytes for Sodium-Ion Batteries.

Replacing widely used organic liquid electrolytes with solid-state electrolytes (SSEs) could effectively solve the safety issues in sodium-ion batteries. Efforts on seeking novel solid-state electrolytes have been continued for decades. However, issues about SSEs still exist, such as low ionic conductivity at ambient temperature, difficulty in manufacturing, low electrochemical stability, poor compatibility with electrodes, etc. Here, sodium carbazolide (Na-CZ) and its THF-coordinated derivatives are rationally fabricated as Na+ conductors, and two of their crystal structures are successfully solved. Among these materials, THF-coordinated complexes exhibit fast Na+ conductivities, i.e., 1.20×10-4  S cm-1 and 1.95×10-3  S cm-1 at 90 °C for Na-CZ-1THF and Na-CZ-2THF, respectively, which are among the top Na+ conductors under the same condition. Furthermore, stable Na plating/stripping is observed even over 400 h cycling, showing outstanding interfacial stability and compatibility against Na electrode. More advantages such as ease of synthesis, low-cost, and cold pressing for molding can be obtained. In situ NMR results revealed that the evaporation of THF may play an essential role in the Na+ migration, where the movement of THF creates defects/vacancies and facilitates the migration of Na+ .

Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity.

Renal injury is the main adverse reaction of cisplatin, and many traditional Chinese medicines (TCMs) were proven active against renal toxicity. Here, an integrated metabolomics and network pharmacology strategy was proposed to discover active TCM ingredients for the alleviation of cisplatin nephrotoxicity. First, by interrogating the Human Metabolome Database (HMDB) we collected targets connected to 149 cisplatin nephrotoxicity-related metabolites. Second, targets of kidney damage were obtained from the Therapeutic Target Database (TTD), PharmGKB, Online Mendelian Inheritance in Man (OMIM), and Genetic Association Database (GAD). Common targets of both dysregulated metabolites and kidney damage were then used for TCM active ingredient screening by applying the network pharmacology approach. Eventually, 22 ingredients passed screening criteria, and their antinephrotoxicity activity was assessed in human kidney tubular epithelial (HK2) cells. As a result, 14 ingredients were found to be effective, in which kaempferol showed relatively better activity. Further metabolomics analysis revealed that kaempferol exerted an antinephrotoxicity effect in rats by regulating amino acid, pyrimidine, and purine metabolism as well as lipid metabolism. Collectively, this proposed integrated strategy would promote the transformation of metabolomics research in the field of drug pair discovery for the purpose of reduced toxicity and increased efficiency.

Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown.

Saikosaponin d (SSd) is one of the main active ingredients in Radix Bupleuri. In our study, network pharmacology databases and metabolomics were used in combination to explore the new targets and reveal the in-depth mechanism of SSd. A total of 35 potential targets were chosen through database searching (HIT and TCMID), literature mining, or chemical similarity predicting (Pubchem). Out of these obtained targets, Neuropilin-1 (NRP-1) was selected for further research based on the degree of molecular docking scores and novelty. Cell viability and wound healing assays demonstrated that SSd combined with NRP-1 knockdown could significantly enhance the damage of HepG2. Metabolomics analysis was then performed to explore the underlying mechanism. The overall difference between groups was quantitatively evaluated by the metabolite deregulation score (MDS). Results showed that NRP-1 knockdown exhibited the lowest MDS, which demonstrated that the metabolic profile experienced the slightest interference. However, SSd alone, or NRP-1 knockdown in combination with SSd, were both significantly influenced. Differential metabolites mainly involved short- or long-chain carnitines and phospholipids. Further metabolic pathway analysis revealed that disturbed lipid transportation and phospholipid metabolism probably contributed to the enhanced anti-hepatoma effect by NRP-1 knockdown in combination with SSd. Taken together, in this study, we provided possible interaction mechanisms between SSd and its predicted target NRP-1.

[Antibody druggability screening process and evaluation strategy].

Since the approval of OKT3 as the first therapeutic monoclonal antibody in 1986, there has been rapid development in antibody technology and antibody drugs. Monoclonal antibodies, antibody fragments, bi (multi) specific antibodies, fusion proteins, nanobodies, and antibody-drug conjugates (ADCs) have been introduced and play a significant role in the treatment of oncology, hematology, immunology, respiratory, metabolic and other related diseases. The process of antibody drug discovery involves multiple rounds of biological function and druggability assessments to identify the best candidate sequences that are safe, effective, stable, and scalable. This lays the foundation for the efficiency and success of drug development and clinical studies. In the phase of antibody drug discovery, "druggability screening and evaluation" has received increasing attention. It involves drug discovery and design, screening and optimization of lead molecules as well as the validation of candidate molecules, with the aim of detecting potential physicochemical risk factors and evaluating controllability to ensure the quality stability of the subsequent drug development process. This paper classifies and defines the process of druggability screening and evaluation in the antibody discovery phase, covering monoclonal antibodies, bispecific antibodies, nanobodies, ADCs and other related technologies and drug forms. It also summarizes the quality attributes and high-throughput detection technology that should be emphasized in the druggability screening and evaluation. The systematic elaboration of the druggability development process and strategy provides a reference for the druggability screening and evaluation of emerging innovative drugs, significantly improving the efficiency and success rate of antibody drug development.

Efficient electrochemical reduction of CO2 to CO in a flow cell device by a pristine Cu5tz6-cluster-based metal-organic framework.

The electrochemical reduction of CO2 to CO is a powerful approach to achieving carbon neutrality. Herein, we report a five-nuclear copper cluster-based metal-azolate framework CuTz-1 as an electrocatalyst for the electrochemical CO2 reduction reaction. It achieved a faradaic efficiency (FE) of 62.7% for yielding CO with a partial current density of -35.1 mA cm-2 in flow cell device, which can be preserved for more than ten hours with negligible changes of the current density and FE(CO). Studies of electrocatalytic mechanism studies revealed that the distance of Cu-N was increased, and the coordination number of the Cu ion was reduced, while the oxidation state of Cu was decreased after the electrocatalysis. These findings offer valuable insights into structural changes that influence the performance of the catalyst during the process of the electrochemical reduction of CO2 process.

Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan.

Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.