Rational Design of Vinylene Carbonate-Inspired 1,3-Dimethyl-1H-imidazol-2(3H)-one Additives to Stabilize High-Voltage Lithium Metal Batteries.

Lithium metal batteries (LMBs) employing high-voltage nickel-rich cathodes represent a promising strategy to enable higher energy density storage systems. However, instability at the electrolyte-electrode interfaces (EEIs) currently impedes the translation of these advanced systems into practical applications. Herein, 1,3-dimethyl-1H-imidazol-2(3H)-one (DMIO), integrating structural features of vinylene carbonate (VC) while substituting oxygen with electron-donating nitrogen, has been synthesized and validated as a multifunctional electrolyte additive for high-voltage LMBs. Theoretical calculations and experimental results demonstrate that the potent electron-donating nitrogen in DMIO enables preferential DMIO oxidation at the cathode while preserving its carbon-carbon double bond for a concomitant reduction on the anode. Thereby, robust DMIO-derived EEIs are generated, reinforcing cycling in the full cells. Additionally, DMIO leverages Lewis acid-based interactions to coordinate and sequester protons from acidic LiPF6 decomposition byproducts, concurrently retarding LiPF6 hydrolysis while attenuating parasitic consumption of EEIs by acidic species. Consequently, incorporating DMIO into conventional carbonate electrolytes enables an improved capacity retention of Li||NCM622 cells to 81% versus 26% in the baseline electrolyte after 600 cycles. Similarly, DMIO improves Li anode cycling performance, displaying extended life spans over 200 h in Li||Li symmetric cells and enhancing Coulombic efficiency from 76% to 88% in Li||Cu cells. The synergistic effects of DMIO on both the cathode and anode lead to substantially improved cell lifetime. This rationally designed, multifunctional electrolyte additive paradigm provides vital insights that can be translatable to further electrolyte molecular engineering strategies.

Clozapine affects the pharmacokinetics of risperidone and inhibits its metabolism and P-glycoprotein-mediated transport in vivo and in vitro: A safety attention to antipsychotic polypharmacy with clozapine and risperidone.

Antipsychotic polypharmacy (APP), as one maintenance treatment strategy in patients with schizophrenia, has gained popularity in real-world clinical settings. Risperidone (RIS) and clozapine (CLZ) are the most commonly prescribed second-generation antipsychotics, and they are often used in combination as APP. In this study, the pharmacokinetics of RIS and CLZ in rats were examined after co-administration to explore the reliability and rationality of co-medication with RIS and CLZ. In addition, the effects of CLZ on RIS metabolism and transport in vitro were investigated. The results illustrated that in the 7-day continuous administration test in rats, when co-administered with CLZ, the area under curve and peak concentrations of RIS were increased by 2.2- and 3.1-fold at the first dose, respectively, increased by 3.4- and 6.2-fold at the last dose, respectively. The metabolite-to-parent ratio of RIS was approximately 22% and 33% lower than those of RIS alone group at the first and last doses, respectively. Moreover, CLZ significantly increased RIS concentrations in the brain (3.0-4.8 folds) and cerebrospinal fluid (2.1-3.5 folds) in rats, which was slightly lower than the impact of verapamil on RIS after co-medication. Experiments in vitro indicated that CLZ competitively inhibited the conversion of RIS to 9-hydroxy-RIS with the inhibition constants of 1.36 and 3.0 µM in rat and human liver microsomes, respectively. Furthermore, the efflux ratio of RIS in Caco-2 monolayers was significantly reduced by CLZ at 1 µM. Hence, CLZ may affect the exposure of RIS by inhibiting its metabolism and P-glycoprotein-mediated transport. These findings highlighted that APP with RIS and CLZ might increase the plasma concentrations of RIS and 9-hydroxy-RIS beyond the safety ranges and cause toxic side effects.

PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo.

Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood-brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.

Development and validation of indirect and generic immunoassays to quantify free and total evolocumab in rat serum.

Aim: Evolocumab is a human monoclonal antibody used in the treatment of cardiovascular diseases, which targeted proprotein convertase subtilisin kexin type 9. To accurately quantify free (including partially bound) and total evolocumab concentrations in serum, indirect and generic ELISA methods were developed and validated in rat serum. Results: Indirect ELISA was accurate and precise over the concentration range of 23.4-1500 ng/ml, and the method was validated for selectivity, specificity, accuracy and precision, dilution linearity, parallelism and stability. Similarly, generic antihuman IgG ELISA method was validated for selectivity, accuracy and precision, and dilution linearity. Moreover, incurred sample reanalysis were carried out for the above two methods, and the percent difference met the acceptable criteria. Conclusion: The validated methods can be effectively used to evaluate pharmacokinetics of free and total evolocumab after subcutaneous administration of evolocumab to rats.

Pharmacokinetics of S-EPA, and its inhibition on indoleamine 2,3-dioxgenase: a case of sulfur-substitution affecting distributions in blood cells.

1. S-EPA is a sulfur-substitution analog of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2. Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1.2, 4.8, 2.2 and 40.6, respectively. While the distribution ratio of EPA ranged from 0.94 to 1.30 in mice, rats, dogs and was 3.1 in monkeys. 3. The pharmacokinetic study in rats showed the exposure (AUClast) of S-EPA in plasma and blood cells was 1.7-fold and 3.9-fold higher than that of EPA, respectively. Moreover, the exposure ratio of S-EPA in blood cells to plasma was 3.7, while the ratio of EPA was 1.6. 4. In CT26 tumor bearing mice, the IDO inhibition of S-EPA and EPA on plasma or tumor kynurenine was generally consistent. And the inhibition ratio could reach at more than 50% at 3 h after single dose, at least lasting up to 8 h.

Determination of kynurnine and tryptophan, biomarkers of indoleamine 2,3-dioxygenase by LC-MS/MS in plasma and tumor.

AIM: Tryptophan (Trp) and kynurnine (Kyn) are a pair of biomarkers for indoleamine 2,3-dioxygenase which closely related to the tumor immune escape. To evaluate the effect of drugs on the indoleamine 2,3-dioxygenase activity, the specific and accurate LC-MS/MS methods were developed and validated for simultaneous determination Kyn and Trp in mouse plasma and tumor tissues using surrogate analytes Kyn-d4 and Trp-d5 calibrators. RESULTS: Plasma and tumor homogenates samples were pretreated with the solid phase extraction which assured the method having high recovery (>90% in plasma and >80% in tumor) and no matrix effect. The methods were validated for specificity, linearity, accuracy and precision, recovery, matrix effect and stability using surrogate analytes Kyn-d4 and Trp-d5 in authentic matrices. CONCLUSION: The validated methods have been successfully applied to the pharmacodynamic study of INCB024360 in CT26 tumor bearing mice after single dose and multiple dosing.

The requirement of integrins for breast epithelial proliferation.

Epithelial cells forming mammary gland ducts and alveoli require adhesion to the extracellular matrix for their function. Mammary epithelial cells need ß1-integrins for normal cell cycle regulation. However, the role of ß1-integrins in tumorigenesis has not been fully resolved. ß1-integrin is necessary for tumour formation in transgenic mice expressing the Polyomavirus Middle T antigen, but it is dispensable in those overexpressing ErbB2. This suggests that some oncogenes can manage without ß1-integrin to proliferate and form tumours, while others still require it. Here we have developed a model to test whether expression of an oncogene can surpass the need for ß1-integrin to drive proliferation. We co-expressed the ErbB2 or Akt oncogenes with shRNA to target ß1-integrin in mammary epithelial cells, and found that they show a differential dependence on ß1-integrin for cell division. Moreover, we identified a key proliferative role of the Rac1-Pak axis downstream of ß1-integrin signalling. Our data suggest that, in mammary epithelial cells, oncogenes with the ability to signal to Pak surpass the requirement of integrins for malignant transformation. This highlights the importance of using the correct combination therapy for breast cancer, depending on the oncogenes expressed in the tumour.

Open access to journal articles in dentistry: Prevalence and citation impact.

OBJECTIVES: To investigate the current prevalence of open access (OA) in the field of dentistry, the means used to provide OA, as well as the association between OA and citation counts. METHODS: PubMed was searched for dental articles published in 2013. The OA status of each article was determined by manually checking Google, Google Scholar, PubMed and ResearchGate. Citation data were extracted from Google Scholar, Scopus and Web of Science. Chi-square tests were used to compare the OA prevalence by different subjects, study types, and continents of origin. The association between OA and citation count was studied with multivariable logistic regression analyses. RESULTS: A random sample of 908 articles was deemed eligible and therefore included. Among these, 416 were found freely available online, indicating an overall OA rate of 45.8%. Significant difference in OA rate was detected among articles in different subjects (P<0.001) and among those from different continents (P<0.001). Of articles that were OA, 74.2% were available via self-archiving ('Green road' OA), 53.3% were available from publishers ('Gold road' OA). According to multivariable logistic regression analyses, OA status was not significantly associated with either the existence of citation (P=0.37) or the level of citation (P=0.52). CONCLUSIONS/CLINICAL SIGNIFICANCE: In the field of dentistry, 54% of recent journal articles are behind the paywall (non-OA) one year after their publication dates. The 'Green road' of providing OA was more common than the 'Gold road'. No evidence suggested that OA articles received significantly more citations than non-OA articles.

[Study on candida infections in intensive care unit from 2008 to 2012].

OBJECTIVE: To investigate and analyze the candida infection situation at the intensive care unit (ICU) in Tianjin Fourth Central Hospital from 2008 to 2012. METHODS: Critically ill patients admitted in ICU Department in Tianjin Fourth Central Hospital from Jan. 2008 to Dem. 2012 were selected, and candida in all blood, sputum and other specimens of patients, were tested. Data on the following items as:hospital sections and distribution of candida infection on the places where the fungus was identified, distribution of different species of candida, antifungal drug resistance of candidates commonly used in ICU department in the last five years etc., were statistically analyzed. RESULTS: Among 4 529 cases of critically ill patients stayed in the hospital ICU Department between 2008 and 2012, 76 cases of candida infection were identified, with the rate as 1.68%. In the past five years, candida in hospital ICU was mainly detected in sputum samples in 52 cases which accounted for 68.4%. Another 9 cases were detected in blood, accounted for 11.8%, 8 cases were detected in urine, which accounted for 10.5% , 36 cases (47.4%) of candida infection detected at the hospital ICU department in the last 5 years with major species as Candida albicans infection, followed by Candida glabrata, Candida tropicalis, Candida parapsilosis and Portugal Candida. The highest rate of resistance was to itraconazole, with a resistance rate of 19.7%, followed by voriconazole, with the rate as 15.8%. CONCLUSION: In recent years, the number of patients infected with candida at the ICU department had increased annually with most cases as respiratory infections, which were caused by Candida albicans. The rate of resistance of candida to itraconazole was the highest, which called for special attention.