Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion. IE plays a major role in the elimination of apixaban (36 ± 14

Background: Nanocomposite Hydrogels (NHs) are 3D molecular networks formed by physically or covalently crosslinking polymer with nanoparticles or nanostructures, which are particularly suitable for serving as carriers for drug delivery systems. Many articles pertaining to the applications of Nanocomposite Hydrogels for drug delivery have been published, however, the use of bibliometric and visualized analysis in this area remains unstudied. The purpose of this bibliometric study intended to comprehensively analyze the knowledge domain, research hotspots and frontiers associated with the applications of Nanocomposite Hydrogels for drug delivery. Methods: We identified and retrieved the publications concerning the applications of NHs for drug delivery between 2003 and 2022 from Web of Science Core Collection Bibliometric and visualized analysis was utilized in this investigative study. Results: 631 articles meeting the inclusion criteria were identified and retrieved from WoSCC. Among those, 2,233 authors worldwide contributed in the studies, accompanied by an average annual article increase of 24.67%. The articles were co-authored by 764 institutions from 52 countries/regions, and China published the most, followed by Iran and the United States. Five institutions published more than 40 papers, namely Univ Tabriz ( n = 79), Tabriz Univ Med Sci ( n = 70), Islamic Azad Univ ( n = 49), Payame Noor Univ ( n = 42) and Texas A&M Univ ( n = 41). The articles were published in 198 journals, among which the International Journal of Biological Macromolecules ( n = 53) published the most articles, followed by Carbohydrate Polymers ( n = 24) and ACS Applied Materials and Interfaces ( n = 22). The top three journals most locally cited were Carbohydrate Polymers, Biomaterials and Advanced materials. The most productive author was Namazi H (29 articles), followed by Bardajee G (15 articles) and Zhang J (11 articles) and the researchers who worked closely with other ones usually published more papers. “Doxorubicin,” “antibacterial” and “responsive hydrogels” represent the current research hotspots in this field and “cancer therapy” was a rising research topic in recent years. “(cancer) therapeutics” and “bioadhesive” represent the current research frontiers. Conclusion: This bibliometric and visualized analysis offered an investigative study and comprehensive understanding of publications regarding the applications of Nanocomposite Hydrogels for drug delivery from 2003 to 2022. The outcome of this study would provide insights for researchers in the field of Nanocomposite Hydrogels applications for drug delivery.

Osteoarthritis (OA) is a chronic degenerative joint disease associated with pain, inflammation, and cartilage degradation. However, no current treatment can effectively halt the progression of the disease. Therefore, the use of NSAIDs and intra-articular corticosteroids is usually recommended as the primary treatment for OA-associated pain and inflammation. However, there is accumulating evidence that the long-term use of oral NSAIDs and intra-articular corticosteroids can lead to a myriad of negative side effects. Although numerous efforts have been made to develop intra-articular formulations for NSAIDs, the systemic exposure of intra-articular injection of NSAIDs and its potential side effects have not been explicitly investigated. To ascertain the evident and potential side effects of intra-articular injection of anti-inflammatory agents, we have summarised in this review the systemic exposure, local side effects, and systemic side effects of intra-articular injections of anti-inflammatory agents, including NSAIDs and corticosteroids. For developing a safer treatment to fulfil the unmet long-term use needs of patients, a new therapy, which combines the locally active drug and a sustained-release formulation, has been proposed in this review.

Organic anion transporting polypeptides (OATPs) belong to the superfamily of solute carrier (SLC) and are an important family of uptake transporters. OATPs play critical roles in the distribution of multiple endogenous and exogenous compounds. Intra- and intersubject variation in activity and expression of OATPs may cause unexpected pharmacokinetic behaviors or toxicity in humans. FDA recommended to determine the drug–drug interaction potential on OATP1B1 and OATP1B3 of a drug candidate, both as a substrate and as an inhibitor, in the new drug development process. In this chapter, we provided a protocol of an in vitro essay using OATP overexpressed cells, including materials required for the experiment and methods determining whether a compound is a substrate and/or an inhibitor of the transporter. We also included a set of real data as an example for data analysis of uptake and inhibition kinetics.

Early research on cytochrome P450s initially believed that the rate and extent of metabolism were the key factors influencing the disposition of metabolized compounds. However, as research advanced, it became apparent that a complex relationship exists between Phase I metabolic enzymes and efflux transporters like P-gp. This kind of interplay involving communication between multiple proteins sparked enthusiasm in drug transporter research, leading to significant discoveries and ongoing trends in the field. In the present article, we first introduce the enzymes involved in drug metabolism and transport proteins involved in drug disposition. Following the introduction of the basic interactions between these proteins, including enzyme-to-enzyme, enzyme-to-transporter, transporter-to-enzyme, and transporter-to-transporter interactions, prominent theories like the double jeopardy theory, revolving doors theory, and enterohepatic recycling and hepatoenteric recycling, which explain coupling processes, are presented and proposed to explain the coupling processes and complexities of the interplay between metabolic enzymes and transporters. The complexity necessitates further research to identify the key controllers of transporter and enzyme expression and functionality in different organisms, from animals to humans. The ultimate goal is to better understand and characterize the intricate mechanisms involved in enzyme-transporter coupling.

Purpose This paper aims to take Chinese university teachers as the research objects to examine their self-evaluation of online teaching and analyze the main factors influencing their evaluation during COVID-19. Design/methodology/approach According to the theory of educational ecology, the factors influencing teachers' self-evaluation of online teaching in this paper include university background, courses background and teachers' personal background from the macro- to micro-levels. Through exploratory factor analysis, independent sample T -test and one-way analysis of variance (ANOVA), the self-evaluation of online teaching of 13,997 teachers from 334 universities and their relationship with teachers' background have been subject to data statistics and analysis. Findings Teachers' self-evaluation of online teaching mainly includes three dimensions: online teaching methods, online teacher–student interaction and online teaching techniques. There are significant differences in these three dimensions among teachers with different background characteristics, including regions, the types of universities, the nature of universities in macro background levels, the types and numbers of online courses in meso background levels, and the gender, years of teaching, professional titles and disciplines in micro background levels. Practical implications To improve teachers' self-evaluation of online teaching, it is suggested to build an online teaching self-evaluation system for teachers, strengthen university support and guarantee, strengthen online teaching training and improve the information accomplishments of teachers. Originality/value This large-scale empirical survey of online teaching evaluation of Chinese teachers can provide scholars with a deeper understanding of the implementation of online teaching in China and the self-evaluation of online teaching by teachers.

The development of aggregation-induced emission luminogens (AIEgens) has attracted increasing attention due to their potential applications in various areas in recent years. In this study, a facile conversion from aggregation-caused quenching (ACQ) to aggregation-induced emission (AIE) was achieved by an efficient regioisomerization strategy based on the rofecoxib scaffold. Two compounds, named PYR2 and PYR4, were identified as regioisomers of rofecoxib derivatives to show dramatically different fluorescent properties. Compound PYR2 with an ortho-substituted piperidine group showed typical AIE activity while compound PYR4 with a para-piperidine group exhibited typical ACQ behavior. Notably, compound PYR2 showed polymorphism with two forms of crystals. It was also endowed with reversible mechanochromic luminescence and acidochromic properties. The different fluorescent properties were elucidated by UV/Vis absorption spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analyses. Its application as a security ink and in lipid droplets imaging have been demonstrated.

Objective:We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods:An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results:A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11-17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion:In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.

The development of aggregation induced emission luminogens (AIEgens) has attracted increasing attention in recent years as the potential of their application in various areas, including data storage and bioimaging has been realised. However, most of the AIEgens have large conjugation systems which were obtained via lengthy synthetic processes. Herein, we have successfully developed a new pair of far-red fluorescent molecules (lambda(max) = 652 nm, 688 nm), ROF1 and ROF2, which were designed and derivatized from rofecoxib by one-step reaction. Specifically, ROF1 with a para-piperidine shows a classical aggregation caused quenching (ACQ) effect. In contrast, by shifting the piperidine group from para-to ortho-position, the ROF2 exhibits typical AIE behavior. Based on the analyses of single-crystal X-ray data, the AIE property of ROF2 could be ascribed to the highly twisted molecular conformation and loose packing modes caused by the ortho-position of piperidine. These findings allow us to have a better understanding of the impact of the substituent position on the AIE properties. Moreover, the fluorescence of ROF2 was sensitive to multi-stimulus, such as grinding, immersing (solvating), heating and altering pH value, which enabled its potential application in data storage, security ink and pH sensing. In biological experiments, ROF2 could selectively image lipid droplets (LDs) in living HeLa cells. In summary, the regio-isomerization effect used in this article successfully developed a promising AIEgen, ROF2, and provided a principle for the design of new AIEgens.

Cyclooxygenase-2 (COX-2) fluorescent probes are promising tools for early cancer diagnosis. Traditionally, COX-2 probes were designed by connecting two parts, a fluorophore and a COX-2 binding unit, via a flexible linker. Herein, a new class of COX-2-specific fluorescent probes have been developed by one-step modification from rofecoxib by an integrative approach to combining the fluorophore and binding units into one. Among them, several new rofecoxib analogues not only retained their COX-2 binding ability but also exhibited attractive fluorescent properties, such as tunable Blue-Red emission, solvatochromism, AIE behavior and mechanochromism. Notably, the emission of 2a16 can be switched between greenish-yellow in the crystalline state to red-orange in the amorphous state by grinding and fuming treatments. Furthermore, the highly fluorescent compound 2a16 (Фf = 0.94 in powder) displayed much stronger fluorescent imaging of COX-2 in HeLa cancer cells overexpressing COX-2 than RAW264.7 normal cells with minimal expressing of COX-2. Most importantly, 2a16 can light up human cancer tissues from adjacent normal tissues with much brighter fluorescence by targeting COX-2 enzyme. These results illustrate the potential of 2a16 as a new red fluorescent probe for human cancer imaging in clinical applications.

COX-2 fluorescent probes are promising tools for cancer diagnosis. Such probes have been conventionally designed by conjugating a fluorophore to COX-2 inhibitors through lengthy synthetic processes. Herein, a type of fluorescent probe for COX-2 imaging has been developed using a single-step process from rofecoxib. In total, six rofecoxib analogues were designed using this unique strategy. Several analogues retained comparative COX-2 targeting activity of rofecoxib and also exhibited attractive fluorescent properties, which were investigated using a combination of experimental and theoretical approaches. The most potent analogue, 2a1, displayed strong fluorescent imaging of COX-2 in HeLa cells overexpressing COX-2 compared to Raw 264.7 cells and celecoxib-treated HeLa cells that expressed low levels of COX-2. Notably, our studies indicate that 2a1 can differentiate human cancer tissue from adjacent tissue with much brighter fluorescence either in histological section or cultured 3D organoids. These results illustrate the potential of 2a1 as a COX-2 near infrared fluorescent probe for human cancer imaging in clinical settings.

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)-a free-radical gas-plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.

疫情期间我国高校在线教学大规模开展,许多教师积极参与在线教学.对全国334所高校13997名教师在线教学开展情况进行问卷调查后发现:八成左右的教师在疫情发生之前没有开展过在线教学;教龄为1-10年的新手型教师和11-20年的熟练型教师在线教学经历更加丰富,且疫情期间开设的在线课程数量更多;理工农医学科的教师在疫情发生之前和疫情期间开设的在线课程数量均高于人文学科和社会科学学科的教师;疫情发生之前有过在线教学经历的教师对在线教学的评价更高;教师对自身在线教学方法、师生互动和教学技术使用的评价均对其教学满意度有显著影响,其中主要的影响因素是师生互动和教学方法,而非教学技术.

基于全国57所高校的线上教学质量报告及福建、山东两省课程平台数据统计报告,对疫情期间在线教学平台的使用、教师教学的情况、学生学习的情况、在线教学管理方面的数据分析显示,线上教学给教师和学生带来了新的体验,线上教学所产生的大数据更便于管理者的精准施策.同时,也暴露出在线教学过程中平台流畅度、灵活性受阻;教师在线教学操作不熟悉,师生互动未达到预期效果并缺乏良好的教学设计;学生自我管理难以把控并增加了学生的任务量,学生个人条件差异大等问题.另外,城乡差别的教育公平问题再次被聚焦.后续的网络教学应强化学校对课程资源及平台的支撑,开展团队建课及教师技能培训来保障在线教学质量,注重学生主体能力的发挥,提高学生的学习效果.

教学满意度是教学质量的重要反映.在疫情期间在线教学的广泛开展中,提高教师在线教学满意度,对于确保在线教学质量与成效具有重要意义.文章对全国334所高校、13997名教师的在线教学问卷调查发现:教师对于在线教学的满意度呈现出东部>中部>西部,研究型大学>一般本科院校>高职院校;学生因素、教师因素和支持保障因素是影响教师在线教学满意度的主要因素;东部地区各院校教师的在线教学满意度主要受教师自身因素影响,中部地区和西部地区各院校教师受到教师、学生和支持保障三方面因素的影响.

谢作栩教授作为比较教育学者长期以来一直关注国内外高等教育研究动态,并坚持扎根中国大地的实践,通过对高等教育大众化理论的思考,寻找中国高等教育发展的道路.他提出要用数据与事实来说话,通过对全国168所高校的调查,建立起在线数据库,分析高等教育大众化发展阶段学生接受高等教育的具体情况.随着研究的不断深入,他进一步学习大数据的挖掘,对学生的学习情况进行研究.他指出,高等教育研究将向着智能化与多元化方向发展,高等教育研究者要与时俱进,在具备教育学基本素养的同时了解跨学科知识的应用.

本研究采用了厦门大学教师发展中心在疫情期间对高校教师在线教学的调查和统计数据,分析了不同背景和不同在线教学经历的13997名高校教师对疫情期间在线教学的态度,结果发现:超过3/4的高校教师乐于接受采用"线上+线下"混合式教学,而且这种教学经历还是影响教师在线教学态度的重要因素;不同类型、不同性质、不同地区以及不同教龄、不同学科的教师对在线教学改进意愿的差异显著;不同背景的教师均把学生的改进意见列为继续线上教学最需要加强的因素.通过调查我们还发现:疫情期间参与在线教学的经历对教师接受疫情后的在线教学非常有利;对教学改进意见的差异反映了高校师资、办学条件、教学水平和学科本身的差异;传统教学的惯性是开展在线教学的阻碍因素;教师应该更加明确作为学生学习引导者的责任.基于此,我们从高校制度、技术支持及教师个人等方面提出了后疫情时代促使更多教师认可并开展线上教学的建议.

Cyclooxygenase-2 (COX-2) imaging agents are potent tools for early cancer diagnosis. Almost all of the COX2 imaging agents using celecoxib as backbone were chemically modified in the position of N-atom in the sulfonamide group. Herein, a novel COX-2 probe (CCY-5) with high targeting ability and a near-infrared wavelength (achieved by attaching a CY-5 dye on the pyrazole ring of celecoxib using a migration strategy) was evaluated for its ability to probe COX-2 in human cancer cells. CCY-5 is expected to have high binding affinity for COX-2 based on molecular docking and enzyme inhibition assay. Meanwhile, CCY-5 caused stronger fluorescence imaging of COX-2 overexpressing cancer cells (Hela and SCC-9 cells) than that of normal cell lines (RAW 264.7 cells). Lipopolysaccharide (LPS) treated RAW264.7 cells revealed an enhanced fluorescence as LPS was known to induce COX-2 in these cells. In inhibitory studies, a markedly reduced fluorescence intensity was observed in cancer cells, when they were co-treated with a COX-2 inhibitor celecoxib. Therefore, CCY-5 may be a selective bioimaging agent for cancer cells overexpressing COX-2 and could be useful as a good monitoring candidate for effective diagnosis and therapy in cancer treatment.

Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.