[Application of discrete element method (DEM) in pharmaceutical process of solid traditional Chinese medicine preparations].

In recent years, the application of numerical simulation in the research and development(R&D) as well as the pharmaceutical processes of new drugs has expanded considerably. The discrete element method(DEM), an important approach among numerical simulation methods, offers an effective tool for the simulation of discontinuous media. Referring to the research progress of DEM and the formulation of solid traditional Chinese medicine(TCM) preparations in recent years, this paper summarizes and analyzes the application of DEM in the pharmaceutical processes of solid TCM preparations, and discusses the challenges of its application in these processes, in order to provide new methods and ideas for promoting the high-quality production of TCM preparations.

[Current situation and development trend of digital traditional Chinese medicine pharmacy].

The 21st century is a highly information-driven era, and traditional Chinese medicine(TCM) pharmacy is also moving towards digitization and informatization. New technologies such as artificial intelligence and big data with information technology as the core are being integrated into various aspects of drug research, manufacturing, evaluation, and application, promoting interaction between these stages and improving the quality and efficiency of TCM preparations. This, in turn, provides better healthcare services to the general population. The deep integration of emerging technologies such as artificial intelligence, big data, and cloud computing with the TCM pharmaceutical industry will innovate TCM pharmaceutical technology, accelerate the research and industrialization process of TCM pharmacy, provide cutting-edge technological support to the global scientific community, boost the efficiency of the TCM industry, and promote economic and social development. Drawing from recent developments in TCM pharmacy in China, this paper discussed the current research status and future trends in digital TCM pharmacy, aiming to provide a reference for future research in this field.

Integration of Metabolomics, Lipidomics, and Proteomics Reveals the Metabolic Characterization of Nonalcoholic Steatohepatitis.

Metabolic dysfunction is associated with nonalcoholic steatohepatitis (NASH) development. However, omics studies investigating metabolic changes in NASH patients are limited. In this study, metabolomics and lipidomics in plasma, as well as proteomics in the liver, were performed to characterize the metabolic profiles of NASH patients. Moreover, the accumulation of bile acids (BAs) in NASH patients prompted us to investigate the protective effect of cholestyramine on NASH. The liver expression of essential proteins involved in FA transport and lipid droplets was significantly elevated in patients with NASH. Furthermore, we observed a distinct lipidomic remodeling in patients with NASH. We also report a novel finding suggesting an increase in the expression of critical proteins responsible for glycolysis and the level of glycolytic output (pyruvic acid) in patients with NASH. Furthermore, the accumulation of branched chain amino acids, aromatic amino acids, purines, and BAs was observed in NASH patients. Similarly, a dramatic metabolic disorder was also observed in a NASH mouse model. Cholestyramine not only significantly alleviated liver steatosis and fibrosis but also reversed NASH-induced accumulation of BAs and steroid hormones. In conclusion, NASH patients were characterized by perturbations in FA uptake, lipid droplet formation, glycolysis, and accumulation of BAs and other metabolites.

Chemical Composition Analysis and Discrimination of Essential Oils of Artemisia Argyi Folium from Different Germplasm Resources Based on Electronic Nose and GC/MS Combined with Chemometrics.

In this study, the electronic nose and GC/MS were used to analyze the chemical components of essential oils from different germplasm resources of Artemisia argyi Folium (A. argyi), in order to quickly identify essential oils of A. argyi from different germplasm resources and clarify the differences among different A. argyi samples. The essential oils of A. argyi were extracted by steam distillation. This article describes for the first time that electronic nose combined with chemometrics can distinguish the essential oils of A. argyi from different germplasm, which proves the reliability and potential of this technology. GC/MS was used to identify 134 volatile components from the essential oil of A. argyi. The main bioactive components were cineole, thujarone, artemisia ketone, ß-caryophyllene, (-)-4-terpinol, 3,3,6-trimethyl-1,5-heptadien-4-ol, (-)-α-thujone, camphor, borneol. In addition, the results of principal component analysis (PCA) and hierarchical cluster analysis (HCA) showed that there were significant differences in the essential oils of A. argyi from different germplasm resources, terpenes, alcohols and ketones played an important role in identifying the essential oils of A. argyi from different germplasm resources. This indicates that electronic nose and GC/MS combined with chemometrics can be used as reliable techniques to identify different germplasm resources of A. argyi, and provide certain reference value for quality evaluation, selection of high-quality varieties and rational development of resources of A. argyi.

[Conversion of traditional Chinese medicine (TCM) into nanomedicine:application of theory of unification of medicines and excipients].

In recent years, the use of active substances as excipients or as substitutes for other excipients in the design of modern drug delivery systems has received widespread attention, which has promoted the development of the theory of unification of medicines and excipients in the design of traditional Chinese medicine(TCM) preparations. Adopting the theory of unification of medicines and excipients to design drug delivery systems can reduce the use of excipients and thus the cost of preparations, reduce drug toxicity, increase drug solubility and biocompatibility, enhance synergistic effect, and realize targeted delivery and simultaneous delivery of multiple components. However, the research on the application of this theory in the modern drug delivery system of TCM preparations is still insufficient, with few relevant articles. In addition, the TCM active substances that can be used as the excipients remain to be catalogued. In this paper, we review the types and applications of the drug delivery systems with TCM active substances as excipients and describe their common construction methods and mechanisms, aiming to provide references for the in-depth research on the modern drug delivery systems for TCM preparations.

[Application and problems analysis of traditional Chinese medicine volatile oil preparation technology based on ionic liquids].

Ionic liquids(ILs) are salts composed entirely of anions and cations in a liquid state at or near room temperature, which have a variety of good physicochemical properties such as low volatility and high stability. This paper mainly reviewed the research overview of ILs in the application of traditional Chinese medicine(TCM) volatile oil preparation technology. Firstly, it briefly introduced the application of TCM volatile oil preparation technology and composition classification and physicochemical properties of ILs, and then summarized the application of ILs in the extraction, separation, analysis, and preparation of TCM volatile oil. Finally, the problems and challenges of ILs in the application of TCM volatile oil were explained, and the application of ILs in TCM volatile oil in the future was prospected.

Rational design of a facile camphor-based fluorescence turn-on probe for real-time tracking of hypochlorous acid in vivo and in vitro.

A simple yet highly effective camphor-derived fluorescent probe named 3-(anthracen-9-ylmethylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one oxime (ATHO) was developed based on an oxime recognition receptor and anthracene fluorophore. The probe ATHO exhibited a remarkably enhanced fluorescence response to HClO (∼7.2 fold). Meanwhile, this probe exhibited a low detection limit (0.118 µM), ultrafast response time (within seconds), excellent photostability (>260 min), wide linear range (0-180 µM), low probe concentration (2 µM), and high selectivity toward HClO over various interfering species. The sensing mechanism of the probe ATHO for HClO was supported by HRMS analysis and theoretical calculations. Furthermore, the probe ATHO was utilized to quantitatively determine HClO levels in environmental water samples. Additionally, the biological imaging of the probe ATHO for exogenous and endogenous HClO was successfully demonstrated in vitro and in vivo.

A Novel Schiff Base-Modified Dialdehyde Cellulose-Based Fluorescent Probe for Al3+ and Its Application in Environmental Analysis.

Cellulose is the most abundant natural polymer with good biodegradability and biocompatibility. In this paper, a novel fluorescent probe DAC-SD-NA for aluminum (Al3+ ) detection is successfully synthesized based on dialdehyde cellulose (DAC). DAC-SD-NA exhibited a remarkable "turn-on" fluorescence response to Al3+ in a wide pH range, and the fluorescence color of DAC-SD-NA solution turned from colorless to bright blue at the presence of Al3+ . The detection limit for Al3+ is computed to be 6.06×10-7 m. The reaction mechanism of DAC-SD-NA towards Al3+ is confirmed by Job's plot, X-ray photoelectron spectroscopy, and density functional theory (DFT) calculations. In view of DAC-SD-NA exhibited good sensitivity and selectivity, it is applied to detect Al3+ in real water. What's more, DAC-SD-NA-loaded fluorescent hydrogel can serve as a convenient tool for the detection of Al3+ .

A highly effective "turn-on" camphor-based fluorescent probe for rapid and sensitive detection and its biological imaging of Fe2.

In this work, a novel fluorescent probe CBO was synthesized for detecting Fe2+ using the natural monoterpenketone camphor as the starting material. The probe CBO displayed turn-on fluorescence to Fe2+ accompanied by the solution change from colorless to green. As expected, there was an excellent linear relationship between the fluorescence intensity of probe CBO and the concentration of Fe2+ (0-20 µM), and the detection limit was as low as 1.56×10-8 M. In particular, CBO could selectively sense Fe2+ more than other analytes (Fe3+ included) through the N-oxide strategy, and quickly responded to Fe2+ (60 s) over a wide pH (4-14) range. Additionally, based on the rapid fluorescence response of CBO to Fe2+, a simple test strip-based detector was designed for boosting practical applicability. The probe CBO had been successfully applied to the fluorescence imaging of Fe2+ in onion cells and living zebrafish. The probe CBO was a powerful tool of detecting Fe2+ level in organisms, which was of significance to understand the role of Fe2+ in Fe2+-related physical processes and diseases.

A nopinone based multi-functional probe for colorimetric detection of Cu2+ and ratiometric detection of Ag.

A dual-signal probe PPN based on the natural ß-pinene derivative nopinone was synthesized for the colorimetric detection of Cu2+ and ratiometric detection of Ag+. Upon the addition of Ag+, a significant fluorescence change from blue to green was observed with a low detection limit (0.86 µM). However, upon the addition of Cu2+, a significant color change from colorless to yellow was observed with a low detection limit (0.56 µM). The novel probe PPN was applied as a probe for the colorimetric detection of Cu2+ and ratiometric detection of Ag+ with a high selectivity, good sensitivity and fast response time. The detection mechanisms of probe PPN for Cu2+/Ag+ were confirmed by 1H NMR and HRMS-ESI. Besides, probe PPN could sense Cu2+/Ag+ on test strips. Additionally, probe PPN could be applied to quantitatively detect the concentration of Ag+ in water samples and image Ag+ in living cells.

A novel nopinone-based fluorescent probe for colorimetric and ratiometric detection of hypochlorite and its applications in water samples and living cells.

A novel fluorescent probe (OFN) based on nopinone for the detection of hypochlorite has been developed. The probe OFN exhibited a colorimetric and ratiometric response to hypochlorite with good selectivity, high sensitivity (the low detection limit is 0.136 µM) and fast response time (30 s). In response to ClO-, an obvious change was observed in both the fluorescence and absorption spectra, followed by the visible color change from colorless to yellow and the fluorescence color change from yellow to green. The sensing mechanism confirmed that the oxime group of OFN was oxidized to the aldehyde group, which was proved by HRMS and 1H NMR. What is more, the probe was used not only to detect the concentration of ClO- in water samples but also for monitoring ClO- in living cells.

Design, synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives.

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by 1H NMR, 13C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC50 values of 2.79±0.38, 2.64±0.17 and 3.64±0.13µM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.

Regional brain shrinkage and change in cognitive performance over two years: The bidirectional influences of the brain and cognitive reserve factors.

We examined relationships between regional brain shrinkage and changes in cognitive performance, while taking into account the influence of chronological age, vascular risk, Apolipoprotein E variant and socioeconomic status. Regional brain volumes and cognitive performance were assessed in 167 healthy adults (age 19-79 at baseline), 90 of whom returned for the follow-up after two years. Brain volumes were measured in six regions of interest (ROIs): lateral prefrontal cortex (LPFC), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), cerebellar hemispheres (CbH), and primary visual cortex (VC), and cognitive performance was evaluated in three domains: episodic memory (EM), fluid intelligence (Gf), and vocabulary (V). Average volume loss was observed in Hc, PhG and CbH, but reliable individual differences were noted in all examined ROIs. Average positive change was observed in EM and V performance but not in Gf scores, yet only the last evidenced individual differences in change. We observed reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in Gf, but differences in LPFC volume change were in part explained by baseline level of cognitive performance. In one region (PFw), individual change in volume was coupled with change in Gf. Larger initial brain volumes did not predict slower shrinkage. The results underscore the complex role of brain maintenance and cognitive reserve in adult development.

Path Complexity in Virtual Water Maze Navigation: Differential Associations with Age, Sex, and Regional Brain Volume.

Studies of human navigation in virtual maze environments have consistently linked advanced age with greater distance traveled between the start and the goal and longer duration of the search. Observations of search path geometry suggest that routes taken by older adults may be unnecessarily complex and that excessive path complexity may be an indicator of cognitive difficulties experienced by older navigators. In a sample of healthy adults, we quantify search path complexity in a virtual Morris water maze with a novel method based on fractal dimensionality. In a two-level hierarchical linear model, we estimated improvement in navigation performance across trials by a decline in route length, shortening of search time, and reduction in fractal dimensionality of the path. While replicating commonly reported age and sex differences in time and distance indices, a reduction in fractal dimension of the path accounted for improvement across trials, independent of age or sex. The volumes of brain regions associated with the establishment of cognitive maps (parahippocampal gyrus and hippocampus) were related to path dimensionality, but not to the total distance and time. Thus, fractal dimensionality of a navigational path may present a useful complementary method of quantifying performance in navigation.

A novel ratiometric fluorescent sensor from modified coumarin-grafted cellulose for precise pH detection in strongly alkaline conditions.

Accurate and convenient monitoring of pH under extreme alkaline conditions is still a challenge. In this work, 4-(3-(7-hydroxy-2-oxo-2H-chromen-3-yl)-3-oxoprop-1-en-1-yl)benzamide (HCB), a coumarin derivative, was grafted onto dialdehyde cellulose (DAC) to obtain a sensor DAC-HCB, which exhibited a ratiometric fluorescent response to the pH of alkaline solutions, resulting in a significant fluorescent color change from yellow to blue (FI459 nm/FI577 nm) at pH 7.5-14. The structure of DAC-HCB was characterized through FT-IR, XRD, XPS, SEM. The pKa of sensor DAC-HCB was 13.16, and the fluorescent intensity ratio FI459 nm/FI577 nm possessed an excellent linear characteristic with pH in the scope of 9.0-13.0. Meanwhile, sensor DAC-HCB showed good selectivity, anti-interference, and fast response time to basic pH, which is an effective fluorescent sensor for examination of pH in alkali circumstance. The recognition mechanism of DAC-HCB to OH- was elucidated with HRMS and density-functional theory (DFT) computational analyses. Sensor DAC-HCB was successfully used for precise detection of environmental water samples pH. This work furnished a new protocol for test strips as a convenient and highly efficient pH detection tool for the high pH environment, and it has great potential for application in environmental monitoring.

Rational design of a highly effective cellulose-based macromolecular fluorescent probe for real-time recognition of palladium ion in environmental samples and its applications in plant and zebrafish.

Palladium ion (Pd2+) plays an important role in our daily life, but poses a great threat to the environment and human health. Thus, it is desirable to exploit a rapid and sensitive approach to realize the detection of Pd2+. In this study, a cellulose acetate-based macromolecular fluorescent probe CA-NA-PA was successfully prepared for tracking amounts of Pd2+. CA-NA-PA showed an obvious "on-off" fluorescence response to Pd2+, accompanied by the fluorescence color changed from bright yellow to colorless. CA-NA-PA had some outstanding detection performances such as low detection limit (26 nM), extremely short response time (1 min), good selectivity and anti-interference ability. Based on the advantages of probe mentioned above, CA-NA-PA could realize recognition of Pd2+ concentration in environmental water and soil samples. What's more, the probe CA-NA-PA was applied to image Pd2+ in zebrafish as well as in live onion tissue due to the good biocompatibility and cell membrane permeability of cellulose, suggesting its wide application prospect in biosystems.

A novel colormetric and light-up fluorescent sensor from flavonol derivative grafted cellulose for rapid and sensitive detection of Hg2+ and its applications in biological and environmental system.

Mercury ion (Hg2+) is one of harmful heavy metal ions that can accumulate inside the human organism and cause some health problems. In the article, a highly effective fluorescent probe named EC-T-PCBM was prepared by grafting flavonol derivatives onto ethyl cellulose for the specific recognition of Hg2+. EC-T-PCBM exhibited a remarkable fluorescence light-up response toward Hg2+ with excellent sensitivity. EC-T-PCBM possessed several prominent sensing properties for Hg2+, such as low detection limit (43.9 nM), short response time (5 min), and wide detection pH range (6-9). The response mechanism of EC-T-PCBM to Hg2+ has been verified through 1H NMR titration and DFT computation. Additionally, EC-T-PCBM not only can be used for accurately determining trace amount of Hg2+ in actual environmental water samples, but also can serve as a portable and rapid device by loading it on test strips for sensitive and selective visualization of Hg2+. More importantly, the confocal fluorescence imaging of onion cells suggested the favorable cell membrane permeability of EC-T-PCBM and its prominent ability to continuously monitor the enrichment from Hg2+ within fresh plant tissues.

An ultrasensitive cellulose-based fluorescent sensor for Al3+ detection and its applications in plant tissue and food samples.

Fluorescent sensors available for metal ions detection have been extensively developed in recent years. However, developing an ultrasensitive fluorescent sensor for highly selectively detecting Al3+ based on cellulose remains a challenge. In this study, an ethylcellulose-based flavonol fluorescent sensor named EC-BHA was synthesized by the esterification of ethylcellulose (EC) with a new flavonol derivative 4-(2-(2,3-bis(ethoxymeothy)phenyl)-3-hydroxy-4-oxo-4-H-chromen-7-yl) benzoic acid (BHA). The fluorescence intensity of EC-BHA exhibited a 180-fold increase at 490 nm after binding with Al3+ and provided an ultralow detection limit of 13.0 nM. The sensor showed some exceptional sensing properties including a broad pH range (4-10), large Stokes shifts (190 nm), and a short response time (3 min). This sensor was successfully applied for determining trace Al3+ in food samples as well as in plant tissue. Moreover, the electrostatic spun film EBP was fabricated by blending EC-BHA with PS (polystyrene) via electrostatic spinning technique and utilized for selective detection of Al3+ as soon as possible.

Volume of white matter hyperintensities in healthy adults: contribution of age, vascular risk factors, and inflammation-related genetic variants.

Aging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44-77 years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP)-286C>A>T, and interleukin-1ß (IL-1ß) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1ß-511T allele and carriers of CRP-286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Smart supply chain management in Industry 4.0: the review, research agenda and strategies in North America.

The emerging information and communication technologies (ICT) related to Industry 4.0 play a critical role to enhance supply chain performance. Employing the smart technologies has led to so-called smart supply chains. Understanding how Industry 4.0 and related ICT affect smart supply chains and how smart supply chains evolve with the support of the advanced technologies are vital to practical and academic communities. Existing review works on smart supply chains with ICT mainly rely on the academic literature alone. This paper presents an integrated approach to explore the effects of Industry 4.0 and related ICT on smart supply chains, by combining introduction of the current national strategies in North America, the research status analysis on ICT assisted supply chains from the major North American national research councils, and a systematic literature review of the subject. Besides, we introduce a smart supply chain hierarchical framework with multi-level intelligence. Furthermore, the challenges faced by supply chains under Industry 4.0 and future research directions are discussed as well.