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It remains inconclusive about the stability and optimal fixation scheme of screw internal fixation for lateral malleolus oblique fractures in clinical practice. In this study, the effects of different screw internal fixation methods on the biomechanics of lateral malleolus oblique fractures were investigated. These efforts are expected to lay a theoretical foundation for the selection of internal fixation methods and rehabilitation training regimens in the treatment of lateral malleolus fractures. A healthy ankle joint model and a lateral malleolus fracture internal fixation model were established based on CT data with the aid of some software. Besides, the effects of screw internal fixation modalities on the fracture displacement of fibula fractures, fibula Von Mises stress, and screw Von Mises stress under different physiological conditions and loading conditions were investigated using finite element methods (FEMs) and in vitro physical experiments. The double screw vertical fibular axis internal fixation approach had the lowest fracture displacement of fibula fractures and screw Von Mises stress values; while the double screw vertical fracture line internal fixation approach had the lowest fibula Von Mises stress values. Under different physiological conditions, the magnitude of the peak Von Mises stress of the fibula and screw was ranked as plantarflexion 20° > plantarflexion 10° > neutral position > dorsiflexion 10° > dorsiflexion 20°; and the magnitude of the peak displacement of the fibula fracture breaks was ranked as plantarflexion 20° > plantarflexion 10° > neutral position > dorsiflexion 20° > dorsiflexion 10°. The results of in vitro physical experiments and finite element analyses were in good agreement, which validated the validity of finite element analyses. The vertical fracture line screw implantation method displays a better load-sharing ability; while the vertical fibular axis screw implantation method exhibits a better ability to prevent axial shortening of the fibula and also reduces the risk of screw fatigue damage. Overall, the double screw achieves better therapeutic effects than the single screw. Given that the ankle joint has high stability in the dorsiflexion position, it is recommended to prioritize dorsiflexion rehabilitation training, rather than dorsiflexion and plantarflexion rehabilitation training with too large angles, in the treatment of lateral malleolus fractures., (© 2024 John Wiley & Sons Ltd.)

Astragalus polysaccharides (APS) are known for their prebiotic properties, and fermentation by probiotics is a promising strategy to enhance the prebiotic activity of polysaccharides. In this study, Lactobacillus rhamnosus was used to ferment APS, and response surface methodology was applied to optimize the fermentation parameters. The optimal conditions were determined as follows: 10.28% APS addition, 5.83% inoculum, 35.6 h of fermentation time, and a temperature of 34.6 °C. Additionally, the effects of Fermented Astragalus polysaccharides (FAPS) on human gut microbiota were investigated through in vitro anaerobic incubation. Fecal samples were obtained from 6 healthy volunteers, which were then individually incubated with FAPS. Results demonstrated that FAPS significantly regulated microbial composition and diversity, increasing the abundance of beneficial gut bacteria such as Lactobacillus, E. faecalis, and Brautobacterium, while inhibiting harmful species such as Shigella, Romboutsia, and Clostridium_sensu_stricto_1. Furthermore, FAPS enhanced the production of short-chain fatty acids (SCFAs), which are increasingly recognized to play a role in intestinal homeostasis. These findings suggested that FAPS offers several advantages in terms of increasing beneficial metabolites and regulating gut microbial composition. This study provides valuable insights for expanding the use of plant-derived polysaccharides in the food industry and for developing functional dietary supplements., Competing Interests: Declarations. Conflict of Interest: The authors declare there are no conflicts of interest. Ethical Approval: This study and included experimental procedures were approved by the Beijing University of Chinese Medicine. Protocol Number BUCM-2021102102-1021. Consent to Participate: All the volunteers have approved the participate. Consent for Publication: All the participants in studies have read and approved the publication manuscript., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The purpose of this study is to observe whether there is a difference in the anesthetic effect of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery, so as to provide reference for clinical application., Methods: Fifty patients, aged 18-65 years, ASA I-II, scheduled for hysteroscopy under total intravenous anesthesia were selected. The patients were randomly divided into two groups (n = 25): remimazolam tosilate group (group T) and remimazolam besylate group ( group R). The main observation index was the induction dose of remimazolam; secondary observation indicators were sleep time, anesthesia maintenance time, recovery time, induction maintenance dose of alfentanil, maintenance dose of remimazolam, and incidence of adverse events during anesthesia ( hypertension, hypotension, bradycardia, tachycardia)., Results: There was no significant difference in anesthesia induction dose, recovery time, sleep time, anesthesia maintenance time, and incidence of adverse events during anesthesia ( body movement, cough, hypertension, hypotension, bradycardia, tachycardia) between the two groups (P > 0.05)., Conclusion: There was no significant difference in the anesthetic effect of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery., Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR2400081688., (© 2024. The Author(s).)

Merging traditional Chinese medicine's (TCM) principles of medicine-food homology with modern flavor chemistry, this research unveils PungentDB (http://www.pungentdb.org.cn/home), a database documenting 205 unique pungent flavor compounds from 231 TCMs. It provides detailed insights into their chemical attributes, biological targets (including IC50/EC50 values), and molecular structures (2D/3D), enriched with visualizations of target organ distribution and protein structures, exploring the pungent flavor space with the help of a feature-rich visual interface. This collection, derived from over 3249 sources and highlighting 9129 targets, delves into the compounds' unique pungent flavors-taste, aroma, and thermal sensations-and their interaction with taste and olfactory receptors. PungentDB bridges ancient wisdom and culinary innovation, offering a nuanced exploration of pungent flavors' role in enhancing food quality, safety, and sensory experiences. This initiative propels flavor chemistry forward, serving as a pivotal resource for food science advancement and the innovative application of pungent flavors., Competing Interests: In the preparation of our manuscript titled “PungentDB: Bridging Traditional Chinese Medicine of medicine food homology and Modern Food Flavor Chemistry,” submitted to the special issue on Flavor Chemistry of Food in Food Chemistry: X, we have meticulously adhered to the ethical standards of scientific research and publishing. We hereby declare that there are no conflicts of interest, including financial, consultative, institutional, or other relationships that might lead to bias or a conflict of interest. Our research is purely academic in nature, aiming to contribute to the body of knowledge within the realms of food science, traditional Chinese medicine, and flavor chemistry. All data were collected and processed with the utmost integrity, and all contributors to this work have been duly acknowledged. This work has not received funding or support from any organization that could have influenced its outcome. Furthermore, this manuscript is original, has not been published elsewhere, and is not currently under consideration by any other journal. We have cited all references appropriately to acknowledge the contributions of previous research in our work. Through this submission, we aim to contribute valuable insights into the interplay between traditional Chinese medicine and modern food flavor chemistry, with a particular focus on the chemistry of pungent flavors and their potential applications in enhancing food quality, safety, and sensory properties. Conflict of interest statement: None declared., (© 2024 The Authors. Published by Elsevier Ltd.)

While healthcare big data brings great opportunities and convenience to the healthcare industry, it also inevitably raises the issue of privacy leakage. Nowadays, the whole world is facing the security threat of healthcare big data, for which a sound policy framework can help reduce privacy risks of healthcare big data. In recent years, the Chinese government and industry self-regulatory organizations have issued a series of policy documents to reduce privacy risks of healthcare big data. However, China's policy framework suffers from the drawbacks of the mismatched operational model, the inappropriate operational method, and the poorly actionable operational content. Based on the experiences of the European Union, Australia, the United States, and other extra-territorial regions, strategies are proposed for China to amend the operational model of the policy framework, improve the operational method of the policy framework, and enhance the operability of the operational content of the policy framework. This study enriches the research on China's policy framework to reduce privacy risks of healthcare big data and provides some inspiration for other countries., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi.)

Intestinal absorption of compounds is significant in drug research and development. To evaluate this efficiently, a method combining mathematical modeling and molecular simulation was proposed, from the perspective of molecular structure. Based on the quantitative structure-property relationship study, the model between molecular structure and their apparent permeability coefficients was successfully constructed and verified, predicting intestinal absorption of drugs and interpreting decisive structural factors, such as AlogP98, Hydrogen bond donor and Ellipsoidal volume. The molecules with strong lipophilicity, less hydrogen bond donors and receptors, and small molecular volume are more easily absorbed. Then, the molecular dynamics simulation and molecular docking were utilized to study the mechanism of differences in intestinal absorption of drugs and investigate the role of molecular structure. Results indicated that molecules with strong lipophilicity and small volume interacted with the membrane at a lower energy and were easier to penetrate the membrane. Likewise, they had weaker interaction with P-glycoprotein and were easier to escape from it and harder to export from the body. More in, less out, is the main reason these molecules absorb well., (© 2024 John Wiley & Sons Ltd.)

Background and Objective: The lower extremity movement involves a complex and large amplitude extremity movement process, and arterial stents implanted in the lower extremity are prone to complex mechanical deformation behavior. Hence, the lower extremity arterial stent is required to have favorable comprehensive mechanical properties., Methods: In this study, a new lower extremity arterial stent (New) was proposed, and its deformation behavior and mechanical properties were analyzed by numerical simulations under different deformation modes, such as radial compression, axial compression/tension, bending, and torsion. Stents with different diameters were modeled to compare the effect of diameter size on their biomechanical properties. Additionally, a comparative analysis was conducted between this new stent and seven commercially available stents., Results: The results demonstrated that the stent diameter exerted a significant effect on its deformation behavior and mechanical properties. Specifically, with the increase of the stent diameter, the radial expansion rate, radial shrinkage rate, radial support stiffness, axial compression stiffness, and axial tensile stiffness tended to decrease, and the expansion inhomogeneity, stenosis rate, bending stiffness, and torsional stiffness tended to increase. In contrast, the stent diameter exerted a small effect on the stent axial shortening rate and ellipticity. The new lower extremity arterial stent was validated to outperform other stents in terms of most performance indicators. Especially, the radial expansion rate and ellipticity of the New stent were better than those of all commercially available stents. Moreover, the New stent presented favorable mechanical properties and flexibility under the premise of ensuring the support performance., Conclusions: Based on these findings, this lower extremity arterial stent may play a better therapeutic effect in clinical application. Furthermore, these analysis results may provide reference for the clinical application and selection of the stent., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Umbilical paste therapy is a promising method to promote transdermal drug delivery of topical formulations. This work investigated the effect and mechanism of transdermal drug delivery through the umbilical skin. The transdermal permeation studies showed the phenomenon of higher cumulative penetration and faster penetration rates for drug through the umbilical skin compared with non-umbilical skin, namely umbilical pro-permeability. This special transdermal permeability of drugs is influenced by their molecular weight, logP value, ability to form hydrogen bonds, and molecular volume. The underlying mechanism of umbilical pro-permeability was elucidated from unique structure and regulation the effect of drugs on microcirculation in the umbilical skin. Mechanistic studies revealed that this phenomenon was not only associated with the structural and physiological properties of the skin but also to the interactions between drugs and different skin layers. The umbilical pro-permeation is attributed to the thinner stratum corneum layer, differences in stratum corneum lipid composition and keratin structure, and lower levels of intercellular tight junction proteins in the viable epidermis and dermis layer of the skin. Our research indicated that umbilical paste therapy enhanced the transdermal delivery and absorption of drugs by stimulating local blood flow through mast cell activation. Surprisingly, skin temperature modulation and calcitonin gene-related peptide and substance P levels did not appear to significantly affect this process. In conclusion, umbilical drug administration, as a straightforward and non-invasive approach to enhance transdermal drug delivery, presents novel concepts for continued investigation and practical implementation of transdermal drug delivery systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effect of flumazenil antagonizing remimazolam on postoperative nausea and vomiting (PONV) after gynecologic day surgery., Patients and Methods: 141 cases of gynaecological daycase surgery patients in Weifang People's Hospital were selected, randomized into group F (flumazenil group, 71 cases) and group C (control group, 70 cases). Dexamethasone 5 mg, flurbiprofen axetil 50 mg, and droperidol 1 mg were given intravenously before induction of anesthesia in both groups. Anesthesia induction: Remimazolam 0.25mg / kg was injected within 1 minute. After the patient fell asleep, mivacurium chloride 0.2mg / kg was injected for 30 seconds and alfentanil 20ug / kg was injected for 30 seconds. Anesthesia maintenance: Remimazolam 1mg/kg/h and alfentanil 40ug/kg/h were continuously pumped by micro pump. Stopping the injection of remimazolam and alfentanil at the end of the operation. Flumazenil 0.2 mg was given to antagonize remimazolam in group F after 1 minute. Group C was given an equal volume of saline. The incidence of PONV in the postoperative PACU and over a 24-hour period, patient awakening time, and general patient information were recorded., Results: The incidence of PONV in both groups within 24 hours was 50.70% in group F was significantly higher than 32.86% in group C. The difference was statistically significant (P < 0.05). The incidence of PONV in the PACU was 5.6% in group F and 8.6% in group C. The difference was not statistically significant (p > 0.05)., Conclusion: Flumazenil antagonism of remimazolam increases the incidence of PONV within 24 hours in gynecologic day surgery patients and has no significant effect on the incidence of PONV in the PACU., Competing Interests: The authors have no competing interests in this work., (© 2024 Wei et al.)

Molecular switches that reversibly change their structures and physical properties are important for applications such as sensing and information processing at molecular scales. In order to avoid the intermolecular aggregation that is often detrimental to the stimuli-responses of molecular switches, previous studies of molecular switches have been often conducted in dilute solutions which are difficult for applications in solid-state devices. Here we report molecular design and synthesis that integrates anthraquinodimethane as molecular switching units into polymers with amenable processibility in solid states. Optical and electron spin resonance characterizations indicate that the four-arm polymers of poly(ϵ-caprolactone) or poly(D,L-lactide) tethered from anthraquinodimethane slow down the dynamics of the conformational switching between the folded and the twisted conformations, enhance the photoluminescence in solid states and impart materials with a small energy gap from singlet ground state to thermally accessible triplet state., (© 2023 Wiley-VCH GmbH.)

Introduction: Drug delivery systems (DDSs) formed by natural active compounds be instrumental in developing new green excipients and novel DDS from natural active compounds (NACs). 'Unification of medicines and excipients'(UME), the special inherent nature of the natural active compounds, provides the inspiration and conduction to achieve this goal., Areas Covered: This review summarizes the typical types of NACs from herbal medicine, such as saponins, flavonoids, polysaccharides, etc. that act as excipients and their main application in DDS. The comparison of the drug delivery systems formed by NACs and common materials and the primary formation mechanisms of these NACs are also introduced to provide a deepened understanding of their performance in DDS., Expert Opinion: Many natural bioactive compounds, such as saponins, polysaccharides, etc. have been used in DDS. Diversity of structure and pharmacological effects of NACs turn out the unique advantages in improving the performance of DDSs like targeting ability, adhesion, encapsulation efficiency(EE), etc. and enhancing the bioavailability of loaded drugs.

Excessive emissions of carbon dioxide and other greenhouse gases have seriously affected the ecological environment, public health, and the normal operation of the social economy, and the development of the low-carbon economy has become an international consensus. The policy norms are one of the important factors affecting the development of the low-carbon economy; however, the implementation of low-carbon economic policy in many countries has been inhibited. This study chose Liaoning Province of China for the case study, and the policy system, the policy tools, the administrative system, the low-carbon technology, and the low-carbon concept are found to be factors that led to the inhibition of the policy effectiveness of the low-carbon economy in Liaoning Province. We applied the modified Schweller Neoclassical Realist Theory to establish a multi-factor linkage model to demonstrate the overall relationship among various variables. The results show that the equilibrium of policy effectiveness of the low-carbon economy in Liaoning Province depends on different permutations of variables. We also discussed the problems of the policy system, the policy tools, the administrative system, the low-carbon technology, and the low-carbon concept that lead to policy effectiveness inhibition, and used the economic method to set a special mathematical model for maximizing the equilibrium of policy effectiveness of the low-carbon economy in Liaoning Province. In response to the problems of the above factors, strategies to promote the development of the low-carbon economy in Liaoning Province are proposed. This study enriches the research on the policy effectiveness of the low-carbon economy in China and provides some inspiration for the goal of carbon neutrality and other developing countries with high carbon emissions.

Pancreatic cancer is a common gastrointestinal tract malignancy. Currently, the therapeutic strategies for pancreatic cancers include surgery, radiotherapy, and chemotherapy; however, the surgical procedure is invasive, and the overall curative outcomes are poor. Furthermore, pancreatic cancers are usually asymptomatic during early stages and have a high degree of malignancy, along with a high rate of recurrence and metastasis, thereby increasing the risk of mortality. Studies have shown that ferroptosis regulates cell proliferation and tumour growth and reduces drug resistance. Hence, ferroptosis could play a role in preventing and treating cancers. Wogonin is a flavonoid with anticancer activity against various cancers, including pancreatic cancer. It is extracted from the root of Scutellaria baicalensis Georgi . In this study, we show that wogonin inhibits the survival and proliferation of human pancreatic cancer cell lines and induces cell death. We performed RNA-sequencing and analysed the differentially expressed gene and potential molecular mechanism to determine if wogonin reduced cell survival via ferroptosis. Our results showed that wogonin upregulates the levels of Fe 2+ , lipid peroxidation and superoxide and decreases the protein expression levels of ferroptosis suppressor genes, and downregulates level of glutathione in pancreatic cancer cells. In addition, ferroptosis inhibitors rescue the ferroptosis-related events induced by wogonin, thereby confirming the role of ferroptosis. A significant increase in ferroptosis-related events was observed after treatment with both wogonin and ferroptosis inducer. These results show that wogonin could significantly reduces pancreatic cancer cell proliferation and induce ferroptosis via the Nrf2/GPX4 axis. Therefore, wogonin could be potentially used for treating patients with pancreatic cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Peng, Cen, Yang, Ma and Shi.)

The disorder of amino acid metabolism and the abuse of small molecule drugs pose serious threats to public health. However, due to the limitations of existing detection technologies in sensing cinnamaldehyde (CAL) and l-Arginine/l-Lysine (l-Arg/l-Lys), there is an urgent need to develop new sensing strategies to meet the severe challenges currently facing. Herein, nitrogen-doped carbon dots (N-CDs) were developed using a simple one-pot hydrothermal carbonization method. These N-CDs exhibited numerous distinctive characteristics such as excellent photoluminescence, high water dispersibility, favorable biocompatibility, and superior chemical inertness. Strikingly, the as-prepared CDs as a highly efficient fluorescent probe possessed significant sensitivity and selectivity toward CAL and l-Arg/l-Lys over other analytes with a low detection limit of 58 nM and 16 nM/18 nM, respectively. The fluorescence of N-CDs could be quenched by CAL through an electron transfer process. Then, the strong electrostatic interaction between l-Arg/l-Lys and N-CDs induced the efficient fluorescence recovery. More importantly, the outstanding biosafety and excellent analyte-responsive fluorescence characteristics of N-CDs have also been verified in living cells as well as in serum and urine. Overall, the N-CDs had a wide application prospect in the diagnosis of amino acid metabolic diseases and small molecule drug sensing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Dopamine hydrochloride (DH) and D-Glutamic acid (D-Glu) are important excitatory neurotransmitters, which are closely relative to central nervous system diseases. Therefore, it is critical to develop the sensitive and facile sensor to precisely monitor the changes of these neurotransmitters. Herein, the gadolinium-doped carbon dots (Gd-CDs) were synthesized by a low-cost and effortless one-pot solvothermal method. These CDs exhibited rapid and reliable fluorescent and colorimetric response signals towards DH and D-Glu. Interestingly, the fluorescence of Gd-CDs could be selectively quenched by DH owing to the fact that the Gd-CDs could coordinate with phenolic hydroxyl groups of DH. Moreover, the quench process was effectively inhibited because the D-Glu competitively coordinated with Gd-CDs-DH system to form a more stable complex. In fluorescence mode, the designed fluorescence sensor possessed an excellent linear relationship for DH in the range from 1 to 10 μM with a low detection limit of 1.26 nM, and the fluorescence could be selectively recovered by D-Glu. In colorimetric manner, DH and D-Glu could be detected by UV-Vis absorption spectrum in the range of 1-15 μM and 1-1.50 mM, respectively. Moreover, the proposed method could not only easily monitor the DH and D-Glu in aqueous solutions as well as mouse serum and human urine samples, but also be employed for detecting DH and D-Glu in cells. Fortunately, the fluorescent and colorimetric dual readout AND logic operation was successfully demonstrated in all-aqueous media. Accordingly, the prepared Gd-CDs hold the potential to become a promising nano-sensor for DH and D-Glu sensing in disease diagnosis areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Saponins are an important class of surface-active substances. When formulated as an active ingredient or co-used with other drugs, the effect of their surface activity on efficacy or safety must be considered. In this paper, diammonium glycyrrhizinate (DG), a clinical hepatoprotective drug that has long been used as a biosurfactant, was taken as the research object to study its combined hepatoprotective effect with baicalin (BAI). Animal experiments proved that the preparation of DG and BAI integrated into micelles (BAI-DG Ms) had a better protective effect on acute liver injury caused by carbon tetrachloride than the direct combined use of the two. From the perspective of biopharmaceutics, the synergistic mechanism of BAI-DG Ms was further explored. The results showed that after forming BAI-DG Ms with DG, the solubility of BAI increased by 4.75 to 6.25 times, and the cumulative percentage release in the gastrointestinal tract also increased by 2.42 times. In addition, the negatively charged BAI-DG Ms were more likely to penetrate the mucus layer and be absorbed by endocytosis. These findings provide support for the rational application of glycyrrhizin, and other saponins.

Purpose: Children with cochlear implants (CIs) have less experience accessing spoken language. Mandarin Chinese uses pitch information to contrast word meaning, and the signal that the CI devices provide is degraded. Thus, Mandarin-speaking children with CIs may face more challenges in the development of language skills. This study examines preschool Mandarin-speaking children's performance in lexical access. We hypothesized that children with CIs and their peers with normal hearing (NH) have comparable naming ability, but they process phonological or semantic information differently., Method: Twenty children with CIs and 20 age-matched children with NH were tested. The cross-modal visual-auditory picture-word interference paradigm was applied. The distractor was either phonologically related ( mao 55 cat - mao 51 hat), semantically related ( mao 55 cat - shu 214 mouse) or unrelated ( mao 55 cat - zhi 214 paper) to the target, and it was aurally presented at four different points in time relative to the picture. Accuracy was compared between the two groups to tap into the children's naming abilities, and reaction time was analyzed to examine the effects of phonological and semantic information., Results: No group difference in accuracy was found. The phonologically related distractors led to significantly higher accuracy scores and shorter reaction times, whereas the semantically related distractors did not. Unlike the NH group, the CI group did not respond significantly faster or slower in phonologically related condition when the distractor and picture occurred simultaneously. Finally, the CI group made overall quicker responses than the NH group., Conclusions: Children with CIs are as successful as children with NH in word retrieval and production, and the two groups both show phonological priming effect and lack semantic effect. However, children with CIs do not process phonological information as early as their NH peers, and they may be more tasks directed and hence make quicker responses.

Aims: This study investigated the efficacy of Limosilactobacillus fermentum-fermented ginseng for improving colitis and the gut microbiota profiles in rats and explored the benefits of the L. fermentum fermentation process to ginseng., Methods and Results: Ginseng polysaccharide and ginsenoside from fermented ginseng were analysed by UV and HPLC. Antibiotic-fed rats were treated with fermented ginseng and a L. fermentum-ginseng mixture. Histopathology- and immune-related factors (TNF-α, IL-1β, IL-6 and IL-10) of the colon were assayed by using pathological sections and ELISA. After treatment, fermented ginseng relieved the symptoms of antibiotic-induced diarrhoea and colon inflammation, and the expression of colon immune factors returned to normal. The gut microbial communities were identified by 16S rRNA gene sequencing. The results showed that the alterations in the gut microbiota returned to normal. In addition, the gut microbiota changes were correlated with immune factor expression after treatment. The fermented ginseng had better biological functions than a L. fermentum-ginseng mixture., Conclusions: Fermented ginseng can relieve diarrhoea and colon inflammation and restore the gut microbiota to its original state. The process of L. fermentum fermentation can expand the therapeutic use of ginseng., Significance and Impact of the Study: This research suggested the potential function of fermented ginseng to relieve diarrhoea and recover the gut microbiota to a normal level and explored the benefits of the Limosilactobacillus fermentum fermentation process to ginseng., (© 2022 Society for Applied Microbiology.)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may progress to colorectal cancer in severe cases. Carnitine palmitoyltransferase-1A (CPT1A) has been reported to be upregulated in colorectal cancer. This paper aims to explore the role of CPT1A in UC and its pathogenesis. An in vivo mice model of UC was constructed by administrating 3% dextran sulfate sodium (DSS). The expression level of CPT1A was examined by quantitative real-time polymerase chain reaction and Western blot. The intestinal damage, inflammatory response and oxidative stress were assessed by hematoxylin and eosin staining, colon length, and commercial kits. Thereafter, an in vitro cell model of UC was established by stimulating HT-29 cells with 2% DSS. The peroxisome proliferator-activated receptor α (PPARα) signaling agonist GW7647 was used for treatment. Cell viability and apoptosis was assayed by cell counting kit-8 assay and terminal dUTP nick-end labeling assay, respectively. The inflammatory cytokines and oxidative stress-related factors was evaluated using corresponding commercial detection kits. In DSS-induced mice model of UC, CPT1A expression was upregulated. Interference of CPT1A attenuated histological damage, the disease activity index and colon length in colitis. We also found downregulation of CPT1A inhibited inflammatory response and oxidative stress, and inhibited PPARα signaling pathway in UC mice. Additionally, in DSS-induced HT-29 cells, downregulation of CPT1A promoted cell viability, reduced cell apoptosis, inflammatory response, and oxidative stress, which was partly abolished by additional treatment with GW7647. In summary, downregulation of CPT1A exerts a protective effect in DSS-induced UC partially through suppressing PPARα signaling, suggesting that CPT1A might be a potential target for the treatment of UC., (© 2022 Wiley Periodicals LLC.)

In this study, molecular dynamics simulation was applied to the construction of the small intestinal epithelial cell membrane and prediction of drug absorption. First, we constructed a system of a small intestinal epithelial cell membrane that was close to the real proportion and investigated the effects of temperature, water layer thickness, and ionic strength on membrane properties to optimize environmental parameters. Next, three drugs with different absorptivity, including Ephedrine (EPH), Quercetin (QUE), and Baicalin (BAI), were selected as model drugs to study the ability of drugs through the membrane by the free diffusion and umbrella sampling simulation, and the drug permeation ability was characterized by the free diffusion coefficient D and free energy barrier (△G) in the processes. The results showed that the free diffusion coefficient D and △G orders of the three drugs were consistent with the classical experimental absorption order, indicating that these two parameters could be used to jointly characterize the membrane permeability of the drugs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The occurrence and development of diabetic nephropathy (DN) are closely related to gut microbiota. Paecilomyces cicadae is a medicinal and edible fungus. Radix astragali is a therapeutic material for unifying Chinese Qi. They can delay the occurrence and development of kidney disease. In recent years, solid-state fermentation of edible fungi and traditional Chinese medicine has become a hot issue. Hypothesis/Gap Statement. We assumed that solid-state fermentation products of R. astragali and Paecilomyces cicadidae (RPF) could ameliorate diabetic nephropathy and modulate gut microbiota composition. We aimed to study the function and mechanism of the RPF for ameliorating DN in mice. We investigated the effect of the potential roles of RPF in DN mice and interaction between DN and gut microbiota using animal experiments and gut microbiota measurements. We found that RPF dramatically reduced urine protein, serum creatinine and blood urea nitrogen in DN mice. Furthermore, RPF ameliorated the physiological condition of DN mice by regulating the abundance of intestinal microbiota such as Ruminococcaceae&#95;UCG-014 , Allobaculum , Unclassified&#95;f&#95;&#95;Lachnospiraceae Alloprevotella and Bacteroides . RPF can ameliorate diabetic nephropathy and modulate gut microbiota composition.

Formulation design and mechanism study of the drug delivery system (DDS) is an important but difficult subject in pharmaceutical research. The study of formulation factors is the most time- and labor-consuming work of formulation design. In this paper, a multiscale computational pharmaceutics strategy was developed to guide the systematic study of formulation factors of a typical polymer-based DDS, hydrogel, and further to guide the formulation design. According to the strategy, the combination of solubility parameter (δ) and diffusion coefficient (D) calculated by the AA-MD simulation was suggested as the general evaluation method for the matrix screening of the hydrogels at the pre-formulation stage. At the formulation design stage, the CG-MD simulation method was suggested to predict the morphology and drug-releasing behavior of the hydrogels under different formulation factors. The influence mechanism can be explained by the combination of multiple parameters, such as the microstructure diagram, the radius of gyration (Rg), the radial distribution function (RDF), and the free diffusion volume (V diffusion ). The simulation results are in good agreement with the in vitro release experiment, indicating that the strategy has good applicability., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ferroptosis is an iron-dependent programmed cell death process. Although ferroptosis inducers hold promising potential in the treatment of breast cancer, the specific role and mechanism of the ferroptosis-related gene EMC2 in breast cancer have not been entirely determined. The potential roles of EMC2 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Tumor Immune Estimation Resource (TIMER), Shiny Methylation Analysis Resource Tool (SMART), starBase, and cBioPortal for cancer genomics (cBioPortal) datasets. The expression difference, mutation, survival, pathological stage, DNA methylation, non-coding RNAs (ncRNAs), and immune cell infiltration related to EMC2 were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify the differences in biological processes and functions among different related genes. The expression levels of core prognostic genes were then verified in breast invasive carcinoma samples using immunohistochemistry and breast invasive carcinoma cell lines using real-time polymerase chain reaction. High expression levels of EMC2 were observed in most cancer types. EMC2 expression in breast cancer tissue samples correlated with poor overall survival. EMC2 was mutated and methylated in a variety of tumors and affected survival. The LINC00665-miR-410-3p axis was identified as the most potential upstream ncRNA-related pathway of EMC2 in breast cancer. EMC2 levels were significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. Our study offers a comprehensive understanding of the oncogenic roles of EMC2 across different tumors. The upregulation of EMC2 expression mediated by ncRNAs is related to poor prognosis and tumor immune infiltration in breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Yang, Han, Zhou, Qu and Shi.)

Background: Gastric cancer is a common gastrointestinal cancer and currently has the third-highest mortality rate. Research shows that the natural compound narciclasine has a variety of biological activities. The present study aimed to investigate the effect of narciclasine on gastric cancer cells and its molecular mechanisms and determine whether this compound could be a novel therapy for gastric cancer., Methods: MTT and clone assays were employed to detect the proliferation of gastric cancer cells. The cell apoptosis was detected by flow cytometry. The formation of autophagosomes and autophagosomal lysosomes was observed by transmission electron microscopy and laser confocal scanning microscopy. Western blotting was used to detect the expression of apoptosis, autophagy and Akt/mTOR pathway-related proteins., Results: In this study, we found that narciclasine could inhibit the proliferation of gastric cancer cells and promote apoptosis in gastric cancer cells. Further experiments showed that narciclasine promoted the levels of autophagy proteins LC3-II, Atg-5 and Beclin-1, reduced the expression of the autophagy transporter p62, and increased autophagic flux. By using the autophagy inhibitors 3-MA and CQ, it was shown that narciclasine could induce autophagy-mediated apoptosis in gastric cancer cells. Finally, we found that narciclasine had no significant effects on the total content of Akt and mTOR in gastric cancer cells, and it involved autophagy in gastric cancer cells by reducing the phosphorylation level of p-Akt and p-mTOR., Conclusions: Narciclasine can induce autophagy-dependent apoptosis in gastric cancer cells by inhibiting the phosphorylation level of Akt/mTOR and thus reduce the proliferation of gastric cancer cells., (© 2021. The Author(s).)

Ethnopharmacological Relevance: Ginseng (Panax ginseng Meyer) is rich in a variety of biologically active ingredients, which shows good effect in the treatment of metabolic diseases. Monascus has lipid-lowering activity and one of its metabolites, lovastatin, is widely used in clinical practice., Aim of the Study: The main purpose of this study was to clarify the effects of fermented Panax ginseng by Monascus ruber (PM) on lipid metabolism and gut microbiota in rats fed a high-fat diet., Materials and Methods: SPF Sprague-Dawley rats were randomly divided into 5 groups, the therapeutic effect of PM on HFD-induced obesity, hyperlipidemia, hepatic steatosis, and disordered gut microbiota were determined in rats., Results: PM could attenuate features of obesity in rats, decrease serum TC, LDL-C and IgA levels, increase excretion of bile acids in feces. Hepatic histopathologic analysis revealed that PM decrease lipid accumulation in hepatocytes. Consistently, mRNA expression levels of cholesterol metabolism-related genes were regulated in the livers of HFD-fed rats administered with PM. In addition, PM could enhance the diversity and relative abundance of gut microbiota, reduce the Firmicutes/Bacteroidetes (F/B) ratio, increase significantly the relative abundance of Prevotella&#95;9, and decrease these of Muribaculaceae., Conclusions: PM could regulate lipid metabolism and the structure of the gut microbiota in the HFD rats. Our findings provide valuable experience for the development of ginseng. PM could be a potentially effective strategy to prevent and treat metabolic diseases and alleviate the gut microbiota disturbance caused by it., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Saponins are a group of compounds widely distributed in the plant kingdom. Due to their amphiphilic characteristic structure, saponins have high surface activity and self-assembly property and can be used as natural biosurfactants. Therefore, saponin has become a potential drug delivery system (DDS) carrier and has attracted the attention of many researchers. Increasing studies have found that when drugs combining with saponins, their solubility or bioavailability are improved. This phenomenon may be due to a synergistic mechanism and provides a potentially novel concept for DDS: saponins may be also used for carrier materials. This review emphasized the molecular characteristics and mechanism of saponins as carriers and the research on the morphology of saponin carriers. Besides, the article also introduced the role and application of saponins in DDS. Although there are still some limitations with the application of saponins such as cost, applicability, and hemolysis, the development of technology and in-depth molecular mechanism research will provide saponins with greater application prospects as DDS carriers., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this study, liposome and transfersome were successfully constructed using molecular dynamics simulation. Three drugs with different polarity, including 5-fluorouracil, ligustrazine, and osthole, were selected as model drugs to study the distribution of drugs in lipid vesicles by calculating the radial distribution function and the potential of mean force. The solubility parameters between drugs and different regions in lipid vesicles were calculated to characterize the compatibility of drugs in different regions in lipid vesicles, which provided the basis for the conclusion of this paper. It showed that the radial distribution function and the potential of mean force were consistent in the characterization of drug distribution in vesicles, and the drug distribution in vesicles was closely related to the compatibility between drugs and vesicles. Therefore, the radial distribution function and the potential of mean force can be used to characterize the distribution of drugs in vesicles, and molecular simulation technology has a great potential in studying the characteristics of vesicles. Graphical abstract.

Ethnopharmacological Relevance: Ginseng (Panax ginseng Meyer) is a well-known herb in traditional Chinese medicine and has been used to treat many diseases for thousands of years. Recent studies have shown that ginseng is a promising agent for improving the gut microbiota and treating ulcerative colitis. Fermentation is a common process in traditional Chinese medicine making that can be used to enhance efficacy and reduce toxicity., Aim of the Study: The purpose of the present study was to research the efficacy of ginseng fermented with probiotics (Lactobacillus fermentum) on the gut microbiota and immunity of rats with antibiotic-associated diarrhea (AAD)., Materials and Methods: SPF Sprague-Dawley rats were randomly divided into eight groups: control group, antibiotic group, natural recovery group, and five groups treated with different doses of fermented ginseng (FG1 to FG5). A model of AAD was established by treating the rats with triple antibiotics, and obvious symptoms of AAD were observed. A histopathological analysis of the colon was performed. The total bacteria in the intestinal microbiota and five types of gut microbes in the feces were detected by quantitative PCR. The expression levels of related immune factors TLR4 and NF-κB in the colon were assayed., Results: An appropriate dose of fermented ginseng (0.5 g/kg/d) relieved some of the symptoms of AAD and colon inflammation and reduced the expression of the immune factors TLR4 and NF-κB in the colon. The alteration of the gut microbiota observed in the rats treated with antibiotics also returned to normal after treatment with fermented ginseng. Moreover, different doses of fermented ginseng exerted different influences on the gut microbiota, and excessively high or low doses of fermented ginseng were disadvantageous for resolving the symptoms of AAD and promoting recovery., Conclusions: These results demonstrate that fermented ginseng can treat AAD symptoms and colon inflammation and restore the gut microbiota to its original state., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ginseng ( Panax ginseng C. A. Meyer ) is a famous Traditional Chinese Medicine, which is widely used to treat cardiovascular disease. Monascus ruber ( M. ruber ) is a fungus used in food and medicine fermentation, and lovastatin, its metabolite, is used extensively in the treatment of dyslipidemia. In this study, ginseng has been fermented by M. ruber , and the response surface methodology (RSM) was applied to optimize fermentation parameters to obtain optimal fermentation system, with further exploring to lipid-lowering activity of P. ginseng C. A. Meyer - M. ruber fermentation products (PM). The concentration of ginseng, temperature, and rotating speed were set as variables and the lovastatin yield was optimized by a Box-Behnken design (BBD) analyzed by RSM. The binding capacity of PM for sodium taurocholate and sodium cholate was assayed by UV spectrophotometry. The highest content of lovastatin production (85.53 μg g -1 ) was obtained at a ginseng concentration of 1.96%, temperature of 30.11 °C, and a rotating speed of 160.47 rpm. PM exhibited bile acid binding capacity, which was stronger than unfermented ginseng. The RSM can be used to optimize the fermentation system to obtain the best fermentation process. In addition, the fermentation of ginseng by M. ruber can enhance the lipid-lowering effect.

Radix astragali, a medicinal material for tonifying Chinese Qi, has widely been used for the treatment of Kidney disease in China and East Asia, especially in reducing the apoptosis of glomerular podocytes. Paecilomyces Cicadidae is a medicinal and edible fungus. In recent years, the application of traditional Chinese medicine (TCM) in solid-state fermentation of edible and medicinal fungi has become a hot issue. Fermentation is a special method to change the properties of TCM. Therefore, the potential roles and molecular mechanisms on podocytes of solid-state fermentation products of Radix astragali and Paecilomyces cicadidae (RPF) in diabetic nephropathy (DN) were studied. In vivo, the effect of RPF and Radix astragali on DN in mice was evaluated by detecting the biochemical indexes of blood and urine, renal function and podocyte integrity. In vitro, the expression of podocyte marker protein, autophagy marker protein and PI3K/AKT/mTOR signaling pathway protein were detected by Western blotting using a high glucose-induced podocyte injury model. The results showed that RPF had a significant alleviative effect on DN mice. RPF can significantly reduce urine protein, serum creatinine, and blood nitrogen urea in DN mice. Morphological analysis showed that RPF could improve kidney structure of DN and reduce the apoptosis of podocytes, and the effect was better than Radix astragali. In vitro results indicated that RPF could enhance autophagy and protect podocytes by inhibiting the PI3K/AKT/mTOR signaling pathway. In summary, RPF has better effect on delaying the development of DN than Radix astragali. RPF enhances autophagy in podocytes and delays DN probably by inhibiting the PI3K/AKT/mTOR signaling pathway., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Qu-feng-sheng-shi Granules (QFSSG), a common prescription for the treatment of chronic inflammation and allergic rhinitis, is widely used in the clinic as a traditional Chinese medicine. Chemical analysis and quality control studies of this formulation are relatively limited compared with pharmacological studies. In this study, a high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q/TOF-MS n ) was used to identify the components in this prescription. Next, to quantify six major compounds, an HPLC-UV method was developed and validated. The results showed that 53 compounds were identified based on the MS n data, retention time and previous reports, including 17 coumarins, 14 lignans, 10 chromones, nine phenylethanoid glycosides and three other compounds, were identified or tentatively assigned. Contents of six major bioactive compounds (4'-O-β-glucopyranosyl-5-O-methylvisamminol, Prim-O-glucosylcimifugin, forsythin, magnolin, imperatorin, isoimperatorin) could be determined by HPLC simultaneously. In addition, the potential anti-inflammatory activity of six major compounds was determined too, and we found that four compounds (4'-O-β-glucopyranosyl-5-O-methylvisamminol, Prim-O-glucosylcimifugin, forsythin, imperatorin) have a potent nitric oxide inhibitory effect. In conclusion, this work provided comprehensive information on the quality control of QFSSG and evaluated the potential biological activity of the main components in QFSSG, which can contribute to understanding and using it more scientifically., (© 2020 John Wiley & Sons, Ltd.)

Physical stability is one of critical characteristics of liposome, especially to its clinical application. Vesicle fusion was one of the common physical stability phenomena that occurred during the long storage period. Because vesicle fusion could be easily checked by the change of vesicle size, it was widely applied in the evaluation of liposome physical stability. However, since the method requires the liposome to be placed under certain conditions for long-term observation, a liposome physical stability test usually takes several weeks, which greatly hinders the research efficiency. In this study, to speed up the research efficiency, coarse-grained molecular dynamics was first applied in the study of liposome physical stability. By analyzing the microprocess of vesicle fusion, two parameters including diffusion constant and the total time of the vesicle morphology transition process were employed to study the liposome physical stability. Then, in order to verify the applicability of two parameters, the physical stability of elastic liposomes and conventional liposomes was compared at 3 different temperatures. It was found that the fusion probability and speed of elastic liposomes were higher than those of conventional liposomes. Thus, elastic liposomes showed a worse physical stability compared with that of conventional liposomes, which was consistent with former research. Through this research, a new efficient method based on coarse-grained molecular dynamics was proposed for the study of liposome physical stability.

D-borneolum is commonly used as a permeation enhancer in Traditional Chinese Medicine (TCM) formulas for transdermal application. Additionally, two other sources of borneolums were recorded in the 2015 edition of the Chinese Pharmacopoeia (ChP), including L-borneolum and borneolum syntheticum. To guide the selection and application of borneolum, the safety and enhancing effect of three sources of borneolums were investigated on transdermal permeation of compounds with different octanol-water partition coefficient (log P) values and molecular weights (MWs). Both the results of cellular cytotoxicity and in vitro transdermal permeation experiments showed that all three sources of borneolums could be applied in TDDS as permeation enhancers. Moreover, all three sources of borneolums achieved optimal permeation-enhancing performances on transdermal drugs with lower log P values as well as higher MWs. Further study was carried out to elucidate the potential molecular mechanism of borneolum enhancing transdermal drug delivery via transmission electron microscope (TEM) and coarse-grained molecular dynamic (CG-MD) simulation. Borneolum significantly promoted transdermal delivery of drugs via changing the dense morphology of the stratum corneum (SC), disturbing the ordered arrangement of ceramide (CER) and free fatty acid (FFA) molecules in lipid layers, and further increasing the diffusion rate of drugs in the lipid layers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this paper, a compression behavior classification system (CBCS) for direct compression (DC) pharmaceutical powders is presented. Seven descriptors from a series of compression models for powder compressibility, compactibility and tabletability analysis were included in the CBCS. A new tabletability index d was proposed to differentiate three categories of tensile strength (TS) vs. pressure relationships, and its physical meaning was explained thoroughly. 130 materials containing diverse pharmaceutical excipients and natural product powders (NPPs) were fully characterized and were compiled into an in-house developed material library, in which 70 materials with potential DC applications were used to justify the effectiveness of the CBCS. Principle component analysis (PCA) was used to uncover the latent structure of compression variables. Moreover, partial least squares (PLS) regression models are established in prediction of both tablet TS and solid fraction (SF) based on the raw materials' physical characteristics, the compression behavior indices and the compression force. The obtained scores and loadings are used to group the materials and the compression variables, respectively. Different categories of tabletability for DC powders were clearly clustered along two orthogonal directions pointing to the index d and the compression force. Finally, a multi-objective design space was identified under the latent variable space, summarizing the operationally possible region for both material properties and compression pressure required in DC tablet formulation design., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Transfersomes (TRS) can provide sustained drug delivery and themselves are biocompatible, biodegradable and nontoxic. Edge activators (EAs) are key factors for increasing the deformability of TRS, and this active deformation mechanism is of commercial interest, especially at the molecular level. Accordingly, in this paper, the deformability of pure dipalmitoyl phosphatidylcholine (DPPC) vesicles, TRS with sodium cholate as an EA, and DPPC vesicles containing pogostone (POG) were compared via umbrella sampling technology. The DPPC conformation and membrane fluidity of these three types of bilayer systems were evaluated, and the changes in the membrane properties of vesicles caused by EAs were studied. EAs could increase the deformability of TRS by decreasing the deformation energy barrier due to their amphiphilic structures, which was similar to those of DPPC molecules. The membrane properties also changed via treatment with EAs including altering the tail chain angle, disturbing the ordered tail chain arrangement and prompting lateral diffusion of DPPC molecules. In addition, the impact of EAs on DPPC bilayers was further demonstrated to be concentration dependent. An ideal concentration was identified for the lowest amount of EA that offered a gel-liquid-crystalline phase transition of DPPC bilayers. Importantly, POG, a lipophobic transdermal drug, can also affect the skin permeation behavior of vesicles but had weaker effects than EA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Elastic liposoxy1mes (ELs) are biocompatible bilayer vesicular systems commonly used in the transdermal delivery of drugs. Compared with conventional liposomes (CLs), the strong deformation ability conferred by edge activators (EAs) is one of the most critical properties of ELs. However, due to limited research methods, little is known about the effect of EAs on the deformation abilities of vesicles. In this study, taking sodium cholate as an example, a multiscale study was carried to study the effect of EAs on the deformability of ELs, including in vitro diffusion experiment at macroscale, "vesicle-pore" model experiment at the microscale and flat patch model experiment at the molecular scale. As a result, it was found that sodium cholate could decrease the kc of DPPC bilayer, which enabled it to remain morphologically intact during a strong deformation process. Such kind of differences on deformation ability made pogostone ELs (contain sodium cholate) present a better permeation effect compared with that of pogostone CLs. All of these provide a multiscale and thorough understanding of the effect of sodium cholate on the deformation ability of ELs.

In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.

Cordyceps cicadae (Chanhua) is a parasitic fungus that grows on Cicada flammata larvae and is used to relieve exhaustion and treat numerous diseases, in part through its active constituent, cordycepin. We used de novo Illumina HiSeq 4000 sequencing to obtain transcriptomes of C. cicadae mycelium, fruiting body, and sclerotium, and identify differentially expressed genes. In the mycelium versus sclerotium libraries, 1576 upregulated and 2300 downregulated genes were identified. In the mycelium versus fruiting body and fruiting body versus sclerotium body libraries, 1604 and 1474 upregulated and 1365 and 1320 downregulated genes, respectively, were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified 19 genes differentially expressed in mycelium versus fruiting body as related to the purine pathway, along with 28 and 16 genes differentially expressed in the mycelium versus sclerotium and fruiting body versus sclerotium groups, respectively. Gene expression of six key enzymes was validated by quantitative polymerase chain reaction. Specifically, 5'-nucleotidase (c62060g1) and adenosine deaminase (c35629g1) in purine nucleotide metabolism, which are involved in cordycepin biosynthesis, were significantly upregulated in the sclerotium group. These findings improved our understanding of genes involved in the biosynthesis of cordycepin and other characteristic secondary metabolites in C. cicadae ., Competing Interests: The authors declare no competing interests.

The purpose of this study was to describe the raw material variability that influenced the in-vitro dissolution behavior of high drug-load sustained-release matrix tablet and to ensure the consistent quality of the final product. The Panax notoginseng saponins (PNS) - hydroxypropyl methylcellulose - anhydrous lactose - magnesium stearate (57:20:23:0.5%, w/w) was used as the model formulation. PNS extract powders with lot-to-lot and source-to-source differences were collected to cover the common cause variations and their physicochemical properties were characterized by the chromatographic fingerprints and the SeDeM expert system. It was found that the release behavior of active pharmaceutical ingredients (APIs) in PNS from different batches exhibited considerable variations. Latent variable modeling results demonstrated that the physical properties of raw materials played major roles in predicting the drug dissolution. PNS extracts with high specific surface area, the width of particle size distribution and hygroscopicity or low moisture content led to an increase in drug release. In order to perform efficient pass/fail judgments for incoming new materials, multivariate specifications of critical material attributes (CMAs) were established and the multivariate design space in line with the quality by design (QbD) principles was explored to achieve the release target.

In general, data fusion can improve the classification performance of the model, but little attention is paid to the influence of the data fusion on the spatial distribution of the modeling samples. In this paper, the effect of data fusion on sample spatial distribution was studied through integrating NIR data and UHPLC-HRMS data for sulfur-fumigated Chinese herb medicine. Twelve samples collected from four different geographical origins were sulfur fumigated in the lab, and then metabolomics analysis was conducted using NIR and UHPLC-LTQ-Orbitrap mass spectrometer. First of all, the discriminating power of each technique was respectively examined based on PCA analysis. Secondly, combining NIR and UHPLC-HRMS data sets together with or without variable selection was parallelly compared. The results demonstrated that the discriminable ability was remarkably improved after data fusion, indicating data fusion could visualize variable selection and enhance group separation. Samples in the margin between two classes of samples may increase the experience error but has positive effect on the separation direction. Besides, an interesting feature extraction could obtain better discriminable effect than common data fusion. This study firstly provided a new path to employ a comprehensive analytical approach for discriminating SF Chinese herb medicines to simultaneously benefit from the advantages of several technologies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Borneol (BO) and menthol (MEN) are two widely used natural permeation enhancers in the transdermal drug delivery system. In previous studies, their permeation enhancement effects and mechanisms of action on the hydrophobic drug osthole (logP = 3.8) and hydrophilic drug 5-fluorouracil (logP = -0.9) have been studied. In this study, ligustrazine (LTZ), whose logP is 1.3, was used as a model drug to provide a comprehensive understanding of the influence of its logP on the permeation-enhancing effects of BO and MEN. Both BO and MEN enhanced the permeation of LTZ through the skin stratum corneum, as determined using the modified Franz diffusion cell experiment. The enhancement mechanisms were illustrated by coarse-grained molecular dynamics simulations as follows: at low concentrations, the enhancing ratio of MEN was higher than that of BO because of the stronger perturbation effects of MEN on the lipid bilayer, making it looser and facilitating LTZ diffusion. However, at high concentrations, in addition to the diffusion mechanism, BO induced the formation of water channels to improve the permeation of LTZ; however, MEN had no significant effects through this mechanism. Their results were different from those found with osthole and 5-fluorouracil and have been discussed in this study., (© 2018 John Wiley & Sons A/S.)

Background: The bi-directional solid fermentation product extract of Trametes robiniophila Murr (Huaier) with Radix Isatidis (TIF) has been shown to have good anti-tumor activity. However, the mechanisms of this activity are still unknown. In the present study, we aimed to investigate its inhibitory effect on both SK-BR-3 and MDA-MB-231 cells, and explore the possible mechanisms of its anti-cancer effect in vitro., Methods: The experiment comprised a control group, Radix Isatidis group, Huaier group, and TIF group. The cell viability was measured by MTT and the distribution of cell cycle and apoptosis levels were analyzed by flow cytometry. Cell scratch, Transwell, and adhesion assays were used to measure the effects of the test compounds on the migration, invasion, and adhesion capability of SK-BR-3 and MDA-MB-231 cells. The effects of TIF on the mRNA and protein expression related to apoptosis and migration were measured by using semi-quantitative RT-PCR and western blotting., Results: TIF strongly inhibited the cell proliferation of the SK-BR-3 and MDA-MB-231 cells in a time-dependent manner and induced G2/M arrest and apoptosis. Furthermore, TIF significantly inhibited the proliferation, migration, invasion, and adhesion capabilities of SK-BR-3 and MDA-MB-231 cells. Compared with other treatments, the anticancer effect of TIF were stronger in MDA-MB-231 cells. Semi-quantitative RT-PCR suggested that TIF may upregulate the expression of p53 and caspase-3 to inhibit cell proliferation, and downregulate the expression of MMP-9/Snail and MMP-9/MMP-2 to inhibit the migration, invasion, and adhesion capabilities of SK-BR-3 and MDA-MB-231 cells. Western blotting results showed that TIF increased the expression of p53 protein and decreased the expression of MMP-9 protein in SK-BR-3 and MDA-MB-231 cells., Conclusion: The results indicated that the bi-directional solid fermentation may enhance the efficacy of Huaier in MDA-MB-231 cells and that TIF may be an effective complementary medicine for cancer treatment., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

Xylanases (EC 3.2.1.8) are a kind of enzymes degrading xylan to xylooligosaccharides (XOS) and have been widely used in a variety of industrial applications. Among them, xylanases from thermophilic microorganisms have distinct advantages in industries that require high temperature conditions. The CoXynA gene, encoding a glycoside hydrolase (GH) family 10 xylanase, was identified from thermophilic Caldicellulosiruptor owensensis and was overexpressed in Escherichia coli. Recombinant CoXynA showed optimal activity at 90 °C with a half-life of about 1 h at 80 °C and exhibited highest activity at pH 7.0. The activity of CoXynA activity was affected by a variety of cations. CoXynA showed distinct substrate specificities for beechwood xylan and birchwood xylan. The crystal structure of CoXynA was solved and a molecular dynamics simulation of CoXynA was performed. The relatively high thermostability of CoXynA was proposed to be due to the increased overall protein rigidity resulting from the reduced length and fluctuation of Loop 7.

Borneol and menthol are terpenes that are widely used as penetration enhancers in transdermal drug delivery. To explore their penetration-enhancement effects on hydrophilic drugs, 5-fluorouracil (5-FU) was selected as a model drug. An approach that combined in vitro permeation studies and coarse-grained molecular dynamics was used to investigate their penetration-enhancement effect on 5-FU. The results showed that although both borneol and menthol imparted penetration-enhancement effects on 5-FU, these differed in terms of their mechanism, which may account for the observed variations in penetration-enhancement effects. The main mechanism of action of menthol involves the disruption of the stratum corneum (SC) bilayer, whereas borneol involves multiple mechanisms, including the disruption of the SC bilayer, increasing the diffusion coefficient of 5-FU, and inducing the formation of transient pores. The findings of the present study improve our understanding of the molecular mechanism that is underlying 5-FU penetration-enhancement by borneol and menthol, which may be utilized in future investigations and applications., Competing Interests: The authors declare no conflict of interest.

A rapid and sensitive approach to differentiate sulfur-fumigated (SF) Ophiopogonis Radix based on Multi-Omics Correlation Analysis (MOCA) strategy was first established. It was characterized by multiple data-acquisition methods (NIR, HPLC, and UHPLC-HRMS) based metabonomics and multivariate statistical analysis methods. As a result, SF and non-sulfur fumigated (NSF) Ophiopogonis Radix samples were efficaciously discriminated. Moreover, based on the acquired HRMS data, 38 sulfur-containing discriminatory markers were eventually characterized, whose NIR absorption could be in close correlation with the discriminatory NIR wavebands (5000-5200 cm -1 ) screened by NIR metabonomics coupled with SiPLS and 2D-COS methods. This results were also validated from multiple perspectives, including metabonomics analysis based on the discriminatory markers and the simulation of SF ophiopogonin D and Ophiopogonis Radix sample. In conclusion, our results first revealed the intrinsic mechanism of discriminatory NIR wavebands by means of UHPLC-HRMS analysis. Meanwhile, the established MOCA strategy also provided a promising NIR based differential method for SF Ophiopogonis Radix, which could be exemplary for future researches on rapid discrimination of other SF Chinese herbal medicines.

The influence of temperature on the transdermal permeation enhancing mechanism of borneol (BO) was investigated using a multi-scale method, containing a coarse-grained molecular dynamic (CG-MD) simulation, an in vitro permeation experiment, and a transmission electron microscope (TEM) study. The results showed that BO has the potential to be used as a transdermal penetration enhancer to help osthole (OST) penetrate into the bilayer. With the increasing temperature, the stratum corneum (SC) becomes more flexible, proving to be synergistic with the permeation enhancement of BO, and the lag time ( T Lag ) of BO and OST are shortened. However, when the temperature increased too much, with the effect of BO, the structure of SC was destroyed; for example, a water pore was formed and the micelle reversed. Though there were a number of drugs coming into the SC, the normal bilayer structure was absent. In addition, through comparing the simulation, in vitro experiment, and TEM study, we concluded that the computer simulation provided some visually detailed information, and the method plays an important role in related studies of permeation., Competing Interests: The authors declare no conflict of interest.

This study presented a new strategy of overall uncertainty measurement for near infrared (NIR) quantitative analysis of cryptotanshinone in tanshinone extract powders. The overall uncertainty of NIR analysis from validation data of precision, trueness and robustness study was fully investigated and discussed. Quality by design (QbD) elements, such as risk assessment and design of experiment (DOE) were utilized to organize the validation data. An "I×J×K" (series I, the number of repetitions J and level of concentrations K) full factorial design was used to calculate uncertainty from the precision and trueness data. And a 2(7-4) Plackett-Burmann matrix with four different influence factors resulted from the failure mode and effect analysis (FMEA) analysis was adapted for the robustness study. The overall uncertainty profile was introduced as a graphical decision making tool to evaluate the validity of NIR method over the predefined concentration range. In comparison with the T. Saffaj's method (Analyst, 2013, 138, 4677.) for overall uncertainty assessment, the proposed approach gave almost the same results, demonstrating that the proposed method was reasonable and valid. Moreover, the proposed method can help identify critical factors that influence the NIR prediction performance, which could be used for further optimization of the NIR analytical procedures in routine use., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The dissolution is one of the critical quality attributes (CQAs) of oral solid dosage forms because it relates to the absorption of drug. In this paper, the influence of raw materials, granules and process parameters on the dissolution of paracetamol tablet was analyzed using latent variable modeling methods. The variability in raw materials and granules was understood based on the principle component analysis (PCA), respectively. A multi-block partial least squares (MBPLS) model was used to determine the critical factors affecting the dissolution. The results showed that the binder amount, the post granulation time, the API content in granule, the fill depth and the punch tip separation distance were the critical factors with variable importance in the projection (VIP) values larger than 1. The importance of each unit of the whole process was also ranked using the block importance in the projection (BIP) index. It was concluded that latent variable models (LVMs) were very useful tools to extract information from the available data and improve the understanding on dissolution behavior of paracetamol tablet. The obtained LVMs were also helpful to propose the process design space and to design control strategies in the further research.

Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. However, details of the penetration enhancement mechanism of menthol on the molecular level is rarely involved in the discussion. In this work, the penetration enhancement (PE) mechanism of menthol is explored by a multiscale method containing molecular dynamics simulations, in vitro penetration experiments, and transmission electron microscopy. Osthole is chosen to be the tested drug due to its common use in external preparations and because it often accompanies menthol as a PE in the preparations. The results show that menthol in each testing concentration can impair the lipid packing of stratum corneum (SC) and promote osthole permeating into SC, and the penetration promoting effect has an optimal concentration. At a low concentration, menthol causes the bilayer to relax with a reduction in thickness and increment in the lipid headgroup area. At a high concentration, menthol destroys the bilayer structure of SC and causes lipids to form a reversed micelle structure. The penetration enhancement mechanism of menthol is characterized mainly by the disruption of the highly ordered SC lipid in low concentrations and an improvement in the partitioning of drugs into the SC in high concentrations. The results can provide some assistance for additional studies and applications of menthol as a penetration enhancer.

The quality of Chinese herbal medicine tablets suffers from batch-to-batch variability due to a lack of manufacturing process understanding. In this paper, the Panax notoginseng saponins (PNS) immediate release tablet was taken as the research subject. By defining the dissolution of five active pharmaceutical ingredients and the tablet tensile strength as critical quality attributes (CQAs), influences of both the manipulated process parameters introduced by an orthogonal experiment design and the intermediate granules' properties on the CQAs were fully investigated by different chemometric methods, such as the partial least squares, the orthogonal projection to latent structures, and the multiblock partial least squares (MBPLS). By analyzing the loadings plots and variable importance in the projection indexes, the granule particle sizes and the minimal punch tip separation distance in tableting were identified as critical process parameters. Additionally, the MBPLS model suggested that the lubrication time in the final blending was also important in predicting tablet quality attributes. From the calculated block importance in the projection indexes, the tableting unit was confirmed to be the critical process unit of the manufacturing line. The results demonstrated that the combinatorial use of different multivariate modeling methods could help in understanding the complex process relationships as a whole. The output of this study can then be used to define a control strategy to improve the quality of the PNS immediate release tablet., Competing Interests: The authors report no conflicts of interest in this work.