Key Active Components Research Articles

Exploration of the potential mechanism of Banxia Xiexin Decoction for the effects on TNBS-induced ulcerative colitis rats with the assistance of network pharmacology analysis

Ethnopharmacological relevanceBanxia Xiexin Decoction (BXD), an ancient TCM prescription originating from Treatise on Febrile Diseases (Shang Han Lun) of the Han Dynasty, has been widely used in modern clinical practice, especially for gastrointestinal diseases, including ulcerative colitis (UC). However, the modern decoction method of BXD differs from that of the original method. Thus, an exploration of the influence of the different decoction methods on the pharmacological effects is interesting and significant. Aim of the studyThis study aimed to systematically compare the pharmacological effects of extracts of BXD on TNBS induce UC rats that were prepared by different methods, the ancient method and the modern method. The findings may provide important information for the further mechanical exploration of the classical prescription, contributing to the rational application and enhancing the understanding of BXD in modern applications or scientific research. MethodsFifty-four SD rats were randomly divided into the following nine groups at n = 6/group: control group; model group; salicylazosulfapyridine group; BXD ancient extraction method's low-dose group (BXD-AED-L, 3.6 g BXD-AED/kg), medium-dose group (BXD-AED-M, 7.2 g BXD-AED/kg), and high-dose group (BXD-AED-H, 14.4 g BXD-AED/kg); and BXD modern extraction method's low-dose group (BXD-MED-L, 1 g BXD-MED/kg), medium-dose group (BXD-MED-M, 2 g BXD-MED/kg), and high-dose group (BXD-MED-H, 4 g BXD-MED/kg). All the groups, except the control group, were rectally injected with 70 mg/kg ethanol solution containing TNBS (2,4,6-trinitrobenzenesulfonic acid) to establish the UC models. The pharmacological evaluations including disease activity index, colon weight index, macroscopic and histological evaluation of colon damage, and inflammatory cytokine levels (IL-4, IL-10, IL-1β, TNF-α, and IL-6)were measured. In the network pharmacology analysis, the “herbs-components-targets-disease” network was constructed and visually analyzed with which the targets with a strong correlation with UC were screened out. ResultsThe results showed that both BXD-AED and BXD-MED might alleviate the severity of UC with different degrees according to the majority of indices that were evaluated. At similar doses, the BXD-AED groups performed better compared with the BXD-MED groups. With the assistance of the network pharmacology analysis, some key active components (quercetin, baicalein, wogonin, and baicalin) related to the anti-UC/inflammation were screened out. The contents of the components in BXD-AED were higher than those in BXD-MED. The joint results of the study indicated that BXD, an ancient TCM compound prescription, is an effective drug candidate for the modern treatment of UC.

Electro-optical logic using dual-nanobeam Mach-Zehnder interferometer switches.

The maturity of integrated photonics enables many applications including high-performance computing. Digital photonic computing always considers resonator-based modulators as the key active components due to their compactness as compared to broad-spectrum Mach-Zehnder interferometers (MZIs). In this paper, we investigate the dual-nanobeam (NB) based MZI 2 × 2 switches with much smaller footprint for realizing electro-optical logic circuits. New logic gates and scalable circuits assisted by multiplexing techniques are proposed. Results show that the NB MZI is another promising candidate for electronic-photonic digital computing.

Study on the Mechanism of Jiawei Shengjiang Powder in Improving Male Asthma-Induced Asthenospermia Based on Network Pharmacology and Bioinformatics.

BackgroundJiawei Shengjiang Powder (JWSJP) is a classical Chinese medicinal formula, which has been widely applied in the treatment of asthma and complications for many years due to its curative effect.AimTo verify the effect of JWSJP in improving abnormal sperm motility caused by asthma and to explore its potential mechanism.Materials and MethodsThe active compounds of JWSJP were obtained from high performance liquid chromatography tandem mass spectrometry and the Traditional Chinese Medicine System Pharmacology. The key active components and targets of JWSJP were predicted based on network pharmacological analysis and bioinformatics research. Rats were randomly divided into normal, model and treatment groups. The rat model of allergic asthma was induced by intraperitoneal injection of ovalbumin solution. The experiment judged improvement of semen quality by evaluating sperm motility, and detected the expression of related proteins in testicular tissue of Sprague-Dawley rats by RT-qPCR and Western blot methods. Hematoxylin and eosin (HE) staining was used to observe the changes in testicular tissue structure in rats.ResultsThrough the analysis of network pharmacology and bioinformatics, it was found that beta-sitosterol, quercetin, gallic acid, pelargonidin and kaempferol were the key active components of Jiawei Shengjiang Powder. Tumor necrosis factor (TNF), interleukin-6 (IL-6) and insulin (INS) genes are crucial targets of JWSJP in the treatment of spermatogenic dysfunction caused by acute asthma. After 8 weeks of intervention, compared with the model group, the treatment group had significantly improved sperm motility (P < 0.05). There were significant differences in TNF, IL6, and INS proteins in the treatment group, and the HE staining of testicular tissue structure in the treatment group was significantly improved.ConclusionJWSJP can improve the abnormal sperm motility induced by asthma, and its mechanism may be related to the expression of related proteins and mRNA of TNF, IL6, and INS.

Optimization of Extraction and Purification of Polysaccharides from Veronicastrum axillare, and Evaluation of Their Biological Activities.

Veronicastrum axillare polysaccharides (VAP) were isolated by cellulase-assisted digestion. The optimum conditions (2 % cellulase, 47 °C for 2.5 h, then, 95 °C for 2.5 h, pH 4.1, solid/liquid ratio 1 : 7.6) were identified by a combination of single factor optimization and response surface DOE (design of experiment) methods, and achieved a yield of 4.7 %. Treatment with 1 % TCA for 10 min, then, 2 % DEAE-cellulose removed protein and colored impurities. Purified VAP retained most of the radical-scavenging activities and GES-1 cell protection capability in vitro, indicating VAP were the key active components of V. axillare. Some molecular features were identified by FT-IR and NMR analyses. The molecular weight was estimated from DOSY NMR experiments to be around 21 kDa. There were 6.3 % uronic acid residues in the VAP. The constituent sugars after TFA hydrolysis were identified by HPLC to include glucose, arabinose, rhamnose, galactose, and xylose in a molar ratio of 405 : 259 : 82 : 42 : 1.

Silicate-Enhanced Heterogeneous Flow-Through Electro-Fenton System Using Iron Oxides under Nanoconfinement.

Herein, a silicate-enhanced flow-through electro-Fenton system with a nanoconfined catalyst was rationally designed and demonstrated for the highly efficient, rapid, and selective degradation of antibiotic tetracycline. The key active component of this system is the Fe2O3 nanoparticle filled carbon nanotube (Fe2O3-in-CNT) filter. Under an electric field, this composite filter enabled in situ H2O2 generation, which was converted to reactive oxygen species accompanied by the redox cycling of Fe3+/Fe2+. The presence of the silicate electrolyte significantly boosted the H2O2 yield by preventing the O-O bond dissociation of the adsorbed OOH*. Compared with the surface coated Fe2O3 on the CNT (Fe2O3-out-CNT) filter, the Fe2O3-in-CNT filter demonstrated 1.65 times higher kL value toward the degradation of the antibiotic tetracycline. Electron paramagnetic resonance and radical quenching tests synergistically verified that the dominant radical species was the 1O2 or HO· in the confined Fe2O3-in-CNT or unconfined Fe2O3-out-CNT system, respectively. The flow-through configuration offered improved tetracycline degradation kinetics, which was 5.1 times higher (at flow rate of 1.5 mL min-1) than that of a conventional batch reactor. Liquid chromatography-mass spectrometry measurements and theoretical calculations suggested reduced toxicity of fragments of tetracycline formed. This study provides a novel strategy by integrating state-of-the-art material science, Fenton chemistry, and microfiltration technology for environmental remediation.

An Integrative Pharmacology-Based Approach for Evaluating the Potential Effects of Purslane Seed in Diabetes Mellitus Treatment Using UHPLC-LTQ-Orbitrap and TCMIP V2.0.

Portulaca oleracea L., known as the “vegetable for long life,” is an annual succulent herb that is widely distributed worldwide. Many clinical and experimental studies have demonstrated that purslane seed (MCXZ) can be used as an adjunctive and alternative therapy for the treatment of diabetes mellitus (DM). However, the underlying active constituents and pharmacological mechanisms through which MCXZ exerts effects in DM remain unclear. In the present study, we confirmed that MCXZ treatment resulted in hypoglycemic activity, lowering the fasting blood glucose and glycated hemoglobin levels in streptozotocin-induced diabetic mice. Then, ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry was used to systematically analyze the chemical profile of MCXZ, resulting in the identification of 84 constituents, including 31 organic acids and nine flavonoids. Finally, the Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine was employed to analyze the key active components of MCXZ and the molecular mechanisms through which these components acted in DM. Ten key active compounds were identified based on the topological importance of their corresponding putative targets within the known DM-associated therapeutic target network of known MCXZ putative targets. Functionally, these candidate targets play critical anti-hyperlipidemia, anti-hyperglycemia, immunity regulation, and inflammatory roles involving DM-related pathways, such as the vascular endothelial growth factor (VEGF) signaling pathway and Fc gamma R-mediated phagocytosis, which indicated that MCXZ exhibited anti-diabetic activity through multi-faced actions.

Predicting and Exploring the Mechanisms of Erzhi Pill in Prevention and Treatment of Osteoporosis Based on Network Pharmacology and Zebrafish Experiments.

BackgroundErzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.MethodsBy combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.ResultsOur study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.ConclusionOur study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.

Network Pharmacology Integrated Molecular Docking Reveals the Anti-COVID-19 Mechanism of Yinma Jiedu Granules

To investigate the mechanism of action of components of Yinma Jiedu granules in the treatment of coronavirus disease 2019 (COVID-19) using network pharmacology and molecular docking. The main chemical components of Yinma Jiedu granules were collected in the literature and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. Using the SwissTargetPrediction database, the targets of the active component were identified and further correlated to the targets of COVID-19 through the GeneCards database. The overlapping targets of Yinma Jiedu granules components and COVID-19 were identified as the research target. Using the Database for Annotation, Visualization and Integrated Discovery database to carry out the target gene function Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway annotation and Cytoscape 3.6.1 software was used to construct a “component-target-pathway” network. The protein-protein interaction network was built using Search Tool for the Retrieval of Interacting Genes/Proteins database. Using Discovery Studio 2016 Client software to study the virtual docking of key protein and active components. One hundred active components were screened from the Yinma Jiedu Granules that involved 67 targets, including mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor, tumor necrosis factor, tumor protein 53, and MAPK1. These targets affected 109 signaling pathways including hypoxia-inducible factor-1, apoptosis, and Toll-like receptor signaling pathways. Molecular docking results showed that the screened active components have a strong binding ability to the key targets. In this study, through network pharmacology and molecular docking, we justified the multicomponent, multitarget, and multipathways of Yinma Jiedu Granules in the treatment of COVID-19.

Exosome Derived from ADSCs Attenuates Ultraviolet B-mediated Photoaging in Human Dermal Fibroblasts.

Stem cell therapies have attracted a lot of attention in the fields of dermatological and esthetic medicine. The paracrine action of stem cells is deemed to play a crucial role in skin treatments. Many reports have demonstrated the beneficial effects of conditioned medium (CM) derived from ADSCs on skin photoaging. However, few reports have presented the application of exosome (Exo) derived from ADSCs in the treatment of photoaging. To clarify the effects of Exo, we collected Exo from the CM of ADSCs and the photoprotective effects of Exo, as well as those of the CM with and without Exo, were investigated by detecting the intracellular ROS, DNA damage and some photoaging-associated signal pathways on UVB-treated human dermal fibroblasts. The results showed that Exo had significant efficiency in preventing photoaging, and it could inhibit UVB-induced cellular DNA damage, overexpression of ROS and MMP-1 via regulating Nrf2 and MAPK/AP-1 pathway. In addition, Exo could effectively activate the TGF-β/Smad pathway to elevate the expression of procollagen type I. However, these photoprotective effects were weakened when Exo was removed from the CM. Taken together, the results suggested that Exo, a key component of paracrine activity, played an important role in the treatment of photoaging.

Identification of the active substances and mechanisms of ginger for the treatment of colon cancer based on network pharmacology and molecular docking

Background and objectiveColon cancer is occurring at an increasing rate and ginger (Zingiber officinale), as a commonly used herbal medicine, has been suggested as a potential agent for colon cancer. This study was aimed to identify the bioactive components and potential mechanisms of ginger for colon cancer prevention by an integrated network pharmacology approach.MethodsThe putative ingredients of ginger and its related targets were discerned from the TCMSP and Swiss target prediction database. After that, the targets interacting with colon cancer were collected using Genecards, OMIM, and Drugbank databases. KEGG pathway and GO enrichment analysis were performed to explore the signaling pathways related to ginger for colon cancer treatments. The PPI and compound-target-disease networks were constructed using Cytoscape 3.8.1. Finally, Discovery studio software was employed to confirm the key genes and active components from ginger.ResultsSix potential active compounds, 285 interacting targets in addition to 1356 disease-related targets were collected, of which 118 intersection targets were obtained. A total of 34 key targets including PIK3CA, SRC, and TP53 were identified through PPI network analysis. These targets were mainly focused on the biological processes of phosphatidylinositol 3-kinase signaling, cellular response to oxidative stress, and cellular response to peptide hormone stimulus. The KEGG enrichment manifested that three signaling pathways were closely related to colon cancer prevention of ginger, cancer, endocrine resistance, and hepatitis B pathways. TP53, HSP90AA1, and JAK2 were viewed as the most important genes, which were validated by molecular docking simulation.ConclusionThis study demonstrated that ginger produced preventive effects against colon cancer by regulating multi-targets and multi-pathways with multi-components. And, the combined data provide novel insight for ginger compounds developed as new drug for anti-colon cancer.

In situ formed Co from a Co-Mg-O solid solution synergizing with LiH for efficient ammonia synthesis.

A cobalt magnesium oxide solid solution (Co-Mg-O) supported LiH catalyst has been synthesized, in which LiH functions both as a strong reductant for the in situ formation of Co metal nanoparticles and a key active component for ammonia synthesis catalysis. Dispersion of the Co-LiH composite on the Co-Mg-O support results in a significantly higher ammonia synthesis rate under mild reaction conditions (19 mmol g-1 h-1 at 300 °C, 10 bar).

Assessment of the anti-virulence potential of extracts from four plants used in traditional Chinese medicine against multidrug-resistant pathogens

BackgroundMultidrug-resistant pathogens are resistant to many antibiotics and associated with serious infections. Amomum tsaoko Crevost et Lemaire, Sanguisorba officinalis, Terminalia chebula Retz and Salvia miltiorrhiza Bge, are all used in Traditional Chinese Medicine (TCM) against multidrug-resistant pathogens, and the purpose of this study was to evaluate the antibacterial and anti-virulence activity of extracts derived from them.MethodsThe antibacterial activity of ethanol and aqueous extracts from these four plants was examined against several multi-drug resistant bacterial strains, and their anti-virulence potential (including quorum quenching activity, biofilm inhibition, and blocking production of virulence factor δ-toxin) was assessed against different S. aureus strains. The chemical composition of the most effective extract was determined by LC-FTMS.ResultsOnly extracts from S. officinalis and A. tsaoko were shown to exhibit limited growth inhibition activity at a dose of 256 μg·mL-1. The S. officinalis ethanol extract, the ethanol and aqueous extract of A. tsaoko, and the aqueous extract of S. miltiorrhiza all demonstrated quorum quenching activity, but didn’t significantly inhibit bacterial growth. The ethanol extract of S. officinalis inhibited bacterial toxin production and biofilm formation at low concentrations. Chemical composition analysis of the most effective extract of S. officinalis showed that it mainly contained saponins.ConclusionsThe most active extract tested in this study was the ethanol root extract of S. officinalis. It inhibited δ-toxin production and biofilm formation at low concentrations and saponins may be its key active components. While the four plants showed no direct antibacterial effects, their anti-virulence properties may be key to fighting bacterial infections.

Homotherapy for heteropathy active components and mechanisms of Qiang-Huo-Sheng-Shi decoction for treatment of rheumatoid arthritis and osteoarthritis

Qiang-Huo-Sheng-Shi decoction (QHSSD), a classic traditional Chinese herbal formula, which has been reported to be effective in rheumatoid arthritis (RA) and osteoarthritis (OA). However, the concurrent targeting mechanism of how the aforementioned formula is valid in the two distinct diseases OA and RA, which represents the homotherapy-for-heteropathy principle in traditional Chinese medicine (TCM), have not yet been clarified. In the present study, network pharmacology was adopted to analyze the potential molecular mechanism, and therapeutic effective components of QHSSD on both OA and RA. A total of 153 active ingredients in QHSSD were identified, 142 of which associated with 59 potential targets for the two diseases were identified. By constructing the protein-protein interaction network and the compound-target-disease network, 72 compounds and 10 proteins were obtained as the hub targets of QHSSD against OA and RA. The hub genes of ESR1, PTGS2, PPARG, IL1B, TNF, MMP2, IL6, CYP3A4, MAPK8, and ALB were mainly involved in osteoclast differentiation, the NF-κB and TNF signaling pathways. Moreover, molecular docking results showed that the screened active compounds had a high affinity for the hub genes. This study provides new insight into the molecular mechanisms behind how QHSSD presents homotherapy-for-heteropathy therapeutic efficacy in both OA and RA. For the first time, a two-disease model was linked with a TCM formula using network pharmacology to identify the key active components and understand the common mechanisms of its multi-pathway regulation. This study will inspire more innovative and important studies on the modern research of TCM formulas.

Material basis, effect, and mechanism of ethanol extract of Pinellia ternata tubers on oxidative stress-induced cell senescence

BackgroundThe tuber of Pinellia ternata has been used for a thousand years in China. P. ternata possessed the activities of anti-emetic, sedative-hypnotic, anti-cancer, anti-asthmatic, anti-tussive, and anti-inflammatory. It is the representative of expectorant medicines in Traditional Chinese Medicine (TCM). Phlegm is the pathological product and a new pathogenic factor of the metabolite, which is analogous to the damage of oxidative stress. PurposeThe objectives of the study were to investigate the protective activity and mechanism of ethanol extract of P. ternata tubers (PTE) and its main constituents on oxidative stress-induced cell senescence. MethodsH2O2 and AAPH were used to establish cellular senescence models. The anti-aging effects of PTE and its components were evaluated by SA-β-gal staining, flow cytometry, scanning electron microscope (SEM), and multiple microplate reader, the molecular mechanisms of them were investigated by qRT-PCR and Western Blot. ResultsWe found PTE exhibited the apparent effect on cell senescence, evidenced by inhibiting senescence β-Galactosidase (SA-β-gal) expression, lipofuscin accumulation, cell cycle arrest at the G2/M phase, oxidative damage and apoptosis, and increasing telomerase activity. Their mechanisms were related to increase expressions of SIRT1, forkhead box 3a (Foxo3a), Bcl-2, active regulator of SIRT1, RPS19BP1 (AROS), and Hu antigen R (HuR), but decrease Bax, p53 and deleted in breast cancer 1 (DBC1) levels. Furthermore, adenosine, and succinic acid, as the critical substances in PTE, could also inhibit SA-β-gal expression and cell cycle arrest, down-regulate the expression of Bax, and up-regulate Bcl-2, SirT1, and Foxo3a. ConclusionsWe have demonstrated that PTE slows down oxidative stress-induced cell senescence, and adenosine and succinic acid are the key active components.

Modeling and Simulation Techniques of Amorphous Silicon Thin Film Transistors TFT for Large Area and Flexible Microelectronics

The Thin Film Transistor (TFT) is the key active components of emerging large area and flexible microelectronics (LAFM) which includes a flexible display, robotics skin, sensor &amp; disposable electronics. Different semiconducting or organic conducting materials could be used in the fabrication of TFTs. The material used for the active layer also influences the performance of the TFT uniquely[1]. Silicon based thin film transistors have made possible the development of the active-matrix liquid crystal display within cell-touch technology [2,3,4]. Modern-day simulation software does not support the older SPICE code models, and rather rely on the new drag and drop concepts. The TFT(Thin Film Transistor) Model device wasn't readily available on the LT-Spice Tool which was simulated and the circuit level simulation for basic gates using the TFT was carried out successfully. The model symbol shall be useful for analysis and simulation of the TFT based circuits which require continuous behavioral study and analysis. For a device to be simulated that way, a “.lib” file containing a symbol of the device is necessary. This paper focuses on circuit-level simulation of user-defined device parameters from reported experimental data.

Ralstonia solanacearum promotes pathogenicity by utilizing l-glutamic acid from host plants.

Ralstonia solanacearum is an important bacterial pathogen that can infect a broad range of plants worldwide. A previous study showed that R. solanacearum could respond to exogenous organic acids or amino acids to modulate cell motility. However, it was unclear whether R. solanacearum uses these compounds to control infection. In this study, we found that R. solanacearum GMI1000 uses host plant metabolites to enhance the biosynthesis of virulence factors. We demonstrated that l‐glutamic acid from host plants is the key active component associated with increased extracellular polysaccharide production, cellulase activity, swimming motility, and biofilm formation in R. solanacearum GMI1000. In addition, l‐glutamic acid also promoted colonization of R. solanacearum cells in the roots and stems of tomato plants and accelerated disease incidence. Furthermore, genetic screening and biochemical analysis suggested that RS01577, a hybrid sensor histidine kinase/response regulator, is involved in l‐glutamic acid signalling in R. solanacearum. Mutations in RS01577 and exogenous addition of l‐glutamic acid to the GMI1000 wild‐type strain had overlapping effects on both the transcriptome and biological functions of R. solanacearum, including on motility, biofilm formation, and virulence. Thus, our results have established a new interaction mechanism between R. solanacearum and host plants that highlights the complexity of the virulence regulation mechanism and may provide new insight into disease control.

SCIENTIFIC AND METHODICAL BASIS FOR EVALUATION OF DESIGN COMPETENCIES OF FUTURE ENGINEERS

The urgency of the problem is explained by the growing importance of the methodological activities of high school teachers in the training of highly qualified, competitive personnel (qualified engineers) in the higher education system in the context of multi-level education. The goal-oriented approach to learning outcomes. The implementation of a competency-based approach has raised the question of the relevance of higher education teachers to innovative processes of methodological education. This article is devoted to the causes of methodological ability as a key component of the methodological activity of a university teacher, which directly affects the quality of education, characterizing his level of professionalism. The leading approach from the scientific jihad of this paper is modeling, which allows the problem to be viewed by teachers as a process of purposeful and conscious mastery of certain specific competencies in order to carry out highly qualified methodological activities.

Pharmacokinetic and Metabolic Profiling of Key Active Components of Dietary Supplement Magnolia officinalis Extract for Prevention against Oral Carcinoma.

Among the three key active components (KACs) of Magnolia officinalis bark extract (ME), 4-O-methylhonokiol and honokiol showed higher antiproliferation activities than magnolol in the oral squamous cancer cell lines (Cal-27, SCC-9, and SCC-4). Oral bioavailabilities of ME-KACs were poor (<0.2%) in C57BL/6 mice primarily due to their extensive first-pass phase II metabolism and poor solubilities. High plasma concentration of glucuronides upon oral administration and faster rate of glucuronidation by intestinal microsomes indicated intestine as one of the major metabolic organs for ME-KACs. Despite the increase in bioavailabilities of ME-KACs (∼8-10-fold) and decrease in AUC0-24 of glucuronides (∼10-fold) upon ME solubility enhancement, systemic exposure of ME-KACs failed to improve meaningfully. In conclusion, we propose a quality-controlled and chemically defined ME mixture, containing an optimized ratio of three KACs, delivered locally in the oral cavity as the most promising strategy for ME use as an oral cancer chemopreventive dietary supplement.

Crystal structure of monomeric Amuc_1100 from Akkermansia muciniphila.

Many human diseases, such as obesity and diabetes, show annual increases in prevalence and often involve intestinal microbes. One such probiotic bacterium, Akkermansia muciniphila, which was discovered a decade ago, has been reported to influence glucose homeostasis and to contribute to gut health. Amuc_1100, a functionally uncharacterized protein of A. muciniphila, was found to be a key active component in reducing the body weight of mice. Here, the crystal structure of Amuc_1100 (residues 31-317), referred to as Amuc_1100*, is reported at 2.1 Å resolution. Amuc_1100* has a similar fold to three proteins related to pilus formation, PilO, PilN and EpsL, indicating a similar function. Biochemical investigations further confirmed a monomeric state for the soluble region of Amuc_1100, which differs from the dimeric states of PilO, PilN and EpsL. This study provides a structural basis for the elucidation of the molecular mechanism of Amuc_1100.

Nε-Carboxymethyl-Lysine Negatively Regulates Foam Cell Migration via the Vav1/Rac1 Pathway.

Background Macrophage-derived foam cells play a central role in atherosclerosis, and their ultimate fate includes apoptosis, promotion of vascular inflammation, or migration to other tissues. Nε-Carboxymethyl-lysine (CML), the key active component of advanced glycation end products, induced foam cell formation and apoptosis. Previous studies have shown that the Vav1/Rac1 pathway affects the macrophage cytoskeleton and cell migration, but its role in the pathogenesis of diabetic atherosclerosis is unknown. Methods and Results In this study, we used anterior tibiofibular vascular samples from diabetic foot amputation patients and accident amputation patients, and histological and cytological tests were performed using a diabetic ApoE−/− mouse model and primary peritoneal macrophages, respectively. The results showed that the atherosclerotic plaques of diabetic foot amputation patients and diabetic ApoE−/− mice were larger than those of the control group. Inhibition of the Vav1/Rac1 pathway reduced vascular plaques and promoted the migration of macrophages to lymph nodes. Transwell and wound healing assays showed that the migratory ability of macrophage-derived foam cells was inhibited by CML. Cytoskeletal staining showed that advanced glycation end products inhibited the formation of lamellipodia in foam cells, and inhibition of the Vav1/Rac1 pathway restored the formation of lamellipodia. Conclusion CML inhibits the migration of foam cells from blood vessels via the Vav1/Rac1 pathway, and this process affects the formation of lamellipodia.