Exploring the potential mechanisms of Yi-Yi-Fu-Zi-Bai-Jiang-San therapy on the immune-inflamed phenotype of colorectal cancer via combined network pharmacology and bioinformatics analyses.

BACKGROUND: The development and progression of colorectal cancer (CRC) is closely associated with its complex tumor microenvironment (TME). Assessment of the modified pattern of immune cell infiltration (ICI) will help increase knowledge regarding the characteristics of TME infiltration. Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) has been shown to have positive effects on the regulation of the immune microenvironment of CRC. However, its pharmacological targets and molecular mechanisms remain to be elucidated. METHODS: Network pharmacological analysis was used to identify the target of YYFZBJS in the TME of CRC. Patients with the immune-inflamed phenotype (IIP) were identified using CRC samples from The Cancer Genome Atlas (TCGA) database. Consensus genes were identified by intersecting YYFZBJS targets, CRC disease targets and differentially expressed genes in the CRC microenvironment. Then, least absolute shrinkage and selection operator (LASSO) Cox analyses were used to identify a prognostic signature from the consensus genes. Cytoscape software was further used to build a unique herb-compound-target network diagram of the important components of YYFZBJS and prognostic gene targets. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed using the prognostic gene sets to explore the molecular mechanism of the prognostic genes in drug therapy for CRC IIP patients. Finally, single-cell analysis was performed to validate the expression of the prognostic genes in the TME of CRC using the TISCH2 database. RESULTS: A total of 284 IIP patients were identified from 480 patients with CRC. A total of 35 consensus genes were identified as targets of YYFZBJS in the TME of CRC patients. An eleven-gene prognostic signature, including PIK3CG, C5AR1, PRF1, CAV1, HPGDS, PTGS2, SERPINE1, IDO1, TGFB1, CXCR2 and MMP9, was identified from the consensus genes, with areas under the receiver operating characteristic (ROC) curve (AUCs) values of 0.84 and 0.793 for the training and test cohorts, respectively. In the herb-compound-target network, twenty-four compounds were shown to interact with the 11 prognostic genes, which were significantly enriched in the IL-17 signaling, arachidonic acid metabolism and metabolic pathways. Single-cell analysis of the prognostic genes confirmed that their abnormal expression was associated with the TME of CRC. CONCLUSION: This study organically integrated network pharmacology and bioinformatics analyses to identify prognostic genes in CRC IIP patients from the targets of YYFZBJS. Although this data mining work was limited to the study of mechanisms related to prognosis based on the immune microenvironment, the methodology provides new perspectives in the search for novel therapeutic targets of traditional Chinese medicines (TCMs) and accurate diagnostic indicators of cancers targeted by TCMs.

Total Synthesis of (+)-Aberrarone.

The structurally intriguing diterpene (+)-aberrarone has been assembled in only 12 steps from the commercially available (S,S)-carveol without protecting group manipulations. This concise synthesis features a Cu-catalyzed asymmetric hydroboration to generate the chiral methyl group, a Ni-catalyzed reductive coupling to link two fragments, and a Mn-mediated radical cascade cyclization to construct the triquinane system.

Flexible enzymatic biofuel cell based on 1, 4-naphthoquinone/MWCNT-Modified bio-anode and polyvinyl alcohol hydrogel electrolyte.

To meet the emerging power demand of microelectronic and electronic skin based sensing platform, enzymatic fuel cells have received increasing attention due to their good human's compatibility, easy integration and cost effectiveness. Herein, we use multi-walled carbon nanotube/naphthoquinone to modify the lactate oxidase bio-anode to facilitate the electron transfer between electrocatalytic active site and electrode support. Polyvinyl alcohol hydrogel serves as the separator and lactate container. The bio-anode, Pt/C cathode and hydrogel are assembled in layer-by-layer structure, which can successfully utilize pre-stored and external lactate from human's sweat to generate the electricity. It delivers a power-density of 62.2 ± 2.4 µW cm-2 under bending/torsion conditions. Given that the broad substrate scope in sweat and easily assembled structure, it provides a plausible solution to power the miniaturized sensors and generic circuits.

Hybrid AI-assistive diagnostic model permits rapid TBS classification of cervical liquid-based thin-layer cell smears.

Technical advancements significantly improve earlier diagnosis of cervical cancer, but accurate diagnosis is still difficult due to various factors. We develop an artificial intelligence assistive diagnostic solution, AIATBS, to improve cervical liquid-based thin-layer cell smear diagnosis according to clinical TBS criteria. We train AIATBS with >81,000 retrospective samples. It integrates YOLOv3 for target detection, Xception and Patch-based models to boost target classification, and U-net for nucleus segmentation. We integrate XGBoost and a logical decision tree with these models to optimize the parameters given by the learning process, and we develop a complete cervical liquid-based cytology smear TBS diagnostic system which also includes a quality control solution. We validate the optimized system with >34,000 multicenter prospective samples and achieve better sensitivity compared to senior cytologists, yet retain high specificity while achieving a speed of <180s/slide. Our system is adaptive to sample preparation using different standards, staining protocols and scanners.

[Study on rapid quality analysis method of Shengxuebao Mixture].

A rapid analysis method based on ultraviolet-visual(UV-Vis) spectroscopy, near infrared(NIR) spectroscopy and multivariable data analysis was established for quality evaluation of Shengxuebao Mixture. The contents of eight active ingredients of Shengxuebao Mixture including albiflorin, paeoniflorin, 2, 3, 5, 4'-tetra-hydroxy-stilbene-2-O-ß-D-glucopyranoside, specnuezhenide,ecliptasaponin D, emodin, calycosin-7-glucoside and astragaloside Ⅳ were simultaneously detected by using this method. HPLC-UV-MS was used as a reference method for determining the contents of these ingredients. Partial least squares(PLS) analysis was implemented as a linear method for multivariate models calibrated between UV spectrum/NIR spectrum and contents of 8 ingredients. Finally, the performance of the model was evaluated by 24 batches of test samples. The results showed that both UV-Vis and NIR models gave a good calibration ability with an R~2 value above 0.9, and the prediction ability was also satisfactory, with an R~2 value higher than 0.83 for UV-Vis model and higher than 0.79 for NIR model. The overall results demonstrate that the established method is accurate, robust and fast, therefore, it can be used for rapid quality evaluation of Shengxuebao Mixture.

Characterization of the Metabolic Fate of Datura metel Seed Extract and Its Main Constituents in Rats.

Datura metel L. has been frequently used in Chinese traditional medicine. However, little is known on the chemical composition and in vivo metabolism of its seeds. In this study, using the strategy "chemical analysis, metabolism of single representative compounds, and metabolism of extract at clinical dosage" that we propose here, 42 constituents were characterized from D. metel seeds water extract. Furthermore, the metabolic pathways of 13 representative bioactive compounds of D. metel seeds were studied in rats after the oral administration of D. metel seeds water extract at a clinical dosage (0.15 g/kg). These included three withanolides, two withanolide glucosides, four amides, one indole, one triterpenoid, one steroid, and one sesquiterpenoid, and with regard to phase II metabolism, hydroxylation, (de)methylation, and dehydrogenation reactions were dominant. Furthermore, the metabolism of D. metel seeds water extract provided to rats at a clinical dosage was investigated by liquid chromatography-tandem mass spectrometry based on the above metabolic pathways. Sixty-one compounds were detected in plasma, 83 in urine, and 76 in fecal samples. Among them, withanolides exhibited higher plasma exposure than the other types. To our knowledge, this is the first systematic study on the chemical profiling and metabolite identification of D. metel seeds, including all compounds instead of single constituents.

Metabolites Identification of Bioactive Compounds Daturataturin A, Daturametelin I, N-Trans-Feruloyltyramine, and Cannabisin F From the Seeds of Datura metel in Rats.

Datura metel L. is a widely used traditional herbal medicine, and withanolides and amides are the two groups of main bioactive constituents in Datura metel seeds. This study aimed to elucidate the metabolism of four representative bioactive compositions containing daturataturin A (1), daturametelin I (2), N-trans-feruloyltyramine (3), and cannabisin F (4) in rats. After separately oral administration of 20 mg/kg withanolides (1, 2) and amides (3, 4) to rats, a total of 12, 24, and 21 metabolites were detected in the plasma, urine, and fecal samples, respectively. Among them, three hydroxylated metabolites, 1-M3, 2-M2, and 3-M5, were detected in plasma and rat liver microsome incubation system in high abundance. Two metabolites of 1 and 2 were unambiguously identified by comparing with reference standards. Particularly, the methylated metabolite 27α-methoxy-(22R)-22,26-epoxy-27-[(ß-D-glucopyranosyl)oxy]ergosta-2,4,6,24-tetraene-1,26-dione (daturametelin L) is a new compound. The withanolides could readily get hydroxylation or methylation metabolism. Meanwhile, the phase II metabolism (glucuronidation or sulfation) was the major reaction for the amides. This is the first study on in vivo metabolism of these active compounds in seeds of Datura metel.

Continuous Production of Isomalto-oligosaccharides by Thermo-inactivated Cells of Aspergillus niger J2 with Coarse Perlite as an Immobilizing Material.

The coarse perlite 40-80 mesh was selected as an immobilizing material and put into a packed bed reactor (PBR) to continuously convert maltose to isomalto-oligosaccharides (IMOs). The PBR was prepared by mixing the thermo-inactivated cells (TIC) from Aspergillus niger J2 strain with the coarse perlite, then the mixture was put into an overpressure-resistant column. Compared with diatomite 40-80 mesh and thin perlite 80-120 mesh in PBR, coarse perlite was chosen as the best filtration aid, when the ratio of coarse perlite versus TIC was 1:1. The thermal and pH stability of the free and immobilized TIC and the optimum conditions for the transglycosylation reactions were determined. The results show that approximately 75 and 82% and 87 and 91% of α-glucosidase activity were reserved for free and immobilized TIC at temperatures from 30 to 60 °C and pH from 3.00 to 7.00 for 12 h, respectively. With 30% malt syrup under the conditions of 50 °C and pH 4.00, a mini-scale packed bed reactor (Mi-PBR) and medium-scale packed bed reactor (Me-PBR) could continuously produce IMO over 25 and 34 days with the yield of effective IMO (eIMO) ≥ 35% and total IMO (tIMO) ≥ 50%, respectively. The strategy of mixing the coarse perlite with TIC in PBR is a novel approach to continuously produce IMO and has great application potential in industry.