Anti-coronavirus and anti-pulmonary inflammation effects of iridoids, the common component from Chinese herbal medicines for the treatment of COVID-19.

The practice of Chinese herbal medicines for the treatment of COVID-19 in China played an essential role for the control of mortality rate and reduction of recovery time. The iridoids is one of the main constituents of many heat-clearing and detoxifying Chinese medicines that were largely planted and frequently used in clinical practice. Twenty-three representative high content iridoids from several staple Chinese medicines were obtained and tested by a SARS-CoV-2 pseudo-virus entry-inhibition assay on HEK-293 T/ACE2 cells, a live HCoV-OC43 virus infection assay on HRT-18 cells, and a SARS-CoV-2 3CL protease inhibitory FRET assay followed by molecular docking simulation. The anti-pulmonary inflammation activities were further evaluated on a TNF-α induced inflammation model in A549 cells and preliminary SARs were concluded. The results showed that specnuezhenide (7), cornuside (12), neonuezhenide (15), and picroside III (21) exhibited promising antiviral activities, and neonuezhenide (15) could inhibit 3CL protease with an IC50 of 14.3 µM. Docking computation showed that compound 15 could bind to 3CL protease through a variety of hydrogen bonding and hydrophobic interactions. In the anti-pulmonary inflammation test, cornuside (12), aucubin (16), monotropein (17), and shanzhiside methyl ester (18) could strongly decrease the content of IL-1ß and IL-8 at 10 µM. Compound 17 could also upregulate the expression of the anti-inflammatory cytokine IL-10 significantly. The iridoids exhibited both anti-coronavirus and anti-pulmonary inflammation activities for their significance of existence in Chinese herbal medicines, which also provided a theoretical basis for their potential utilization in the pharmaceutical and food industries.

[A new benzopyran glycoside from Gentiana macrophylla].

Thirteen compounds were isolated and identified from 70% ethanol extract of the roots of Gentiana macrophylla by multi-chromatographic methods, including microporous resin, silica gel, and C_(18) reversed-phase column chromatography, as well as HPLC as follows: macrophylloside G(1), macrophylloside D(2), 5-formyl-2,3-dihydroisocoumarin(3),(+)-medicarpin(4),(+)-syringaresinol(5), liquiritigenin(6),(3R)-sativanone(7),(3R)-3'-O-methylviolanone(8), 4,2',4'-trihydroxychalcone(9), latifolin(10), gentioxepine(11), 6α-hydroxycyclonerolidol(12), and ethyl linoleate(13). Compound 1 was a new benzopyran glycoside. Compounds 4, 6-10, 12, and 13 were isolated for the first time from Gentiana plants. Compounds 1 and 2 showed promising hepatoprotective activity against D-GalN-induced AML12 cell damage at the concentration of 10 µmol·L~(-1), and compound 2 exhibited more significant activity than silybin at the same concentration.

Isolation, structure modification, and anti-rheumatoid arthritis activity of isopimarane-type diterpenoids from Orthosiphon aristatus.

Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (1-8), including a new one with a rarely occurring α,ß-unsaturated diketone C-ring, were isolated from O. aristatus. Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (9-15). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1ß, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.

High-efficiency computation for electromagnetic forming process: An explicit-implicit GPU approach.

Low computational efficiency is one of the crucial challenges in electromagnetic forming process simulation. However, the huge gap in switching from the electromagnetic field to mechanics hinders the development of high-efficiency parallel coupling. A graphics processing unit (GPU)-based explicit-implicit coupling method is proposed to address the high-computational cost in simulations of the electromagnetic forming process, in which the large deformation (explicit) and electromagnetic field (implicit) are intimately coupled. The electromagnetic-mechanical coupling is achieved by constructing five parallel algorithms, which include the parallel operations of vector-vector, matrix-matrix, matrix-vector, vector assembly, and matrix-free assembly parallel preconditioned conjugate gradient algorithm. The high-efficiency GPU parallel computing is realized through the special data storage structure and parallel strategies. The explicit-implicit GPU method is validated against the experimental results, and several examples are presented for simulations of the electromagnetic forming process to illustrate both the accuracy and high-efficiency parallel acceleration performance of the present program.

Lignan glucosides from Gentiana macrophylla with potential anti-arthritis and hepatoprotective activities.

Ten lignans, including six previously undescribed phenolic ester glycosyl lignans (1-6), were isolated from a well-known traditional Chinese medicine, Qin-Jiao, which is the dry root of Gentiana macrophylla Pall. (Gentianaceae). Their structures were determined by spectroscopic and chemical methods, especially 2D NMR techniques. Quantum chemical calculations of theoretical ECD spectra allowed the determination of their absolute configurations. Refer to its traditional applications for the treatment of rheumatic arthralgia and hepatopathy, these compounds were evaluated on a TNF-α induced MH7A human synoviocyte inflammation model and a D-GalN induced AML12 hepatocyte injury model. Compounds 1, 2, 5, and 6 significantly reduced the release of proinflammatory cytokine IL-1ß in MH7A cells at 15 µM and they also could strongly protect AML12 cells against D-GalN injury at 30 µM. Flow cytometry and Western blot analysis showed that compound 5 ameliorated D-GalN induced AML12 cell apoptosis by upregulating the expression of anti-apoptotic Bcl-2 protein and down-regulating the expression of pro-apoptotic Bax protein.

Terpenoid Glucosides from Gentiana macrophylla That Attenuate TNF-α Induced Pulmonary Inflammation in A549 Cells.

Four previously undescribed terpenoid glucosides, including one sesquiterpenoid di-glucoside (1), two new iridoid glucosides (2, 3), and a new triterpenoid tri-glucoside (4), were isolated from a 70% ethanol extract of the root of Gentiana macrophylla (Gentianaceae), along with eight known terpenoids. Their structures were determined by spectroscopic techniques, including 1D, 2D NMR, and HRMS (ESI), as well as chemical methods. The absolute configuration of compound 1 was determined by quantum chemical calculation of its theoretical electronic circular dichroism (ECD) spectrum. The sugar moieties of all the new compounds were confirmed to be D-glucose by GC analysis after acid hydrolysis and acetylation. Anti-pulmonary inflammation activity of the iridoids were evaluated on a TNF-α induced inflammation model in A549 cells. Compound 2 could significantly alleviate the release of proinflammatory cytokines IL-1ß and IL-8 and increase the expression of anti-inflammatory cytokine IL-10.

Rare diphenylheptanoid-phenylheptanoid hybrids with α-glucosidase inhibitory effects from the pollen of Typha angustifolia.

Two rarely occurring diphenylheptanoid-phenylheptanoid hybrid dimers (1 and 2) and one new oxygenated fatty acid (3), as well as two known fatty acid analogues (4 and 5), were isolated from the 70% EtOH extract of the pollen of Typha angustifolia. Their planar structures were established by interpretation of MS and NMR spectroscopic data, and the absolute configurations of 1 and 2 were determined by Mosher's method and quantum chemical TD-DFT calculations of ECD spectra. An in vitro anti-diabetic evaluation of these isolates revealed that compounds 1 and 2 exhibited promising inhibitory activity against α-glucosidase with IC50 values of 11.85 ± 0.69 and 17.06 ± 3.08 µM, respectively. It is the first report on both diphenylheptanoid constituents and α-glucosidase inhibitors from the title plant, which represents a significant phytochemical progress of this herbal species and may serve as a reference for its future medicinal applications.

Enantiomeric N-acetyldopamine trimers from Cicadae Periostracum and their absolute configurations.

Six previously undescribed N-acetyldopamine (NADA) trimmer racemates, percicamides A-F (1-6), were isolated from a 70% ethanol extract of Cicadae Periostracum. Subsequent chiral-phase separation afforded six pairs of enantiomers, (+)- and (-)-percicamides A-F (1a/1b-6a/6b). Their structures including absolute configurations were elucidated by combined extensive spectroscopic data and quantum chemical calculations. Compounds 1-6 represent the first examples of NADA trimmers with a cis-relationship of H-7'/H-8' or H-7''/H-8''. Bioassays verified that all isolated compounds showed weak inhibitory effects on nitric oxide production in RAW 264.7 cells.

[Ontologies Applied in Clinical Decision Support Systems for Diabetes].

A clinical decision support system (CDSS) integrated with electronic health records helps physicians at the grassroots make patient-appropriate and evidence-based treatment decisions and improves the efficiency of diagnosis and treatment. Furthermore, using ontologies to build up the medical knowledge base and patient data for CDSS enhances the automation and transparency of the reasoning process of CDSS and helps generate interpretable and accurate treatment recommendations. Herein, we reviewed the relevant ontologies in the field of diabetes treatment and the progress and challenges concerning ontology-based CDSSs. Firstly, we elaborated on the current status and challenges of diabetes treatment in China, highlighting the urgent need to improve the efficiency and quality of medical services. Then, we presented background information about ontologies and gave an overview of the framework, methodology, and features of using ontologies to construct CDSS. After that, we reviewed the ontologies and instances of ontology-based CDSS in the field of diabetes treatment in China and abroad and summarized their construction methods and features. Last but not the least, we discussed the future prospects of the field, suggesting that integrating evidence-based medicine with ontologies to build a reliable clinical recommendation system should be the current focus of CDSS development.

Identification of biomarkers in laryngeal cancer by weighted gene co-expression network analysis / 中南大学学报(医学版)

OBJECTIVES@#Laryngeal cancer (LC) is a globally prevalent and highly lethal tumor. Despite extensive efforts, the underlying mechanisms of LC remain inadequately understood. This study aims to conduct an innovative bioinformatic analysis to identify hub genes that could potentially serve as biomarkers or therapeutic targets in LC.@*METHODS@#We acquired a dataset consisting of 117 LC patient samples, 16 746 LC gene RNA sequencing data points, and 9 clinical features from the Cancer Genome Atlas (TCGA) database in the United States. We employed weighted gene co-expression network analysis (WGCNA) to construct multiple co-expression gene modules. Subsequently, we assessed the correlations between these co-expression modules and clinical features to validate their associations. We also explored the interplay between modules to identify pivotal genes within disease pathways. Finally, we used the Kaplan-Meier plotter to validate the correlation between enriched genes and LC prognosis.@*RESULTS@#WGCNA analysis led to the creation of a total of 16 co-expression gene modules related to LC. Four of these modules (designated as the yellow, magenta, black, and brown modules) exhibited significant correlations with 3 clinical features: The age of initial pathological diagnosis, cancer status, and pathological N stage. Specifically, the yellow and magenta gene modules displayed negative correlations with the age of pathological diagnosis (r=-0.23, P<0.05; r=-0.33, P<0.05), while the black and brown gene modules demonstrated negative associations with cancer status (r=-0.39, P<0.05; r=-0.50, P<0.05). The brown gene module displayed a positive correlation with pathological N stage. Gene Ontology (GO) enrichment analysis identified 77 items, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified 30 related signaling pathways, including the calcium signaling pathway, cytokine-cytokine receptor interaction, neuro active ligand-receptor interaction, and regulation of lipolysis in adipocytes, etc. Consequently, central genes within these modules that were significantly linked to the overall survival rate of LC patients were identified. Central genes included CHRNB4, FOXL2, KCNG1, LOC440173, ADAMTS15, BMP2, FAP, and KIAA1644.@*CONCLUSIONS@#This study, utilizing WGCNA and subsequent validation, pinpointed 8 genes with potential as gene biomarkers for LC. These findings offer valuable references for the clinical diagnosis, prognosis, and treatment of LC.

Cold Roll Forming Process Design for Complex Stainless-Steel Section Based on COPRA and Orthogonal Experiment.

Cold roll forming can fabricate products with complex profiles, and its parameter optimization can achieve high quality and improved precision of products. In this paper, taking the side shield as a typical product, the cold roll forming of a complex section of stainless steel SUS301L-ST is analyzed, establishing a 3D finite element model by using the professional roll forming software COPRA. We propose a floating roll device for complex sections with asymmetry and large depth. We use an orthogonal experiment to obtain the inter-distance between rolls, friction coefficients, the diameter increments, and line velocities to investigate the effects on the maximum longitudinal strain of the edge. Results show that the diameter increment has the greatest influence on the maximum strain, and its increases can reduce the strain. The inter-distance value needs a suitable range. A small value is not conducive to the release of elastic deformation, while a large value will cause unexpected displacement and increase the cost. The friction coefficient increases; although it helps to reduce the strain, it will cause scratches and other defects on the stainless steel. The increase in velocity increases the strain. We derive the optimal parameters for the complex section, providing a theoretical basis for practical production.

Six pairs of phenylpropanoid enantiomers from Cinnamomum mollifolium.

Six pairs of undescribed phenylglycerol benzoate enantiomers, (±)-mollifolines A-F, which can also be categorized into three two-pairs of epimers, were isolated from Cinnamomum mollifolium H. W. Li (Lauraceae). The relative configurations (threo or erythro) of the epimers were determined by conformational searching of the lowest energy conformers and analyses of the relationship between the dihedral angle of H-7'─C-7'─C-8'─H-8' and the 3JH-7', H-8' coupling constant according to the Karplus equation. Furthermore, intramolecular hydrogen bonds were proved to play an important role in stabilizing the lowest conformations by using reduced density gradient (RDG) method for noncovalent interactions. Chiral resolutions of these enantiomer pairs were accomplished by immobilized polysaccharide derivative-based chiral HPLC columns. Absolute configurations of the 12 optically pure isomers were finally determined by quantum chemical time-dependent density functional theory (TDDFT) calculations of their electronic circular dichroism (ECD) spectra.

(±)-Heterocageflavone, anti-inflammatory isoprenylated flavonoids with a tricyclo[5.3.1.03,8]undecane moiety from Artocarpus heterophyllus.

(±)-Heterocageflavone (1), a pair of enantiomeric isoprenylated flavonoids, were isolated from Artocarpus heterophyllus. Compound 1 incorporates an unusual tricyclo[5.3.1.03,8]undecane moiety, forming a unique caged polycyclic system. The structures of the pair were determined by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction. Compound 1 showed significant inhibitory activity against LPS-induced NO production in RAW264.7 cells with an IC50 value of 49.2 µM.

α-Pyrones with glucose uptake-stimulatory activity from the twigs of Cryptocarya wrayi.

Five new α-pyrones, cryptowratones A-E (1-5), and five known congeners (6-10), together with four other known compounds 11-14 were isolated from the twigs of Cryptocarya wrayi. The structures of the new compounds were elucidated on the basis of extensive spectroscopic data analysis and ECD calculations. All α-pyrones except 6 were evaluated for their stimulatory effects on glucose uptake in vitro with CHO-K1/GLUT4 cells. The positive control insulin displayed an approximate 42 ± 0.14% promotion on glucose uptake at 25 µM, compared with the CHO-K1/GLUT4 group. Compounds 1a/2a, 2, 3, and 10 showed a more significant stimulation of glucose uptake than insulin (25 µM) by 36 ± 0.08%, 27 ± 0.12%, 28 ± 0.12%, and 25 ± 0.12% at 1.5 µM, respectively. Immunofluorescence assays indicated the glucose uptake-stimulatory activity of α-pyrones might be correlated with increased GLUT4 translocation.

Two new isoquinoline alkaloids from Cryptocarya wrayi and their biological activities.

Two new isoquinoline alkaloids, cryptowrayines A (1) and B (2), along with one known pavine alkaloid (-)-12-hydroxyeschscholtzidine (3), were isolated from the twigs of Cryptocarya wrayi. The structures of new compounds were elucidated by extensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Both compounds 1 and 2 exhibited moderate quinone reductase inducing activity in Hepa 1c1c7 cells.

Discovery of a Potential Liver Fibrosis Inhibitor from a Mushroom Endophytic Fungus by Genome Mining of a Silent Biosynthetic Gene Cluster.

Liver fibrosis has accounted for liver diseases and overall mortality, but no relevant drug has been developed. Filamentous fungi are important resources of natural products for pharmaceutical development. Calcarisporium arbuscula is a mushroom endophytic fungus, which primarily produces aurovertins. Here, in an aurovertin null-production mutant, one silent gene cluster (mca17) was activated by overexpression of a pathway-specific zinc finger transcriptional regulator, and a tetramic acid-type compound (1, MCA17-1) was identified. Along with detailed structural characterization, its biosynthesis was proposed to be produced from the core PKS-NRPS hybrid enzyme. Moreover, 1 suppressed the activation of LX-2 upon transforming growth factor-ß (TGF-ß) challenge and had stronger bioactivity than the positive control obeticholic acid (OCA) against liver fibrosis. Our work suggested that this engineered fungus could be a producer of 1 for promising pharmaceutical development, and alternatively, it would be developed as a mushroom ingredient in dietary therapy to prevent liver fibrosis.

A Cryptic Plant Terpene Cyclase Producing Unconventional 18- and 14-Membered Macrocyclic C25 and C20 Terpenoids with Immunosuppressive Activity.

A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18-/14-membered sesterterpenoids including five new ones and two 14-membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3- and 2.5-fold, respectively, more sesterterpenoids than the wild-type enzyme were engineered. Both 18- and 14-membered ring sesterterpenoids displayed significant inhibitory activity on the IL-2 and IFN-γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well-trodden territory of plant terpenoid biosynthesis.

[A new phenylethanol glycoside from Baphicacanthis Cusiae Rhizoma et Radix].

The 95% ethanol extract of Baphicacanthis Cusiae Rhizoma et Radix was purified by multi-chromatographic methods including microporous resin, silica gel, Sephadex LH-20, and C_(18) reversed-phase column chromatography. Fourteen compounds were isolated and structurally identified, including five phenylethanoid glycosides, five phenylpropanoids, one lupinane triterpene, two alkaloids, and one flavonoid, listed as follows: 2-(4-hydroxy-3-methoxyphenyl)-3-(2-hydroxy-5-methoxyphenyl)-3-oxo-1-propanol B(1), threo-2,3-bis-(4-hydroxy-3-methoxybenzene)-3-methoxypropanol(2), 2-(3-hydroxy-4-methoxyphenyl)-ethanol-1-O-[3,4-O-di-acetyl-(1→3)-O-α-L-rhamnopyranosyl]-ß-D-glucopyranoside(3), verbascoside(4), 2″,3″-di-O-acetyl martynoside(5),(+)-pinore-sinol(6), diospyrosin(7), daidzein(8), wiedemannioside B(9), buddlenol A(10), 2″-O-acetyl martyonside(11), lupeol(12), indirubin(13), and tryptanthrin(14). Compound 3 was a new phenylethanoid glycoside, and the other 10 compounds were isolated for the first time from Baphicacanthis Cusiae Rhizoma et Radix except compounds 12, 13, and 14.

Pseudosterins A-C, Three 1-Ethyl-3-formyl-ß-carbolines from Pseudostellaria heterophylla and Their Cardioprotective Effects.

Pseudostellaria heterophylla is used in China not only as a functional food but also as an herb to tonify the spleen, enhance immunity, and treat palpitation. Our previous investigation showed that a fraction enriched in glycosides obtained from the roots of P. heterophylla possessed pronounced protective effects on H9c2 cells against CoCl2-induced hypoxic injury. However, the active compounds responsible for the observed effects were still unknown. In the current investigation, pseudosterins A-C (1-3), three new alkaloids with a 1-ethyl-3-formyl-ß-carboline skeleton, together with polydatin, have been isolated from the active fraction. Their structures were elucidated on the basis of spectroscopic analysis and quantum chemical calculations. The four compounds showed cardioprotective effects against sodium hydrosulfite-induced hypoxia-reoxygenation injury in H9c2 cells, with the three alkaloids being more potent. This is also the first report of alkaloids with a ß-carboline skeleton isolated from P. heterophylla as cardioprotective agents.

Structural Elucidation of Three 9,11-Seco Tetracyclic Triterpenoids Enables the Structural Revision of Euphorol J.

Compounds 1-3, the rare examples of 9,11-seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi. Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1. 1-3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC50 values in the range of 2.9-3.9 µM.