Mapping the regulatory effects of herbal organic compounds on gut bacteria.

Herbal organic compounds (HOCs) are bioactive natural products from medicinal plants and some traditional Chinese medicines (TCMs). Recently, ingestion of a few HOCs with low bioavailability has been associated with alterations in gut microbiota, but the extent of this phenomenon remains unclear. Here, we systematically screened 481 HOCs against 47 representative gut bacterial strains in vitro and found that almost one-third of the HOCs exhibited unique anticommensal activity. Quinones showed a potent anticommensal activity, while saturated fatty acids exhibited stronger inhibition of the Lactobacillus genus. Flavonoids, phenylpropanoids, terpenoids, triterpenoids, alkaloids and phenols displayed weaker anticommensal activity, but steroids, saccharides and glycosides had hardly any effect on strain growth. Notably, S-configuration HOCs demonstrated stronger anticommensal activity than R-configuration HOCs. The strict screening conditions ensured high accuracy (95%) through benchmarking validation. Additionally, the effects of HOCs on human fecal microbiota profiling were positively correlated with their anticommensal activity against bacterial strains. Molecular and chemical features such as AATS3i and XLogP3 were correlated with the anticommensal activity of the HOCs in the random forest classifier. Finally, we validated that curcumin, a polyhydric phenol with anticommensal activity, improved insulin resistance in HFD mice by modulating the composition and metabolic function of gut microbiota. Our results systematically mapped the profile of HOCs directly affecting human gut bacterial strains, offering a resource for future research on HOC-microbiota interaction, and broadening our understanding of natural product utilization through gut microbiota modulation.

Leocarpinolide B Attenuates Collagen Type II-Induced Arthritis by Inhibiting DNA Binding Activity of NF-κB.

Rheumatoid arthritis (RA) is a chronic autoimmune disease triggered by a cascading inflammatory response. Sigesbeckia Herba (SH) has long been utilized as a traditional remedy to alleviate symptoms associated with rheumatism. Our previous study found that leocarpinolide B (LB), a sesquiterpene lactone isolated from the whole plant of SH, possesses potent a anti-inflammatory effect on macrophages. This study was designed to evaluate the therapeutic effects of LB on RA, and further investigate the underlying mechanisms. In collagen type II-induced arthritic mice, LB was demonstrated to decrease the production of autoimmune antibodies in serum and inflammatory cytokines in the joint muscles and recover the decreased regulatory T lymphocytes in spleen. Moreover, LB significantly suppressed the inflammatory infiltration, formation of pannus and bone erosion in the paw joints. In vitro testing showed that LB inhibited the proliferation, migration, invasion, and secretion of inflammatory cytokines in IL-1ß-induced human synovial SW982 cells. Network pharmacology and molecular docking suggested NF-κB p65 could be the potential target of LB on RA treatment, subsequent experimental investigation confirmed that LB directly interacted with NF-κB p65 and reduced the DNA binding activity of NF-κB in synovial cells. In conclusion, LB significantly attenuated the collagen type II-induced arthritis, which was at least involved in the inhibition of DNA binding activity of NF-κB through a direct binding to NF-κB p65. These findings suggest that LB could be a valuable lead compound for developing anti-RA drugs.

Rapid Screening of Lipase Inhibitors from Ophiopogonis Radix Using High-Performance Thin Layer Chromatography by Two Step Gradient Elution Combined with Bioautographic Method.

In this study, a high-performance thin layer chromatography (HPTLC) method by two step gradient elution with two mobile phases was developed for the simultaneous analysis of seven constituents in Ophiopogonis Radix. The chromatography was performed on silica gel 60 F254 plate with dichloromethane-methanol-ethyl acetate-water (70:25:12:3, v/v/v/v) and dichloromethane-methanol (300:1, v/v) as the mobile phase for two step gradient elution. Then, the HPTLC profiles were observed after derivatization with 10% sulfuric acid in ethanol solution. The obtained HPTLC images were further analyzed by chemometric approaches and the samples could be clustered based on regions and/or growth years, which were two important factors affecting the constituents in Ophiopogonis Radix. Furthermore, five compounds including ophiopogonin D, ophiopojaponin C, ophiopogonin D', ophiopogonin C' and methylophiopogonanone B were screened as potential lipase inhibitors from Ophiopogonis Radix by the HPTLC-bioautographic method. The binding modes and interactions between the five compounds and lipase were further explored by molecular docking analysis. The developed HPTLC method could be used for quality control of Ophiopogonis Radix and screening of the potential lipase inhibitors.

[Traditional Chinese medicine network pharmacology: development in new era under guidance of network pharmacology evaluation method guidance].

Traditional Chinese medicine(TCM) has unique advantages in the prevention and treatment of diseases owing to its holistic view and more than 2 000 years of experience in the clinical use of natural medicine. The "holistic" characteristic of TCM gives birth to a new generation of research paradigm featuring "network" and "system", which has been developing rapidly in the era of biomedical big data and artificial intelligence. Network pharmacology, a representative research field, provides new ideas and methods for the research of the interdiscipline of artificial intelligence and medicine, the analysis of massive biomedical data, and the transformation from data to knowledge. TCM plays an important role in proposing the core theory of "network target" and promoting the establishment and development of network pharmacology, and has taken the lead in formulating the first international standard of network pharmacology--Network Pharmacology Evaluation Method Guidance. In terms of theory, network target can systematically link drugs and diseases and quantitatively interpret the overall regulatory mechanism of drugs. In the aspect of method, network pharmacology is developing towards a research model that combines computational, experimental, and clinical approaches. This review introduces the resent important progress of TCM network pharmacology in predicting drug targets, understanding the biological basis of drugs and diseases, and searching for disease and syndrome biomarkers. Under the guidance of Network Pharmacology Evaluation Method Guidance, the development of network pharmacology is expected to become more and more standardized and healthy. Network target will help produce more high-quality research outcomes in TCM and effectively boost the modernization and internationalization of TCM.

Screening of Potential Thrombin and Factor Xa Inhibitors from the Danshen-Chuanxiong Herbal Pair through a Spectrum-Effect Relationship Analysis.

In this study; a spectrum-effect relationship analysis combined with a high-performance liquid chromatography-mass spectrometry (LC-MS) analysis was established to screen and identify active components that can inhibit thrombin and factor Xa (THR and FXa) in Salviae Miltiorrhizae Radix et Rhizoma-Chuanxiong Rhizoma (Danshen-Chuanxiong) herbal pair. Ten potential active compounds were predicted through a canonical correlation analysis (CCA), and eight of them were tentatively identified through an LC-MS analysis. Furthermore; the enzyme inhibitory activity of six available compounds; chlorogenic acid; Z-ligustilide; caffeic acid; ferulic acid; tanshinone I and tanshinone IIA; were tested to verify the feasibility of the method. Among them; chlorogenic acid was validated to possess a good THR inhibitory activity with IC50 of 185.08 µM. Tanshinone I and tanshinone IIA are potential FXa inhibitors with IC50 of 112.59 µM and 138.19 µM; respectively. Meanwhile; molecular docking results show that tanshinone I and tanshinone IIA; which both have binding energies of less than -7.0 kcal·mol-1; can interact with FXa by forming H-bonds with residues of SER214; GLY219 and GLN192. In short; the THR and FXa inhibitors in the Danshen-Chuanxiong herbal pair have been successfully characterized through a spectrum-effect relationship analysis and an LC-MS analysis.

Depressive symptoms, cognitive functions and daily activities: An extended network analysis in monozygotic and dizygotic twins.

BACKGROUND: The network theory posits that depression emerges as the result of individual symptoms triggering each other. Risk factors for depression can impact these between-symptoms interactions through extended networks. The study aimed to model the extended network of depressive symptoms and known depression risk factors - objective cognitive function, intellectual, physical, and social daily activities, and then, compare the observed networks between monozygotic (MZ) and dizygotic (DZ) co-twins. METHODS: Twin pairs, 722 MZ and 2200 DZ, aged 40-79, were selected from the Dansh Twin Registry for having complete measures of depressive symptoms (e.g., sadness), cognitive functions (e.g., verbal memory), physical (e.g., brisk walk), intellectual (e.g., reading newspapers) and social activities (e.g., phone calls). Gaussian graphical models were used to estimate and compare the networks first between co-twins and then, between MZ to DZ twin pairs separately. RESULTS: Specific intellectual, physical and social activities were central in the extended networks of depressive symptoms and, with the exception of processing speed, more central than cognition. The extended networks' structure was more homogeneous between MZ co-twins relative to DZ co-twins. Cognitive nodes were more central in MZ than DZ co-twins. LIMITATIONS: Cross-sectional design, participants were middle-aged or older, mostly affective (non-somatic) depressive symptoms. CONCLUSIONS: In depression networks, core connecting elements were intellectual, physical and social activities. The interaction between cognition and daily activities seems critical for triggering depressive symptoms. Thus, clinical interventions aimed at preventing depression and associated cognitive deficits should focus on maintenance and/or engagement in stimulating daily activities.

Profiling targets and potential target pairs of CAR-T cell therapy in clinical trials.

Since the approval of the first chimeric antigen receptor (CAR)-T product in 2017, the number of new CAR-T clinical trials worldwide exceeds 100 per year. 1649 clinical studies have been conducted to explore possible future clinical applications of targets or target pairs through different biotechnologies. In this study, we aim to take a data-driven analytical approach to explore potential dual-target pairs based on clinical trial information. We screened 1283 non-withdrawal interventional CAR-T clinical trials spanning 96 different targets and 74 target pairs from clinicaltrials.gov. Through the Circos plot and temporal network plots, the information between targets and indications was visualized. Based on the assumption that two targets of a target pair must target the same indication, five new target pairs were inferred, including CD19/CD7, CD19/CD5, CD19/CD37, and CD19/BAFFR and validated by expression pattern, literature and patent information. This study provides novel support for target profiling of CAR-T from the perspective of clinical trials and also provides a reference for researchers and developers to select new targets or target pairs of CAR-T cell therapy.

Microalgae Microneedle Supplies Oxygen for Antiphotoaging Treatment.

UV exposure often triggers photoaging of the skin. Pharmacological treatment suffers from severe side effects as well as poor efficacy because of insufficient skin penetration. Dissolved oxygen has been previously shown to reverse photoaged skin; however, the treatment is often limited by the availability of equipment (e.g., high-pressure oxygen). Poor oxygen diffusion into the skin has also limited its therapeutic efficacy. Herein, we developed a microneedle patch to deliver living microalgae to the deeper layers of the skin for efficient oxygenation and reversal of photoaging. The continuous release of oxygen from microalgae in the skin through photosynthesis reversed the inflammatory microenvironment and reduced reactive oxygen species levels in the photodamaged skin, leading to collagen regeneration and reduced wrinkles. This study provides not only a means for highly efficient skin oxygenation and reversal of photoaging but also an important theoretical basis for the clinical treatment of photoaging.

Expanding potential targets of herbal chemicals by node2vec based on herb-drug interactions.

BACKGROUND: The identification of chemical-target interaction is key to pharmaceutical research and development, but the unclear materials basis and complex mechanisms of traditional medicine (TM) make it difficult, especially for low-content chemicals which are hard to test in experiments. In this research, we aim to apply the node2vec algorithm in the context of drug-herb interactions for expanding potential targets and taking advantage of molecular docking and experiments for verification. METHODS: Regarding the widely reported risks between cardiovascular drugs and herbs, Salvia miltiorrhiza (Danshen, DS) and Ligusticum chuanxiong (Chuanxiong, CX), which are widely used in the treatment of cardiovascular disease (CVD), and approved drugs for CVD form the new dataset as an example. Three data groups DS-drug, CX-drug, and DS-CX-drug were applied to serve as the context of drug-herb interactions for link prediction. Three types of datasets were set under three groups, containing information from chemical-target connection (CTC), chemical-chemical connection (CCC) and protein-protein interaction (PPI) in increasing steps. Five algorithms, including node2vec, were applied as comparisons. Molecular docking and pharmacological experiments were used for verification. RESULTS: Node2vec represented the best performance with average AUROC and AP values of 0.91 on the datasets "CTC, CCC, PPI". Targets of 32 herbal chemicals were identified within 43 predicted edges of herbal chemicals and drug targets. Among them, 11 potential chemical-drug target interactions showed better binding affinity by molecular docking. Further pharmacological experiments indicated caffeic acid increased the thermal stability of the protein GGT1 and ligustilide and low-content chemical neocryptotanshinone induced mRNA change of FGF2 and MTNR1A, respectively. CONCLUSIONS: The analytical framework and methods established in the study provide an important reference for researchers in discovering herb-drug interactions, alerting clinical risks, and understanding complex mechanisms of TM.

A network pharmacology-based study on the quality control markers of antithrombotic herbs: Using Salvia miltiorrhiza - Ligusticum chuanxiong as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza (Danshen, DS), the dried root and rhizome of Salvia miltiorrhiza Bunge and Ligusticum chuanxiong (Chuanxiong, CX), the dried rhizomes of Ligusticum striatum DC are effective in invigorating blood circulation and eliminating stasis which is highly related with cardiovascular disease (CVD). AIM OF STUDY: The identification of activity-based chemical markers is very important, but the complex mechanism of "multi-component, multi-target, and multi-effect" within traditional Chinese medicine (TCM) poses a great challenge to this work. In this study, we combined network pharmacological prediction with experimental validation of the DS and CX to explore an effective method for discovering quality control (QC) of antithrombotic herbs by clarifying the intermediate layer "module/cluster" between the whole complex system and a single component. MATERIALS AND METHODS: Based on structural similarity analysis of compound and the thrombosis network published before, we firstly modularized two layers called chemical cluster (CC) network and functional module (FM) network respectively and linked them into one bilayer modularized compound target (BMCT) network. "Two-step" calculation was applied on identifying the significant compounds as the potential QC markers from CC. The in vitro inhibitory activity of selected QC marker compounds on thrombin was evaluated to partially verify their pharmacological activities. HPLC was used to determine contents. RESULTS: According to the network-based analysis, nine compounds with great importance in the BMCT network were identified as QC markers of DS-CX, including tanshinone I, tanshinone IIA, cryptotanshinone, salvianolic acid B, ferulic acid, salvianolic acid A, rosmarinic acid, chlorogenic acid, and coniferyl ferulate. Enzyme inhibitory test partially verified the activity of tanshinone I and tanshinone IIA. Chemical profiling indicated that the nine marker compounds are the main components in the herbal pair. CONCLUSIONS: This study identified activity-based QC markers of DS-CX herbal pair and provided a new methodology that can be used in the QC of other herbs, herbal pairs, or formulas.

Field experiments of different fracturing designs in tight conglomerate oil reservoirs.

Mahu oilfield is currently the largest tight conglomerate reservoir in the world, where Ma-131 and Ma-18 plays are the first two commercially developed reservoirs. In order to reduce the cost and explore the best fracturing parameters, field experiments have been conducted in these two plays since 2017. Types of proppant and fracturing fluid, the slickwater ratio, and the fracture spacing are mainly changed for comparison, and fracturing effects are evaluated to establish a reference for developing neighboring plays in the Mahu oilfield. This paper summarizes the fracturing parameters and production histories of 74 wells in Ma-131 and Ma-18 plays during four years of field operations. Firstly, results indicate that silica sands perform similar to ceramics in the Ma-131 play where the reservoir depth is smaller than 3300 m; however, in the Ma-18 play where the reservoir is deeper than 3500 m, increasing the sand volume by 1.1-1.2 times still cannot reach the production in wells using ceramics. Secondly, when the fracture spacing is reduced, both oil production and water flowback become even smaller in wells using sands than those using ceramics; this is due to the increase of closure pressure and decrease of fluid volume per cluster respectively. Thirdly, when the crosslinked guar is replaced by the slickwater, no obvious change in oil production is noticed even though the volume of fracturing fluid is almost doubled; limited lengths of propped fractures due to the poor proppant-carrying ability of slickwater likely offset the production enhancement from the decrease of formation damage by slickwater. This paper summarizes learnings from the field experiments during the four-year development of the Mahu oilfield, and help guide the optimization of hydraulic fracturing parameters for future wells.

Multiscale structural changes and retrogradation effects of addition of sodium alginate to fermented and native wheat starch.

This work investigated the changes in multi-scale structure and retrogradation properties of native wheat starches (NS) modified by sodium alginate (AG) with and without fermentation. AG adhered on the surface of NS granules and fermentation promoted the adhesions. Compared with the addition of AG alone, dual modification by fermentation and AG together showed a greater effect to increase the weight-average molecular weight and reduce the relative crystallinity and double helix degree of NS. Small angle X-ray diffraction results showed a significant increase in amorphous region with dual modification compared with AG alone. Additionally, dual modification greatly slowed the increase of relative crystallinity and the enthalpy (ΔH) of NS paste during storage. The results of this study suggest that dual modification is a more effective approach to modify structures and properties of wheat starch than single AG treatment, and suggest its potential industrial application in starch-based foods.

Translating traditional herbal formulas into modern drugs: a network-based analysis of Xiaoyao decoction.

BACKGROUND: Traditional Chinese medicine (TCM) encompasses numerous herbal formulas which play critical therapeutic roles through "multi-components, multi-targets and multi-pathways" mechanisms. Exploring the interaction among these mechanisms can certainly help to depict the core therapeutic function of herbal formulas. Xiaoyao decoction (XYD) is one of the most well-known traditional Chinese medicine formulas which has been widely applied to treat various diseases. In this study, taking XYD as an example, we proposed a network pharmacology-based method to identify the main therapeutic targets of this herbal concoctions. METHODS: Chemical data of XYD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID) and Compound Reference Database (CRD) and screened oral bioavailability attributes from SwissADME using Veber's filter. Targets of sample chemicals were identified using the online tool similarity ensemble approach (SEA), and pathways were enriched using STRING database. On the basis of targets-pathways interactions from the enrichment, a "targets-pathways-targets" (TPT) network was constructed. In the TPT network, the importance of each target was calculated by the declining value of network efficiency, which represents the influential strength of a specific set-off target on the whole network. Network-based predictive results were statistically validated with existing experimental evidence. RESULTS: The TPT network was comprised of 279 nodes and 6549 edges. The declining value of network efficiency of the sample targets was significantly correlated with their involvement frequency in existing studies of XYD using Spearman's test (p < 0.001). The top 10% of candidate targets, such as AKT1, PIK3R1, NFKB1 and RELA, etc., were chosen as XYD's main therapeutic targets, which further show pharmacological functions synergistically through 11 main pathways. These pathways are responsible for endocrine, nutritional or metabolic diseases, neoplasms and diseases of the nervous system, etc. CONCLUSIONS: The network pharmacology-based approach in the present study shows promising potential for identifying the main therapeutic targets from TCM formulas. This study provides valuable information for TCM researchers and clinicians for better understanding the main therapeutic targets and therapeutic roles of herbal decoctions in clinical settings.

Treatment efficacy analysis of traditional Chinese medicine for novel coronavirus pneumonia (COVID-19): an empirical study from Wuhan, Hubei Province, China.

BACKGROUND: A novel coronavirus was identified in December, 2019 in Wuhan, China, and traditional Chinese medicine (TCM) played an active role in combating the novel coronavirus pneumonia (NCP) caused by this fast-spreading virus COVID-19. Thus, we aimed to explore TCM characteristics of clinical efficacy to NCP, as well as to optimize Qingfei Paidu decoction (QFPDD) and the recommended formulas to NCP by National Health Commission (NHC). METHODS: Chinese medical sciences theory and clinical application of TCM were analyzed. A total of 54 NCP patients were observed in a hospital from Wuhan, whose clinical characteristics and utilization of Chinese Medicines (CMs) were described. Paired t test was used to measure the change of patients' hemogram during hospitalization period, indicating the effect of CMs. Multiple linear regression analysis was applied to explore the factors affecting the length of hospital stay. Network pharmacology analysis was applied to figure out the performance of NHC-recommended formulas of five disease stages at levels of compounds, targets and pathways. RESULT: The average length of hospital stay was 8.96 days. Patients over 45 stayed 9.79 days in hospital in average, longer than 7.64 days of patients under 45. Comparing the hemograms between admission and discharge of hospital, the number of leukocytes, neutrophil, lymphocyte and platelet increased, while the numbers of erythrocytes, hemoglobin concentration and hematocrit decreased. According to the standard coefficients of regression, the factor affecting the length of stay for the most was CMs in category of invigorating spleen and removing dampness (ISRD), followed by administrating CMs, male, and cough. Thirty-two CMs were screened after deleting duplication from QFPDD and NHC-recommended formulas. Compound quercetin, luteolin, kaempferol, acacetin etc., were all involved in the treatment of various disease stages on the compound level both in generality and individuality. CONCLUSION: TCM has a systemic theoretical understanding on the pathological evolution and a positive clinical efficacy on NCP. The CMs of ISRD improved patients' recovery, suggesting the importance of regulating intestinal function and keeping microenvironmental balance in TCM treatment of NCP. The active compounds from QFPDD and NHC-recommended formulas contribute to recovery of varied disease progresses during TCM treating NCP.