TMNP: a transcriptome-based multi-scale network pharmacology platform for herbal medicine.

One of the most difficult problems that hinder the development and application of herbal medicine is how to illuminate the global effects of herbs on the human body. Currently, the chemo-centric network pharmacology methodology regards herbs as a mixture of chemical ingredients and constructs the 'herb-compound-target-disease' connections based on bioinformatics methods, to explore the pharmacological effects of herbal medicine. However, this approach is severely affected by the complexity of the herbal composition. Alternatively, gene-expression profiles induced by herbal treatment reflect the overall biological effects of herbs and are suitable for studying the global effects of herbal medicine. Here, we develop an online transcriptome-based multi-scale network pharmacology platform (TMNP) for exploring the global effects of herbal medicine. Firstly, we build specific functional gene signatures for different biological scales from molecular to higher tissue levels. Then, specific algorithms are designed to measure the correlations of transcriptional profiles and types of gene signatures. Finally, TMNP uses pharmacotranscriptomics of herbal medicine as input and builds associations between herbs and different biological scales to explore the multi-scale effects of herb medicine. We applied TMNP to a single herb Astragalus membranaceus and Xuesaitong injection to demonstrate the power to reveal the multi-scale effects of herbal medicine. TMNP integrating herbal medicine and multiple biological scales into the same framework, will greatly extend the conventional network pharmacology model centering on the chemical components, and provide a window for systematically observing the complex interactions between herbal medicine and the human body. TMNP is available at http://www.bcxnfz.top/TMNP.

DNA-inspired nanomaterials for enhanced endosomal escape.

To realize RNA interference (RNAi) therapeutics, it is necessary to deliver therapeutic RNAs (such as small interfering RNA or siRNA) into cell cytoplasm. A major challenge of RNAi therapeutics is the endosomal entrapment of the delivered siRNA. In this study, we developed a family of delivery vehicles called Janus base nanopieces (NPs). They are rod-shaped nanoparticles formed by bundles of Janus base nanotubes (JBNTs) with RNA cargoes incorporated inside via charge interactions. JBNTs are formed by noncovalent interactions of small molecules consisting of a base component mimicking DNA bases and an amino acid side chain. NPs presented many advantages over conventional delivery materials. NPs efficiently entered cells via macropinocytosis similar to lipid nanoparticles while presenting much better endosomal escape ability than lipid nanoparticles; NPs escaped from endosomes via a "proton sponge" effect similar to cationic polymers while presenting significant lower cytotoxicity compared to polymers and lipids due to their noncovalent structures and DNA-mimicking chemistry. In a proof-of-concept experiment, we have shown that NPs are promising candidates for antiviral delivery applications, which may be used for conditions such as COVID-19 in the future.

Immunomodulatory Activity and Its Mechanisms of Two Polysaccharides from Poria cocos.

Polyporaceae is an important fungal family that has been a source of natural products with a range of pharmaceutical activities in China. In our previous study, two polysaccharides, PCWPW and PCWPS, with significant antioxidant and antidepressant activity were obtained from Poria cocos. In this study, we evaluated their potential molecular mechanisms in the immunomodulation of macrophages. PCWPW and PCWPS were characterized by GC-MS analysis to contain 1,3-linked Glcp. ELISA assays results demonstrated that the secretion of TNF-α was significantly enhanced by PCWPW/PCWPS. RNA-seq data demonstrated that PCWPS treatment modulated the expression of immune-related genes in macrophages, which was further confirmed by RT-qPCR assays. The activation of TNF-α secretion was found to be mannose receptor (MR) dependent and suppressed by MR inhibitor pretreatment. Moreover, the amount of TNF-α cytokine secretion in PCWPW/PCWPS-induced RAW264.7 cells was decreased when pretreated with NF-κB or MAPK signaling pathway inhibitors. Collectively, our results suggested that PCWPW and PCWPS possessed immunomodulatory activity that regulates TNF-α expression through the NF-κB/MAPK signaling pathway by binding to mannose receptors. Therefore, PCWPW and PCWPS isolated from Poria cocos have potential as drug candidates for immune-related disease treatment.

A Natural Glucan from Black Bean Inhibits Cancer Cell Proliferation via PI3K-Akt and MAPK Pathway.

A natural α-1,6-glucan named BBWPW was identified from black beans. Cell viability assay showed that BBWPW inhibited the proliferation of different cancer cells, especially HeLa cells. Flow cytometry analysis indicated that BBWPW suppressed the HeLa cell cycle in the G2/M phase. Consistently, RT-PCR experiments displayed that BBWPW significantly impacts the expression of four marker genes related to the G2/M phase, including p21, CDK1, Cyclin B1, and Survivin. To explore the molecular mechanism of BBWPW to induce cell cycle arrest, a transcriptome-based target inference approach was utilized to predict the potential upstream pathways of BBWPW and it was found that the PI3K-Akt and MAPK signal pathways had the potential to mediate the effects of BBWPW on the cell cycle. Further experimental tests confirmed that BBWPW increased the expression of BAD and AKT and decreased the expression of mTOR and MKK3. These results suggested that BBWPW could regulate the PI3K-Akt and MAPK pathways to induce cell cycle arrest and ultimately inhibit the proliferation of HeLa cells, providing the potential of the black bean glucan to be a natural anticancer drug.

Immunoregulation and antioxidant activities of a novel acidic polysaccharide from Radix Paeoniae Alba.

Radix Paeoniae Alba is widely used in Chinese traditional medicine to treat various diseases such as gastrointestinal disorders, immunomodulatory, cancer, and other diseases. In this paper, a novel acidic polysaccharide RPAPS purified from Radix Paeoniae Alba was evaluated for its structural features and potential of immunomodulatory and antioxidant activities. RPAPS (molecular weight: 1.0× 105 Da) was mainly composed of α-(1 → 4)-Glcp, α-Arap, α-Galp, α-Rhap, ß-D-Glcp, α-(1 → 6)-linked Glcp and GalA. Immunological tests indicated that RPAPS could improve RAW264.7 phagocytic activity and LPS-induced splenocyte proliferation. For antioxidant activities, RPAPS showed reducing power and DPPH scavenging activity in dose dependent. Moreover, RPAPS could significantly protect the PC12 cells from H2O2 damage. These data implied polysaccharides RPAPS had the potential to be novel natural antioxidative and immunopotentiating agents for using in functional foods or medicine.

Discovery of Natural Compounds for Cardiac Fibrosis by a Transcriptome-Based Functional Gene Module Reference Approach.

Anti-cardiac fibrosis (CF) is one of the key therapeutic strategies for the treatment of various heart diseases. Therefore, development of drugs targeting CF is promising. However, there are very few studies that systemically explore effective drugs for CF. It has been known that many natural compounds display antifibrosis effects. In this work, we aim to build an integrated model for systematic pursuit of anti-CF agents from natural compounds. We first constructed a heart-specific CF marker-gene-centered functional gene module (HCFM) that represents a set of genes specifically involved in CF based on the CF marker genes and known gene coexpression knowledge. Then, we extracted transcriptional data induced by natural compounds from the Gene Expression Omnibus database. The anti-CF effects of compounds were evaluated by the correlation of HCFM in the compound-induced gene expression profiles by gene set enrichment analysis. Finally, the anti-CF effect of a top-predicted natural monomer, schisantherin A, was experimentally validated in the myocardial infarction animal model. This strategy integrating different types of technologies is expected to help create new opportunities for development of drugs targeting CF.

Network pharmacology based investigation of the effects of herbal ingredients on the immune dysfunction in heart disease.

Dysregulated immune system has been implicated in the pathogenesis of various cardiovascular diseases. Therefore, development of pharmacological interventions targeting the immune system is promising. However, therapy with most common anti-inflammatory and immunomodulatory agents has proved challenging in the clinical translation. It has been proved that many herbal ingredients display definite therapeutic effects on preventing excessive inflammatory and immune responses. Here, we aim to systemically explore the immunomodulatory ability of herbal ingredients on the human heart tissue-specific immune dysfunction through a network pharmacology based approach. The approach matches gene expression data between herbal ingredients and human heart phenotype based on their immunological similarities. Firstly, 608 immunological signatures were produced from 304 transcriptional profiles of immunological cell state changes. Then, the immunological features of 28 human heart phenotypes and 102 herbal ingredients were constructed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients, respectively. Finally, the likelihood that an herbal drug affects the immune system in a heart phenotype was qualified by calculating the immunological similarity between the herbal drug and the heart phenotype. This strategy integrating different types of OMICs data is expected to help create new opportunities for development of drugs targeting the immune dysfunction in heart disease.

A concise total synthesis of cochlearoid B.

A T-type calcium channel inhibiting natural product cochlearoid B was synthesized for the first time in 7 linear steps via a convergent strategy exploiting the Suzuki-Miyaura cross coupling and the acid promoted Prins cyclization cascade. This strategy allows rapid access to its structural analogues for further therapeutical development.

Structural characterization and biological activities of two α-glucans from radix paeoniae alba.

Radix Paeoniae Alba is widely used in Chinese traditional medicine to treat various diseases such as gastrointestinal disorders, cancer, and other diseases. In this study, two polysaccharides RPAPW1 and RPAPW2 were isolated from Radix Paeoniae Alba by DEAE-52 cellulose chromatography and G-25 sephadex. According to physicochemical methods, NMR and methylation analysis, RPAPW1 and RPAPW2 were established to be α-glucans consisting of predominant 4-linked α- Glc residues branched at O-6 and contained trace amount of protein and uronic acid. Immunological tests indicated that RPAPW1, RPAPW2 and could promote splenocyte proliferation and RAW264.7 phagocytic activity. In vitro, RPAPW1 and RPAPW2 elicited a week reducing power, DPPH scavenging activity and could not protect the PC12 cells from H2O2 damage. These data implied polysaccharides RPAPW1 and RPAPW2 had the potential to be a natural immunopotentiating and antioxidant supplement for preparing functional foods and nutraceuticals.

Systems-biology dissection of mechanisms and chemical basis of herbal formula in treating chronic myocardial ischemia.

Herbal medicine is a mixture of multiple compounds, and is intended to exhibit therapeutic effects by attacking multiple disease-causing modules simultaneously. However, it is still a challenge for scientists to untangle the complex biological mechanisms and underlying material basis of herbal medicine. Here, this study was designed to build a systems-biology platform for exploring the molecular mechanisms and corresponding active compounds, with a typical example applied to an herbal formula Qishenkel (QSKL) in the treatment of chronic myocardial ischemia. We have applied an approach integrating transcriptome sequencing, bioactivity profiling inference, computational ligand-receptor evaluation and experimental validation to study the effects on pig myocardial ischemia treated with QSKL. Numerous biological modules were revealed and indicated the coordinated regulation of molecular networks from various aspects of cardiac function. In addition, gene expression profiles were utilized to identify a number of key therapeutic targets of herbal formula, such as angiotensin-converting enzyme and calcium channels. Then, these therapeutic targets were used to fish the potential active ingredients based on a combination of target structure-based and chemical ligand-based methods. Some active compounds, including luteolin, cryptotanshinone, licochalcone A, glycyrrhetinic acid, salsolinol, isoacid chlorogenic C, salvianolic acid A and salvianolic acid B, have been validated by direct biochemical methods. This strategy integrating different types of technologies is expected to provide not only a detailed understanding about the combined therapeutic effects of herbal mixture but also a new opportunity for discovering novel natural molecules with pharmacological activities.

Unveiling the Mode of Action of Two Antibacterial Tanshinone Derivatives.

In this study, 2-(N-pyrrolidine-alkyl) tanshinones bearing pyrrolidine groups were synthesized and the antibacterial mechanism was explored. These derivatives selectively elicited antibacterial activity against Gram-positive bacteria. Moreover, their antibacterial activities were time-, concentration-dependent and persistent. It appeared that Fenton-mediated hydroxyl radicals were involved, and the disruption of cell membranes was observed. This study indicates that 2-(N-pyrrolidine-alkyl) tanshinones might be potential candidates as antibacterial agents.

Alteration in immune responses toward N-deacetylation of hyaluronic acid.

Hyaluronic acid (HA) is an ubiquitous nonsulfated glycosaminoglycan of the extracellular matrix in all mammalian connective tissues. Along with the age growth, HA will lose its N-acetyl groups in vivo; however, the significance of this physiological process remains largely unknown. Herein, three highly N-deacetylated HAs (dHAs), dHA-5 kDa (Mw: 5 kDa, DD: 100%), dHA-16 kDa (Mw: 16 kDa, DD: 94%) and dHA-110 kDa (Mw: 110 kDa, DD: 72%), were generated after hydrazinolysis. Their capability in the activation of antigen-presenting cells (APCs) was compared with that of their respective HAs. Our results demonstrated that both HAs and dHAs could activate the nuclear factor-kappa B (NF-κB) transcription factor in APCs and induced cytokine production through the Toll-like receptor (TLR)/MyD88 pathway. Notably, the capacity of dHAs in cytokine induction was much lower than that of HAs. In addition, the TLR-2 pathway was much involved following the appearance of zwitterionic motifs in dHAs. Thus, our findings highlight that N-deacetylation renders HA divergences in immune response, which might be implicated in age-induced functional change in endogenous glycosaminoglycans due to the structural modification in vivo.

Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery.

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in "hard-to-penetrate" tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

A decrease in moisture absorption-retention capacity of N-deacetylation of hyaluronic acid.

The linear non-sulfated glycosaminoglycan, hyaluronic acid (HA), is widely distributed throughout connective, epithelial and neural tissues etc., and is of great importance in tissue hydration, lubrication and cellular function. Along with the age growth, HA will lose its acetyl groups under action of HA N-deacetylase in vivo. However, the biological consequence of this physiological process remains largely unknown. Herein two highly N-deacetylated HAs, dHA-6 and dHA-10 were generated via the NH2NH2-HIO3 procedure. Their molecular weights were estimated to be 24 and 16 kDa by high performance gel-permeation chromatography (HPGPC), and the N-deacetylation degrees were 79.4 % and 93 % respectively, as determined by (1)H nuclear magnetic resonance (NMR). The study on moisture-absorption (Ra) and -retention (Rh) abilities demonstrated that the Ra values of dHAs under conditions of 81 % or 43 % relative humidity, as well as the Rh values of dHAs under dry condition or 43 % relative humidity, were significantly smaller than that of their respective re-N-acetylated products. The decline of moisture-absorption and -retention capacity after HA N-deacetylation were consistent with the appearance of unsolvated amides remained in the N-deacetylated products, as indicated by circular dichroism (CD) spectroscopy. Our findings implied that HA N-deacetylation, in addition to the decrease of HA contents in the elderly persons, might account for manifestations of naturally aged skin, such as laxity, sagging, and wrinkling.

Self-assembled Janus base nanotubes: chemistry and applications.

Janus base nanotubes are novel, self-assembled nanomaterials. Their original designs were inspired by DNA base pairs, and today a variety of chemistries has developed, distinguishing them as a new family of materials separate from DNA origami, carbon nanotubes, polymers, and lipids. This review article covers the principal examples of self-assembled Janus base nanotubes, which are driven by hydrogen-bond and π-π stacking interactions in aqueous environments. Specifically, self-complementary hydrogen bonds organize molecules into ordered arrays, forming macrocycles, while π-π interactions stack these structures to create tubular forms. This review elucidates the molecular interactions that govern the assembly of nanotubes and advances our understanding of nanoscale self-assembly in water.

Temporal-based Swin Transformer network for workflow recognition of surgical video.

PURPOSE: Surgical workflow recognition has emerged as an important part of computer-assisted intervention systems for the modern operating room, which also is a very challenging problem. Although the CNN-based approach achieves excellent performance, it does not learn global and long-range semantic information interactions well due to the inductive bias inherent in convolution. METHODS: In this paper, we propose a temporal-based Swin Transformer network (TSTNet) for the surgical video workflow recognition task. TSTNet contains two main parts: the Swin Transformer and the LSTM. The Swin Transformer incorporates the attention mechanism to encode remote dependencies and learn highly expressive representations. The LSTM is capable of learning long-range dependencies and is used to extract temporal information. The TSTNet organically combines the two components to extract spatiotemporal features that contain more contextual information. In particular, based on a full understanding of the natural features of the surgical video, we propose a priori revision algorithm (PRA) using a priori information about the sequence of the surgical phase. This strategy optimizes the output of TSTNet and further improves the recognition performance. RESULTS: We conduct extensive experiments using the Cholec80 dataset to validate the effectiveness of the TSTNet-PRA method. Our method achieves excellent performance on the Cholec80 dataset, which accuracy is up to 92.8% and greatly exceeds the state-of-the-art methods. CONCLUSION: By modelling remote temporal information and multi-scale visual information, we propose the TSTNet-PRA method. It was evaluated on a large public dataset, showing a high recognition capability superior to other spatiotemporal networks.

Antioxidative properties of crude polysaccharides from Inonotus obliquus.

The mushroom Inonotus obliquus has been widely used as a folk medicine in Russia, Poland and most of the Baltic countries. In this study, water-soluble and alkali-soluble crude polysaccharides (IOW and IOA) were isolated from I. obliquus, and the carbohydrate-rich fractions IOW-1 and IOA-1 were obtained respectively after deproteination and depigmentation. Their contents, such as neutral carbohydrate, uronic acid and protein, were measured. Their antioxidant properties against chemicals-induced reactive species (ROS) including 1,1'-Diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical and superoxide anion radical, as well as their protective effects on H(2)O(2)-induced PC12 cell death were investigated. Results showed that I. obliquus polysaccharides can scavenge all ROS tested above in a dose-dependent manner. IOA and its product IOA-1 could rescue PC12 cell viability from 38.6% to 79.8% and 83.0% at a concentration of 20µg/mL. Similarly, IOW and its product IOW-1 at the same dose, can also increase cell viability to 84.9% and 88.6% respectively. The antioxidative activities of water-soluble and alkali-soluble polysaccharide constituents from I. obliquus might contribute to diverse medicinal and nutritional values of this mushroom.

A novel chemometric method for the prediction of human oral bioavailability.

Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P-glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R(2)) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design.

Chemical Structure and Immune Activation of a Glucan From Rhizoma Acori Tatarinowii.

Rhizoma Acori Tatarinowii is a traditional Chinese herb used to treat depression and coronary heart disease. Studies on its active components mainly focus on small molecular compounds such as asarone and other essential oil components, while the large molecular active components such as polysaccharides are ignored. In this study, we aimed to study the chemical structure and immune activation of polysaccharides from Rhizoma Acori Tatarinowii. In this study, a polysaccharide (RATAPW) was isolated and purified by DEAE-52 cellulose and Sephadex G-100 column chromatography from alkali extraction polysaccharide of Rhizoma Acori Tatarinowii. The average molecular weight of RATAPW was 2.51 × 104 Da, and the total carbohydrate contents of RATAPW were 98.23 ± 0.29%. The monosaccharide composition, methylation, and nuclear magnetic resonance (NMR) analysis results displayed that the polysaccharide was α-1,4-glucan with short α-1,6 branches. Immunofluorescence assay and inhibitor neutralization assay indicated that RATAPW could promote the TNF-α production of RAW264.7 macrophage through the nuclear factor kappa B (NF-κB) molecular signaling pathway. Treatment with 200 µg/ml of RATAPW enhanced a 38.77% rise in the proliferation rate of spleen lymphocytes. RATAPW also enhances ConA-induced T cells and lipopolysaccharide (LPS)-induced B cell proliferation in a dose-dependent effect. Our study lays a foundation for the discovery of natural polysaccharide immune modulators or functional food from Rhizoma Acori Tatarinowii.