SGAE-MDA: Exploring the MiRNA-disease associations in herbal medicines based on semi-supervised graph autoencoder.

Research indicates that miRNAs present in herbal medicines are crucial for identifying disease markers, advancing gene therapy, facilitating drug delivery, and so on. These miRNAs maintain stability in the extracellular environment, making them viable tools for disease diagnosis. They can withstand the digestive processes in the gastrointestinal tract, positioning them as potential carriers for specific oral drug delivery. By engineering plants to generate effective, non-toxic miRNA interference sequences, it's possible to broaden their applicability, including the treatment of diseases such as hepatitis C. Consequently, delving into the miRNA-disease associations (MDAs) within herbal medicines holds immense promise for diagnosing and addressing miRNA-related diseases. In our research, we propose the SGAE-MDA model, which harnesses the strengths of a graph autoencoder (GAE) combined with a semi-supervised approach to uncover potential MDAs in herbal medicines more effectively. Leveraging the GAE framework, the SGAE-MDA model exactly integrates the inherent feature vectors of miRNAs and disease nodes with the regulatory data in the miRNA-disease network. Additionally, the proposed semi-supervised learning approach randomly hides the partial structure of the miRNA-disease network, subsequently reconstructing them within the GAE framework. This technique effectively minimizes network noise interference. Through comparison against other leading deep learning models, the results consistently highlighted the superior performance of the proposed SGAE-MDA model. Our code and dataset can be available at: https://github.com/22n9n23/SGAE-MDA.

Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways.

BACKGROUND: In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined. AIM: To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo. METHODS: In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo, SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways. RESULTS: The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways. CONCLUSION: In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.

Quercetin, the Ingredient of Xihuang Pills, Inhibits Hepatocellular Carcinoma by Regulating Autophagy and Macrophage Polarization.

BACKGROUND: The key active component(s) in an anti-tumor preparation used in traditional Chinese medicine, Xihuang Pills, remains unclear. METHODS: We used a network pharmacology analysis to construct a component-disease-target network diagram and used this to determine quercetin as a critical active ingredient in Xihuang Pills. Subsequently, human hepatocellular carcinoma (HCC) cell lines, H22 and HepG2 cells, were treated with quercetin, and BALB/c mice were injected with H22 cells and treated with different concentrations of quercetin. Tumor volume and weight were determined in these mice with and without quercetin administration. Immune and pro-inflammatory factors were measured using Enzyme Linked Immunosorbent Assay (ELISA). Macrophage polarization was assessed by western blot and flow cytometry. Finally, PD-L1, autophagy-related proteins, and the NF-κB pathway were also analyzed. RESULTS: Quercetin could significantly inhibit the proliferation, migration, and invasion characteristics of HCC cells and promote apoptosis in a concentration-dependent manner in vitro. After quercetin treatment, tumor volume and weight significantly decreased in vivo. Granulocyte-macrophage and granulocyte colony-stimulating factor (GM-CSF and G-CSF, respectively) levels were blunted in response to quercetin, as well as the PD-L1 level. CD86+ cell ratio was increased, while the CD206+ cell ratio was decreased, suggesting that macrophages tend to undergo M1 polarization in response to quercetin. The expression of LC3 II/I was increased, while the expression of p62 was down-regulated. The pro-inflammatory factors TNF-α, IL-6, and IL-17A, as well as NF-κB signaling were suppressed in a quercetin concentration-dependent manner. CONCLUSIONS: Quercetin is a key ingredient of anti-HCC activity in Xihuang Pills by regulating macrophage polarization and promoting autophagy via the NF-κB pathway.

[Study on effect of gypenosides on insulin sensitivity of rats with diabetes mellitus via regulating NF-κB signaling pathway].

This study focused on the ameliorative effects of gypenosides(GPS) on insulin sensitivity and inflammatory factors in rats with type 2 diabetes mellitus(T2 DM) and explored their possible molecular mechanisms. After the successful establishment of T2 DM model, diabetic rats were randomly divided into four groups, including model group, GPS groups(200, 100 mg·kg~(-1)) and metformin group(100 mg·kg~(-1)), with healthy rats serving as the control. After 6-week intragastric administration, fasting blood glucose(FBG) and oral glucose tolerance were examined. The levels of insulin, C-peptide, tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6) and C-reactive protein(CRP) in serum were examined. Then the homeostasis model assessment of insulin resistance(HOMA-IR) and insulin sensitivity index(ISI) were calculated. The protein expression levels of phosphorylated insulin receptor substrate-1(p-IRS-1) and phosphorylated protein kinase B(p-Akt) in skeletal muscle were measured by Western blot, as well as those of phosphorylated inhibitor of nuclear factor-κB(NF-κB) kinase ß(p-IKKß), phosphorylated alpha inhibitor of NF-κB(p-IκBα) and phosphorylated p65 subunit of NF-κB(p-p65) in adipose tissue. The relative expression levels of glucose transporter 4(GLUT4) mRNA in skeletal muscle and NF-κB mRNA in adipose tissue were measured by qRT-PCR, and the morphological changes of pancreatic tissue were observed. Compared with the model group, the GPS groups witnessed significant decrease in FBG, marked amelioration of impaired oral glucose tolerance and significant increase in ISI. Further, the high-dose GPS group saw significantly reduced HOMA-IR, TNF-α, IL-1ß and CRP, significantly increased expression levels of p-IRS-1(Tyr), p-Akt and GLUT4, and markedly inhibited p-IRS-1(Ser), p-IKKß, p-IκBα, p-p65 and NF-κB. The concentration of CRP and the expression levels of p-IRS-1(Ser), p-IKKß, p-IκBα and NF-κB were remarkably reduced in the low-dose GPS group. However, GPS was found less effective in the regulation of serum insulin, C-peptide and IL-6 levels and the alleviation of pancreatic islet injury. The results indicated that GPS can reduce FBG and improve insulin sensitivity in diabetic rats possibly by regulating the NF-κB signaling pathway, inhibiting inflammation, and thereby regulating the expression of key proteins in the insulin signaling pathway.

[Textual research on Zhuru Tang].

Zhuru Tang( from the Effective Prescriptions for Universal Relief) listed in the Catalogue of Ancient Classical Formulas( The First Batch) by the State Administration of Traditional Chinese Medicine,is usually used to treat stomach fever and vomiting. The first step of the research and development of the classic formula compound preparations is to follow the principle of the ancient method,comb through the literature of all dynasties,and then investigate the historical evolution of the prescription,the evolution of formula significance and the clinical application. Based on this principle,we searched the Chinese Medical Classics Database and relevant literature materials to conduct textual research on the history,evolution of formula significance,clinical application,decocting method,as well as the basis and processing of traditional Chinese medicine from the perspectives of " recipe" and " medicine",in order to provide reference for the development and research of Zhuru Tang.

Flavonoids from the leaves of Carya cathayensis Sarg. inhibit vascular endothelial growth factor-induced angiogenesis.

The total flavonoids (TFs) were isolated from the leaves of Carya cathayensis Sarg. (LCC), a well-known Chinese medicinal herb commercially cultivated in Tianmu Mountain district, a cross area of Zhejiang and Anhui provinces in China. Five flavonoids, i.e. cardamonin, pinostrobin chalcone (PC), wogonin, chrysin, and pinocembrin were the main components of the TFs. The TFs and these pure compounds suppressed vascular endothelial growth factor (VEGF)-induced angiogenesis as detected in the mouse aortic ring assay, and cardamonin showed the best effect among them. To further elucidate the mechanisms for suppressing angiogenesis of these flavonoids, assays of VEGF-induced proliferation and migration in human umbilical vein endothelial cells (HUVECs) were performed. The TFs, cardamonin, pinocembrin, and chrysin obviously suppressed both VEGF-induced HUVEC proliferation and migration. However, PC and wogonin not only slightly inhibited VEGF-induced proliferation but also remarkably suppressed those of migration in HUVECs. Our further study showed that cardamonin decreased the phosphorylation of ERK and AKT induced by VEGF with a dose-dependent manner in HUVECs. Our findings indicate that the TFs and these pure flavonoids may become potential preventive and/or therapeutic agents against angiogenesis-related diseases.

[Rapid propagation of Bletilla striata by synthetic seeds technology].

OBJECTIVE: To establish a new manufacturing method for Bletilla striata synthetic seeds, and provided a new way for rapid propagation of B. striata, the correlated influential factors were studied. METHOD: The synthetic seeds were manufactured by taking seeds of B. striata as materials which were beforehand germinated in 1/2 MS medium for 10 days, and the influential factors such as artificial endosperm components, episperm substances, storage conditions and germination groundmass impact on the germination rate and seedling rate of the synthetic seeds were evaluated. RESULT: Compound 4.0% sodium alginate + 0.2 mol x L(-1) CaCl2 + 0.4 mg x L(-1) penicillin + 0.3% carbendazim powder + 0.2% sodium benzoate served as the best episperm substances while MS + 1.0 mg x L(-1) NAA + 2.0 mg x L(-1) KT as the best endosperm components, in which, high germination rate and seedling rate were obtained. The synthetic seeds storing in the 4 degrees C for a long time was able to have still high vitality. CONCLUSION: The B. striata synthetic seeds manufacturing system was established successfully, while efforts should be taken to improve the sowing technique of the synthetic seeds in non-sterile conditions.