Black ginseng: a novel medicine for treating heart failure.

Introduction: Black ginseng (BG) was processed by "steaming and drying" (generally nine times) repeatedly to produce "rare saponins" and secondary ginsenosides. Both ginseng (GS) and red ginseng (RG) were commonly used in treating heart failure (HF), and the latter was confirmed to be more potent, implying the presence of rare ginsenosides that contribute positively to the treatment of heart failure. Previous research indicated that rare ginsenosides are more abundant in BG than in RG. Consequently, this study aims to investigate the effects of BG and its components on HF to elucidate the active substances and their underlying mechanisms in the treatment of HF. Methods: The effects of BG and its fractions (water-eluted fraction (WEF), total saponin fraction (TSF), and alcohol-eluted fraction (AEF)) on rats with isoproterenol (ISO)-induced HF were explored, and steroids belonging to the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes were determined quantitatively using the ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method. In addition, 16S rDNA sequencing was performed on the gut microbiota, followed by GC-MS analysis of short-chain fatty acids (SCFAs), and the biochemical indexes related to energy metabolism and the serum cyclic nucleotide system were also analyzed by ELISA. Results: Based on a thorough evaluation of energy metabolism and the endocrine system, it was observed that the effects of BG components on the hypothalamic-pituitary-thyroid (HPT) and HPA axes were more pronounced. Notably, the treatment efficacy of the low dose of the total saponin fraction (TSFL), water decoction (WD), and high dose of the polysaccharide fraction (PSFH) was superior based on pharmacodynamic indicators such as brain natriuretic peptide (BNP), creatine kinase (CK), and estradiol (E2)/T). Furthermore, the WD and BG components exhibited significant effects on androgens (T and androstenedione (A4)). The TSFL group exerts an anti-inflammatory effect by regulating Lactobacillus/Erysipelotrichales. The WD, PSFH, and TSFL may impact inflammatory cytokines through the gut microbiota (Lactobacillus/Erysipelotrichales) and their metabolites (acetate and butyrate), exerting an anti-inflammatory effect. Discussion: The BG and all its split components demonstrated varying levels of efficacy in alleviating HF, and TSF and PSF exhibited a significant protective effect on HF. The main active components in TSF were revealed to be ginsenosides Rk1, Rk3, 20-(S)-Rg3, and 20-(S)-Rh2 by the H9C2 cell experiment. The decoction of BG and its components exhibited a potent impact on androgen hormones, with an elevation trend. This phenomenon may be attributed to the activation of the eNOS-NO pathway through androgen regulation, thereby contributing to its anti-HF activities. The WD, PSFH, and TSFL may exert anti-inflammatory effects through the intestinal flora (Lactobacillaceae/Erysipelotrichaceae) and its metabolites (acetic acid and butyric acid), which affect the inflammatory factors. The different mechanisms of action of each component of HF also reflect the significance and necessity of the overall role of traditional Chinese medicine (TCM). Our research was the first to report that the E2/T is related to HF and can be used as an indicator to evaluate HF.

Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma.

Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.

The Ameliorative Effects of Arctiin and Arctigenin on the Oxidative Injury of Lung Induced by Silica via TLR-4/NLRP3/TGF-ß Signaling Pathway.

Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1ß, TGF-ß, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-ß signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.

Application of Proteomics and Metabonomics to Reveal the Molecular Basis of Atractylodis Macrocephalae Rhizome for Ameliorating Hypothyroidism Instead of Hyperthyroidism.

As the treatments of diseases with Chinese herbs are holistic and characterized by multiple components, pathways, and targets, elucidating the efficacy of Chinese herbs in treating diseases, and their molecular basis, requires a comprehensive, network-based approach. In this study, we used a network pharmacology strategy, as well as in vivo proteomics and metabonomics, to reveal the molecular basis by which Atractylodis macrocephalae rhizome (AMR) ameliorates hypothyroidism. Eighteen main compounds from AMR and its fractions (volatile oil fraction, crude polysaccharides fraction, lactones fraction, oligosaccharide fraction, and atractyloside fraction) were identified by HPLC, and their targets were screened using the TCMSP database and Swiss Target Prediction. Disease targets were gathered from the TTD, CTD and TCMSP databases. Hub targets were screened by different plug-ins, such as Bisogene, Merge, and CytoNCA, in Cytoscape 3.7.1 software and analyzed for pathways by the DAVID database. Hypothyroidism and hyperthyroidism pharmacological models were established through systems pharmacology based on proteomic and metabolomic techniques. Finally, AMR and its fractions were able to ameliorate the hypothyroidism model to different degrees, whereas no significant improvements were noted in the hyperthyroidism model. The lactones fraction and the crude polysaccharides fraction were considered the most important components of AMR for ameliorating hypothyroidism. These amelioration effects were achieved through promoting substance and energy metabolism. In sum, the integrative approach used in this study demonstrates how network pharmacology, proteomics, and metabolomics can be used effectively to elucidate the efficacy, molecular basis, and mechanism of action of medicines used in TCM.

Recent progress in the development of ß2 adrenergic receptor agonists: a patent review (2015-2020).

INTRODUCTION: The ß2 adrenergic receptor (ß2AR) is a member of G protein-coupled receptors (GPCRs) that mediate the majority of cellular responses to external stimuli. The agonists can cause smooth muscle relaxation; therefore, many ß2AR agonists have been developed especially for the treatment of pulmonary disorders such as asthma and chronic obstructive pulmonary disease (COPD). Many new natural and synthetic compounds have been discovered and developed as novel ß2AR agonists over the past 5 years. AREAS COVERED: This review offers an update for the development of ß2AR agonists in the patents published from 2015 to 2020, including new natural and synthetic compounds for the treatment of asthma and COPD. In particular, the latest patents about compounds possessing both muscarinic receptor antagonist and ß2 adrenergic receptor agonist activity are reviewed. EXPERT OPINION: ß2AR agonists have been developed extensively for the treatment of asthma and COPD. In the past 5 years, novel agonists from both natural sources and synthetic methods were intensively developed. Compounds possessing both muscarinic receptor antagonist and ß2AR agonist activity represent a new trend in this area because they are possibly able to act together in a synergistic fashion, therefore, relieve the symptoms of patients through two distinct mechanisms.

Two new sesquiterpene lactones from leaves of yacon, Smallanthus sonchifolius.

The chemical constituents of 95% EtOH extract of yacon leaves were separated to yield two new sesquiterpene lactones, together with three known compounds. The two new compounds were characterized to be 8ß-angeloyloxy-13-methoxyl-11, 13-dihydromelampolid-14-oic acid methyl ester (1) and 8ß-(3-methylbut-2-enoyl) oxy-13-methoxyl-11, 13-dihydromelampolid-14-oic acid methyl ester (2) on the basis of NMR spectra, HR-MS and other spectroscopic methods. The cytotoxicity of compounds 1-5 were evaluated on human hepatoma cell Bel-7402 and all the compounds showed moderate cytotoxicity.