Psoraleae Fructus (PF) is an important traditional herbal medicine with a long history of clinical application. It is widely used to treat various diseases, such as osteoporosis, leucoderma and diarrhea. As a traditional nontoxic herb, it has aroused worldwide concern about the potential risks due to increasing adverse reaction events. This article reviews the botany, ancient records of medical uses, adverse reactions, toxicological research advance and detoxification methods of PF. According to clinical studies, liver injury is the most predominant in PF-related adverse reactions. The underlying mechanisms include bile acid metabolism and transport disorders, oxidative stress, mitochondrial damage, inhibition of liver cell regeneration and inflammatory reactions. Furthermore, the potential toxins of PF are summarized. Traditional methods of processing and compatibility will provide reference for reducing the toxicity of PF, which requires further research. In sum, this work systematically summarizes the reserach progress on the safety of PF, which will provide comprehensive insights into the toxicity of PF and facilitate its safe use and future development.
Parthenolide (PTL) is a sesquiterpene lactone derived from medicinal plant feverfew (Tanacetum parthenium). Recent studies have demonstrated that it has multiple pharmacological activities, especially in the treatment of various hematological and solid cancers. The superior anticancer activity of PTL suggests that it has the potential to be a first-line drug. However, due to the limited physical and chemical properties, as well as bioavailability, structural modification strategies are strongly recommended to improve the anticancer activity. This review describes representative PTL derivatives obtained by different modification strategies, which are reported to exert antiproliferative activities superior to the parent compound PTL. Furthermore, we also summarize their basic mechanisms on cancer-related signaling pathways, so as to explain the potential and characteristics of PTL and its derivatives in cancer therapy.
Atherosclerosis (AS) is an invisible killer among cardiovascular diseases (CVD), which has seriously threatened the life of quality. The complex pathogenesis of AS involves multiple interrelated events and cell types, such as macrophages, endothelial cells, vascular smooth muscle cells and immune cells. Currently, the efficacy of recommended statin treatment is not satisfactory. Natural products (NPs) have attracted increasing attention with regard to their broad structural diversity and biodiversity, which makes them a promising library in the demand for lead compounds with cardiovascular protective bio-activity. NPs can preclude the development of AS by regulating lipid metabolism, ameliorating inflammation, stabilizing plaques, and remodeling the gut microbiota, which lays a foundation for the application of NPs in clinical therapeutics.
Steroid saponins are secondary metabolites with multiple medicinal values that are found in large quantities in natural medicines, especially Vernonia amygdalina, a famous nature medicine for the treatment of tonsillitis, diabetes, pneumonia. The current study was designed to combine molecular networking (MN) with diagnostic ions for rapid identification of Δ7,9(11) stigmastane-type saponins which were the α-glucosidase inhibitory active substances in V. amygdalina. First, the α-glucosidase inhibitory activities of five Δ7,9(11) stigmastane-type steroid saponins that were previously isolated were screened, which indicated that the Δ7,9(11) stigmastane-type steroid saponin was one of the active constituents responsible for ameliorating diabetes. Furthermore, a strategy was proposed to identify stigmastane-type steroid saponins and verify the plausibility of derived fragmentation pathways by applying MN, MolNetEnhancer and unsupervised substructure annotation (MS2LDA). Based on this strategy, other seven Δ7,9(11) stigmastane-type steroid saponins were identified from this plant. Our research provide scientific evidence for the antidiabetic potential of the steroid saponin-rich extract of V. amygdalina leaf.
For the purpose of seeking new antibiotics, researchers usually modify the already-existing ones. However, this strategy has been extensively used and is close to its limits, especially in the case of aminoglycosides, and it is difficult to find a proper aminoglycoside antibiotic for novel modification. In this paper, we reported the design, synthesis, and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides. Bioassay results showed that our design strategy was feasible. Our study offers a new way to search for structurally novel aminoglycosides. Meanwhile, our study provides valuable structure-activity relationship information, which will lead to better understanding and exploitation of the drug target, and improved development of new aminoglycoside antibiotics.
Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Natural cyclohexapeptide AFN A1 from Streptomyces alboflavus 313 has moderate antibacterial and antitumor activities. An artificial designed AFN A1 homodimer, di-AFN A1, is an antibiotic exhibiting 10 to 150 fold higher biological activities, compared with the monomer. Unfortunately, the yield of di-AFN A1 is very low (0.09 ± 0.03 mg·L−1) in the engineered strain Streptomyces alboflavus 313_hmtS (S. albo/313_hmtS), which is not friendly to be genetically engineered for titer improvement of di-AFN A1 production. In this study, we constructed a biosynthetic gene cluster for di-AFN A1 and increased its production through heterologous expression. During the collection of di-AFN A1 biosynthetic genes, the afn genes were located at three sites of S. alboflavus 313 genome. The di-AFN A1 biosynthetic gene cluster (BGC) was first assembled on one plasmid and introduced into the model strain Streptomyces lividans TK24, which produced di-AFN A1 at a titer of 0.43 ± 0.01 mg·L−1. To further increase the yield of di-AFN A1, the di-AFN A1 BGC was multiplied and split to mimic the natural afn biosynthetic genes, and the production of di-AFN A1 increased to 0.62 ± 0.11 mg·L−1 in S. lividans TK24 by the later strategy. Finally, different Streptomyces hosts were tested and the titer of di-AFN A1 increased to 0.81 ± 0.17 mg·L−1, about 8.0-fold higher than that in S. albo/313_hmtS. Successful heterologous expression of di-AFN A1 with a remarkable increased titer will greatly facilitate the following synthetic biological study and drug development of this dimeric cyclohexapeptide.