Discovery and Heterologous Production of Tetrapetalones Provide Insights into the Formation of the Tetracyclic System.

Tetrapetalones make up a unique class of pentaketide ansamycins that feature a tetracyclic skeleton and exhibit potent inhibitory activities against soybean lipoxygenase. However, a detailed biosynthetic route to tetrapetalones has not been published. Herein we report the activation of the tetrapetalones' biosynthetic gene cluster (tpt) in Streptomyces sp. S10 by promoter engineering along with constitutive expression of pathway-specific regulator genes, leading to the discovery of seven new derivatives, tetrapetalones E-K (2-8), and the known tetrapetalone A (1). In vivo gene deletion experiments and heterologous expression of the minimized tpt cluster in Streptomyces albus J1074 suggest that the tetracyclic system of tetrapetalones is probably formed spontaneously, and the regioselective glycosylation of tetrapetalones at the C-9 hydroxy group with d-rhamnose or d-rhodinose was catalyzed by the glycosyltransferase Tpt14.

Preparation and antibacterial activity of coronarin E derivatives.

Coronarin E is a main diterpene ever isolated from Hedychium yunnanense. With the aim to enlarge its potential application, four butenolide derivatives (compounds 4a, 4b, 5a and 5b) were obtained from coronarin E via synthetic method, and their antibacterial effects were also evaluated. It is noteworthy that compounds 5a and 5b exhibited stronger antibacterial activities against most of the tested bacterial strains than ampicillin and kanamycin, two first- and second-line antimicrobials in clinical. For example, minimum inhibitory concentration (MIC) of 5a, 5b, ampicillin and kanamycin against Acinetobacter baumanii were 2, 1, 8 and 4 µg/mL, respectively, and MIC of the four compounds mentioned above against Klebsiella pneumonia were 1, 0.5, 16 and 4 µg/mL, respectively. The current studies not only enrich the structural diversity of diterpenes derived from Hedychium genus, but also provide potent candidates for the development of antibacterial medicines.

Analysis of the potential inappropriate use of medications in pediatric outpatients in China.

BACKGROUND: The appropriate use of medications is essential in children. Yet, detailed information on how drugs are being prescribed and dispensed to pediatric populations is not documented in China. AIM: The study objective was to analyze the details of medicine use and categorize the types of inappropriate use of medications on children. METHODS: A retrospective cross-sectional study was conducted on the prescriptions of pediatric outpatients aged < 18 years from 2019 to 2020 at a major Chinese tertiary academic center. Each age group's demographic and clinical characteristics were collected, and the ratios of inappropriate prescriptions were analyzed. RESULTS: The total number of pediatric outpatients was 652,152, and 49.37% (322000) were prescribed medications, in which the most widely used medicines were respiratory, anti-infectives, and Traditional Chinese Medicines (TCMs). The prevalence rate of inappropriate prescriptions reached 20.49%, and in 2019 it was higher (21.71%) than that in 2020 (18.36%). The top three common inappropriate categories were indication-related off-label drug use, improper administration frequency, and overdosing, accounting for 67.93, 17.80 and 11.06% of all inappropriate prescriptions, respectively. The inappropriate prescriptions were more likely seen in patients aged 2-5 years and respiratory medicines. CONCLUSIONS: The study findings indicate that inappropriate drug use in pediatric outpatients is still common, and great attention needs to be paid. More prospective trials are required to identify the effectiveness, safety, and necessity of off-label drug use of medicines in children.

The coupled reaction catalyzed by EchB and EchC lead to the formation of the common 2',3',5'-trihydroxy-benzene core in echosides biosynthesis.

p-Terphenyls represent a unique family of aromatic natural products generated by nonribosomal peptide synthetase-like (NRPS-like) enzyme. After formation of p-terphenyl skeleton, tailoring modifications will give rise to structural diversity and various biological activities. Here we demonstrated a two-enzyme (EchB, a short-chain dehydrogenase/reductase (SDR), and EchC, a nuclear transport factor 2 (NTF2)-like dehydratase) participated transformation from dihydroxybenzoquinone core to 2',3',5'-trihydroxy-benzene in the biosynthesis of echosides. Beginning with polyporic acid as substrate, successive steps of reduction-dehydration-reduction cascade catalyzed by EchB-EchC-EchB were concluded after in vivo gene disruption and in vitro bioassay experiments. These findings demonstrated a conserved synthesis pathway of 2',3',5'-trihydroxy-p-terphenyls in bacteria, such as Actinomycetes and Burkholderia. The parallel pathway in fungi has yet to be explored.

Discovery and identification of proangiogenic chemical markers from Gastrodiae Rhizoma based on zebrafish model and metabolomics approach.

INTRODUCTION: Angiogenesis is closely related to a variety of diseases, and therapies based on angiogenesis are intensely investigated. Studies have shown that the use of Gastrodiae Rhizoma (GR, Gastrodia elata) can benefit the treatment of ischemic cardiovascular diseases and atherosclerosis by stimulating angiogenesis. OBJECTIVE: This study tested the angiogenesis effects of a group of chemical markers isolated from GR. MATERIAL AND METHODS: Zebrafish model was used to evaluate angiogenesis by setting four groups: blank control group, model group, positive control group and treatment group (0.1, 1, and 100 µg/mL RGP). The Gray correlation analysis (GCA) was implemented to calculate the correlation coefficients of each compound between the peak area in liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) and the bioactivity, the top ten components with the correlation degree > 0.9 were listed. RESULTS AND DISCUSSION: The optimum final concentration of GR on proangiogenesis effect was determined to be 100 µg/mL. Ten compounds, including gastrodin, parishin E, stigmasterol, p-hydroxybenzyl alcohol, citric acid, etc., were identified to have high correlation coefficients with proangiogenic activity. Furthermore, the network pharmacologic analysis of these compounds revealed that the compounds systematically regulate the formation of new blood vessels via networked vital targets and signalling pathways. CONCLUSION: GR can promote the growth of blood vessels, ten chemical components discovered contribute to this proangiogenesis activity. These chemical markers of GR thus provide a foundation for further studies on medicinal substances and quality evaluation of GR, also providing a scientific basis for modern interpretation of the processing theory of traditional Chinese medicine.

17-[16,17-Dihydroxycyclooctatinyl]-hexaketide ester from Streptomyces sp. SR107.

A new hexaketide acid esterified by the 17-hydroxyl group of 16,17-dihydroxycyclooctatin, namely 17-[16,17-dihydroxycyclooctatinyl]-hexaketide ester (1), a member of the group of rare bacterial diterpenes with a fused 5-8-5 ring system was isolated from strain Streptomyces sp. SR107. The structure was determined on the basis of its spectral data (1H NMR, 13C NMR, 1H-1H COSY, HSQC, HMBC, NOESY, IR and HR-ESI-MS). The antibacterial activity was also evaluated in this paper.