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Chalkophomycin is a novel chalkophore with antibiotic activities isolated from Streptomyces sp. CB00271, while its potential in studying cellular copper homeostasis makes it an important probe and drug lead. The constellation of N-hydroxylpyrrole, 2H-oxazoline, diazeniumdiolate, and methoxypyrrolinone functional groups into one compact molecular architecture capable of coordinating cupric ions draws interest to unprecedented enzymology responsible for chalkophomycin biosynthesis. To elucidate the biosynthetic machinery for chalkophomycin production, the chm biosynthetic gene cluster from S. sp. CB00271 was identified, and its involvement in chalkophomycin biosynthesis was confirmed by gene replacement. The chm cluster was localized to a ~31 kb DNA region, consisting of 19 open reading frames that encode five nonribosomal peptide synthetases (ChmHIJLO), one modular polyketide synthase (ChmP), six tailoring enzymes (ChmFGMNQR), two regulatory proteins (ChmAB), and four resistance proteins (ChmA′CDE). A model for chalkophomycin biosynthesis is proposed based on functional assignments from sequence analysis and structure modelling, and is further supported by analogy to over 100 chm-type gene clusters in public databases. Our studies thus set the stage to fully investigate chalkophomycin biosynthesis and to engineer chalkophomycin analogues through a synthetic biology approach.

Deep eutectic solvents (DESs) are novel solvents with physicochemical properties similar to those of ionic liquids, and they have attracted extensive attention for the extraction of bioactive compounds from different plant materials in the context of green chemistry and sustainable development. In this study, seven DESs with different polarities were explored as green extraction solvents for cembratrien-diols (CBT-diols) from waste tobacco flowers. The best solvent, DES-3 (choline chloride: lactic acid (1:3)), which outperformed conventional solvents (methanol, ethanol, and ethyl acetate), was selected and further optimized for microwave-assisted DES extraction using the response surface methodology. The maximum yield of CBT-diols (6.23 ± 0.15 mg/g) was achieved using a microwave power of 425 W, microwave time of 32 min, solid/liquid ratio of 20 mg/mL, and microwave temperature of 40 °C. Additionally, the isolated CBT-diols exhibited strong antimicrobial activity against Salmonella, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa and antitumor activity in the human liver cancer HepG2 and SMMC-7721 cell lines. This study highlights the feasibility of recovering CBT-diols from tobacco flower waste using DESs and provides opportunities for potential waste management using green technologies.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.

Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

Diarrheal disease is one of the most important worldwide health problems. Enterotoxigenic Escherichia coli (ETEC) is the most frequently isolated enteropathogen in diarrheal diseases. In developing countries, a very large number of people, especially children, suffer from diarrhea. To combat this problem, World Health Organization has constituted the Diarrhea Diseases Control Program which guides studies on traditional medicinal practices and preventive measures. Gusuibu, a traditional folk medicine, has been claimed to heal certain types of diarrhea. However, so far no scientific study has been carried out on the anti-diarrheal mechanism of Gusiubu. The present study was performed to examine the suppressive activities of ethanol extracts of six sources of folk medicinal ferns used as Gusuibu on heat-labile enterotoxin (LT)-induced diarrhea. Inhibitory effects of six sources were evaluated on the ETEC LT subunit B (LTB) and monosialotetrahexosylganglioside (GMI) interaction by GM1-enzyme linked immunosorbent assay and patent mouse gut assay. Our results indicated that Drynaria fortunei had no anti-diarrheal effect, while, among the remaining five folk medicinal ferns, four belonging to family Davalliaceae had significant abilities on both the blocking of LTB and GM1 interaction and the inhibition of LT-induced diarrhea. In conclusion, these findings suggested the potential application of Gusuibu as an anti-diarrheal remedy.

Dihydroberkleasmin A (1), a new ester-substituted sesquiterpenoid related to the eremophilane class, together with the known compound berkleasmin C (2), were isolated from the fermentation broth of the plant endophytic fungus Pestalotiopsis photiniae. The structure of dihydroberkleasmin A (1) was elucidated by extensive spectroscopic analysis. The stereochemistry was assigned by comparison of the NMR spectroscopic data with those of berkleasmin A.

A series of novel fused heterocyclic compounds bearing benzo[4,5]imidazo[1,2-d][1,2,4]triazine 4a–4w were designed and conveniently synthesized via the intermediates 2-(halogenated alkyl)-1H-benzo[d]imidazoles 2a, 2b, and 2-((1-(substituted phenyl)hydrazinyl)alkyl)-1H-benzo[d]imidazoles 3a–3g. The structures of all target compounds were characterized by FT-IR, 1H NMR, 13C NMR, and EI-MS, of which, the structure of compound 4n was further determined by the single crystal X-ray diffraction. The crystal structure of 4n was crystallized in the triclinic crystal system, space group P 1 ¯ with a = 9.033 (6) Å, b = 10.136 (7) Å, c = 10.396 (7) Å, α = 118.323 (7)°, β = 91.750 (8)°, γ = 104.198 (7)°, Z = 2, V = 800.2 (9) Å3; total R indices: R1 = 0.0475, wR2 = 0.1284. The antifungal activity of title compounds 4a–4w in vitro against the phytopathogenic fungi Botrytis cinerea (B. cinerea), Rhizoctonia solani (R. solani) and Colletotrichum capsici (C. capsici) were evaluated, the bioassay results demonstrated that most of the title compounds exhibited obvious fungicidal activities at 50 μg/mL. This work indicated that benzo[4,5]imidazo[1,2-d][1,2,4]triazine derivatives could be considered as a new leading structure in searching for novel agricultural fungicides.

In this study we investigate the molecular mechanisms of caspases and mitochondria in the extrinsic and intrinsic signal apoptosis pathways in human leukemia HL-60 cells after in vitro exposure to 18α-glycyrrhetinic acid (18α-GA). Cells were exposed to 18α-GA at various concentrations for various time periods and were harvested for flow cytometry total viable cell and apoptotic cell death measurements. Cells treated with 18α-GA significantly inhibited cell proliferation and induced cell apoptosis in a dose-dependent manner, with an IC50 value of 100 μM at 48 h. The cell growth inhibition resulted in induction of apoptosis and decreased the mitochondria membrane potential (ΔΨm) and increased caspase-8, -9 and -3 activities. Furthermore, cytochrome c and AIF were released from mitochondria, as shown by western blotting and confirmed by confocal laser microscopy. Western blotting showed that 18α-GA increased the levels of pro-apoptotic proteins such as Bax and Bid and decreased the anti-apoptotic proteins such as Bcl-2 and Bcl-xl, furthermore, results also showed that 18α-GA increased Fas and Fas-L which are associated with surface death receptor in HL-60 cells. Based on those observations, the present study supports the hypothesis that 18α-GA-induced apoptosis in HL-60 cells involves the activation of the both extrinsic and intrinsic apoptotic pathways.

For the aim of discovering new fungicide, a series of phenylpyrrole-substituted tetramic acid derivatives bearing carbonates 6a–q were designed and synthesized via 4-(2,4-dioxopyrrolidin-3-ylidene)-4-(phenylamino)butanoic acids 4a–k and the cyclized products 1′,3,4,5′-tetrahydro-[2,3′-bipyrrolylidene]-2′,4′,5(1H)-triones 5a–k. The compounds were characterized using IR, 1H- and 13C-NMR spectroscopy, mass spectrometry (EI-MS), and elemental analysis. The structure of 6b was confirmed by X-ray diffraction crystallography. The title compounds 6a–q were bioassayed in vitro against the phytopathogenic fungi Fusarium graminearum, Botrytis cinerea and Rhizoctonia solani at a concentration of 100 μg/mL, respectively. Most compounds displayed good inhibitory activity.

Three indole derivatives, a novel benzoxazine-indole hybrid (1) and two known indole trimers (2, 3), were isolated from the metagenomic library of the marine sponge Discodermia calyx based on functional screening. Their structures were elucidated by extensive spectroscopic analysis and comparison of their NMR data to that of known compounds. The antibacterial assay indicated that only compound 2 displayed significant antibacterial activity against Bacillus cereus, with approximately 20 mm diameter growth inhibition at 10 μg/paper. HPLC analyses revealed that compound 2 is a newly induced metabolite, and the concentration of 3 was obviously enhanced in contrast to negative control, while 1 was not detected, allowing us to predict that the formation of 2 might be induced by exogenous genes derived from the sponge metagenome, whereas compound 1 could be formed through a non-enzymatic process during the isolation procedure. [ABSTRACT FROM AUTHOR]

Dihydroberkleasmin A (1), a new ester-substituted sesquiterpenoid related to the eremophilane class, together with the known compound berkleasmin C (2), were isolated from the fermentation broth of the plant endophytic fungus Pestalotiopsis photiniae. The structure of dihydroberkleasmin A (1) was elucidated by extensive spectroscopic analysis. The stereochemistry was assigned by comparison of the NMR spectroscopic data with those of berkleasmin A. [ABSTRACT FROM AUTHOR]