The Biosynthesis Related Enzyme,Structure Diversity and Bioactivity Abundance of Indole-Diterpenes: A Review

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure–activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure–activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.     

Novel In Situ Growth of ZIF-8 in Porous Epoxy Matrix for Mechanically Robust Composite Electrolyte of High-Performance,Long-Life Lithium Metal Batteries

Polymer electrolytes (PEs) with high flexibility, low cost, and excellent interface compatibility have been considered as an ideal substitute for traditional liquid electrolytes for high safety lithium metal batteries (LMBs). Nevertheless, the mechanical strength of PEs is generally poor to prevent the growth of lithium dendrites during the charge/discharge process, which seriously restricts their wide practical applications. Herein, a mechanical robust ZIF-8/epoxy composite electrolyte with unique pore structure was prepared, which effectively inhibited the growth of lithium dendrites. Meanwhile, the in situ growth of ZIF-8 in porous epoxy matrix can promote the uniform flux and fast transport of lithium ions. Ultimately, the optimal electrolyte shows high ionic conductivity (2.2 × 10⁻³ S cm⁻¹), wide electrochemical window (5 V), and a large Li⁺ transference number (0.70) at room temperature. The Li||NCM811 cell using the optimal electrolyte exhibits high capacity and excellent cycling performance (83.2% capacity retention with 172.1 mA h g⁻¹ capacity retained after 200 cycles at 0.2 C). These results indicate that the ZIF-8/epoxy composite electrolyte is of great promise for the application in LMBs.     

Radiochemical Feasibility of Mixing of 99mTc-MAA and 90Y-Microspheres with Omnipaque Contrast

Yttrium-90 (⁹⁰Y) microspheres are widely used for the treatment of liver-dominant malignant tumors. They are infused via catheter into the hepatic artery branches supplying the tumor under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (^99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumor, the ⁹⁰Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumor. The radiochemical purity of mixing ⁹⁰Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing ^99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing ⁹⁰Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.     

A Sensitive and Selective Colorimetric Method Based on the Acetylcholinesterase-like Activity of Zeolitic Imidazolate Framework-8 and Its Applications

In this study, a simple colorimetric method was established to detect copper ion (Cu²⁺), sulfathiazole (ST), and glucose based on the acetylcholinesterase (AChE)-like activity of zeolitic imidazolate framework-8 (ZIF-8). The AChE-like activity of ZIF-8 can hydrolyze acetylthiocholine chloride (ATCh) to thiocholine (TCh), which will further react with 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB) to generate 2-nitro-5-thiobenzoic acid (TNB) that has a maximum absorption peak at 405 nm. The effects of different reaction conditions (buffer pH, the volume of ZIF-8, reaction temperature and time, and ATCh concentration) were investigated. Under the optimized conditions, the value of the Michaelis-Menten constant (K_m) is measured to be 0.83 mM, which shows a high affinity toward the substrate (ATCh). Meanwhile, the ZIF-8 has good storage stability, which can maintain more than 80.0% of its initial activity after 30 days of storage at room temperature, and the relative standard deviation (RSD) of batch-to-batch (n = 3) is 5.1%. The linear dependences are obtained based on the AChE-like activity of ZIF-8 for the detection of Cu²⁺, ST, and glucose in the ranges of 0.021–1.34 and 5.38–689.66 µM, 43.10–517.24 µM, and 0.0054–1.40 mM, respectively. The limit of detections (LODs) are calculated to be 20.00 nM, 9.25 µM, and 5.24 µM, respectively. Moreover, the sample spiked recoveries of Cu²⁺ in lake water, ST in milk, and glucose in strawberry samples were measured, and the results are in the range of 98.4–115.4% with the RSD (n = 3) lower than 3.3%. In addition, the method shows high selectivity in the real sample analysis.     

The Taste-Masking Mechanism of Chitosan at the Molecular Level on Bitter Drugs of Alkaloids and Flavonoid Glycosides from Traditional Chinese Medicine

Taste masking of traditional Chinese medicines (TCMs) containing multiple bitter components remains an important challenge. In this study, berberine (BER) in alkaloids and phillyrin (PHI) in flavonoid glycosides, which are common bitter components in traditional Chinese medicines, were selected as model drugs. Chitosan (CS) was used to mask their unfriendly taste. Firstly, from the molecular level, we explained the taste-masking mechanism of CS on those two bitter components in detail. Based on those taste-masking mechanisms, the bitter taste of a mixture of BER and PHI was easily masked by CS in this work. The physicochemical characterization results showed the taste-masking compounds formed by CS with BER (named as BER/CS) and PHI (named as PHI/CS) were uneven in appearance. The drug binding efficiency of BER/CS and PHI/CS was 50.15 ± 2.63% and 67.10 ± 2.52%, respectively. The results of DSC, XRD, FTIR and molecular simulation further indicated that CS mainly masks the bitter taste by disturbing the binding site of bitter drugs and bitter receptors in the oral cavity via forming hydrogen bonds between its hydroxyl or amine groups and the nucleophilic groups of BER and PHI. The taste-masking evaluation results by the electronic tongue test confirmed the excellent taste-masking effects on alkaloids, flavonoid glycosides or a mixture of the two kinds of bitter components. The in vitro release as well as in vivo pharmacokinetic results suggested that the taste-masked compounds in this work could achieve rapid drug release in the gastric acid environment and did not influence the in vivo pharmacokinetic results of the drug. The taste-masking method in this work may have potential for the taste masking of traditional Chinese medicine compounds containing multiple bitter components.     

Establishment and Application of a Predictive Growth Kinetic Model of Salmonella with the Appearance of Two Other Dominant Background Bacteria in Fresh Pork

To better guide microbial risk management and control, growth kinetic models of Salmonella with the coexistence of two other dominant background bacteria in pork were constructed. Sterilized pork cutlets were inoculated with a cocktail of Salmonella Derby (S. Derby), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli), and incubated at various temperatures (4–37 °C). The predictive growth models were developed based on the observed growth data. By comparing R² of primary models, Baranyi models were preferred to fit the growth curves of S. Derby and P. aeruginosa, while the Huang model was preferred for E. coli (all R² ≥ 0.997). The secondary Ratkowsky square root model can well describe the relationship between temperature and μ_max (all R² ≥ 0.97) or Lag (all R² ≥ 0.98). Growth models were validated by the actual test values, with B_f and A_f close to 1, and MSE around 0.001. The time for S. Derby to reach a pathogenic dose (10⁵ CFU/g) at each temperature in pork was predicted accordingly and found to be earlier than the time when the pork began to be judged nearly fresh according to the sensory indicators. Therefore, the predictive microbiology model can be applied to more accurately predict the shelf life of pork to secure its quality and safety.     

Iridium-Catalyzed and pH-Dependent Reductions of Nitroalkenes to Ketones

A highly chemoselective conversion of α,β-disubstituted nitroalkenes to ketones is developed. An acid-compatible iridium catalyst serves as the key to the conversion. At a 2500 S/C ratio, nitroalkenes were readily converted to ketones in up to 72% isolated yields. A new mechanistic mode involving the reduction of nitroalkene to nitrosoalkene and N-alkenyl hydroxylamine is proposed. This conversion is ready to amplify to a gram-scale synthesis. The pH value plays an indispensable role in controlling the chemoselectivity.     

Epigallocatechin Gallate Attenuates Gentamicin-Induced Nephrotoxicity by Suppressing Apoptosis and Ferroptosis

Gentamicin (GEN) is a kind of aminoglycoside antibiotic with the adverse effect of nephrotoxicity. Currently, no effective measures against the nephrotoxicity have been approved. In the present study, epigallocatechin gallate (EG), a useful ingredient in green tea, was used to attenuate its nephrotoxicity. EG was shown to largely attenuate the renal damage and the increase of malondialdehyde (MDA) and the decrease of glutathione (GSH) in GEN-injected rats. In NRK-52E cells, GEN increased the cellular ROS in the early treatment phase and ROS remained continuously high from 1.5 H to 24 H. Moreover, EG alleviated the increase of ROS and MDA and the decrease of GSH caused by GEN. Furthermore, EG activated the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). After the treatment of GEN, the protein level of cleaved-caspase-3, the flow cytometry analysis and the JC-1 staining, the protein levels of glutathione peroxidase 4 (GPX4) and SLC7A11, were greatly changed, indicating the occurrence of both apoptosis and ferroptosis, whereas EG can reduce these changes. However, when Nrf2 was knocked down by siRNA, the above protective effects of EG were weakened. In summary, EG attenuated GEN-induced nephrotoxicity by suppressing apoptosis and ferroptosis.     

Lanostane Triterpenoids and Ergostane Steroids from Ganoderma luteomarginatum and Their Cytotoxicity

Macrofungus Ganoderma luteomarginatum is one of the main species of Ganoderma fungi distributed in Hainan province of China, the fruiting bodies of which have been widely used in folk as a healthy food to prevent tumors. To explore the potential cytotoxic constituents from G. luteomarginatum, the phytochemical investigation on the ethyl acetate soluble fraction of 95% ethanolic extract from the fruiting bodies of this fungus led to the isolation of twenty-six lanostane triterpenoids (1–26), including three undescribed ones (1–3), together with eight ergostane steroids (27–34). The structures of three new lanostane triterpenoids were elucidated as lanosta-7,9(11)-dien-3β-acetyloxy-24,25-diol (1), lanosta-7,9(11)-dien-3-oxo-24,26-diol-25-methoxy (2), and lanosta-8,20(22)-dien-3,11,23-trioxo-7β,15β-diol-26-oic acid methyl ester (3) by the analysis of 1D, 2D NMR, and HRESIMS spectroscopic data. All isolates were assayed for their cytotoxic activities using three human cancer cell lines (K562, BEL-7402, and SGC-7901) and seven lanostane triterpenoids (1, 2, 7, 13, 18, 22, and 24), and one ergostane steroid (34) showed definite cytotoxicity with IC₅₀ values that ranged from 6.64 to 47.63 μg/mL. Among these cytotoxic lanostane triterpenoids, compounds 2 and 13 showed general cytotoxicity against three human cancer cell lines, while compounds 1 and 18 exhibited significant selective cytotoxicity against K562 cells with IC₅₀ values of 8.59 and 8.82 μg/mL, respectively. Furthermore, the preliminary structure–cytotoxicity relationships was proposed.     

Alkaloid Derivative (Z)-3β-Ethylamino-Pregn-17(20)-en Inhibits Triple-Negative Breast Cancer Metastasis and Angiogenesis by Targeting HSP90α

Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3β-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.