This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles via chiral phosphoric acid‐catalyzed formal (3+2) cycloadditions of indole‐based ...enaminones as novel platform molecules with 2,3‐diketoesters, where de novo indole‐ring formation is involved. Using this new strategy, various axially chiral N,N′‐bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′‐bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′‐bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.
An organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles has been established via chiral phosphoric acid‐catalyzed formal (3+2) cycloaddition of indole‐based enaminones with 2,3‐diketoesters. This study provides a new strategy for the highly selective synthesis of axially chiral N,N′‐bisindoles and shows the successful application of such skeletons in medicinal and synthetic chemistry.
Fructus Aurantii is a traditional medicated diet in East Asia. To determine the underlying chemical markers responsible for the quality and efficacy of Fructus Aurantii, a sensitive metabolomic ...method was applied to distinguish Fructus Aurantii in Jiangxi Province from other two geographical locations (Hunan Province and Chongqing City) in China. In the present study, multivariate analyses were adopted to compare chemical compositions in 21 batches of Fructus Aurantii samples. Among three geographical origins, 23 differential compounds were structurally identified. Serum pharmacochemistry exhibited that 22 components could be detected in rat serum. Six differential and absorbed components were selected as six potential markers. Statistical analysis revealed that the content of six markers varied widely in three origins of Fructus Aurantii. Six differential and absorbed components were evaluated further by biological activity. Neohesperidin, naringin, and meranzin showed inhibitory effect on acetylcholinesterase that regulates gastrointestinal motility in vitro and in silico, suggesting that these three components may be determined as the active biomarkers of Fructus Aurantii. These findings demonstrate the potential of biomarkers for identification and quality control of Fructus Aurantii.
Chemosensitivity is one of the key factors affecting the therapeutic effect on cancer, but the clinical application of corresponding drugs is rare. Hypoxia, a common feature of many solid tumors, ...including hepatocellular carcinoma (HCC), has been associated with resistance to chemotherapy in part through the activation of the Sonic Hedgehog (SHh) pathway. Hypoxia has also been associated with the increased SUMOylation of multiple proteins, including GLI family proteins, which are key mediators of SHh signaling, and has become a promising target to develop drug-resistant drugs for cancer treatment. However, there are few target drugs to abrogate chemotherapy resistance. Saikosaponin-d (Ssd), one of the main bioactive components of
Radix bupleuri
, has been reported to exert multiple biological effects, including anticancer activity. Here, we first found that Ssd inhibits the malignant phenotype of HCC cells while increasing their sensitivity to the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) drug system under hypoxia
in vitro
and
in vivo
. Furthermore, we had explored that GLI family activation and extensive protein SUMOylation were characteristics of HCC cells, and hypoxia could activate the SHh pathway and promote epithelial-mesenchymal transition (EMT), invasion, and chemosensitivity in HCC cells. SUMOylation is required for hypoxia-dependent activation of GLI proteins. Finally, we found that Ssd could reverse the effects promoted by hypoxia, specifically active sentrin/small ubiquitin-like modifier (SUMO)-specific protease 5 (SENP5), a SUMO-specific protease, in a time- and dose-dependent manner while inhibiting the expression of SUMO1 and GLI proteins. Together, these findings confirm the important role of Ssd in the chemoresistance of liver cancer, provide some data support for further understanding the molecular mechanisms of Ssd inhibition of malignant transformation of HCC cells, and provide a new perspective for the application of traditional Chinese medicine in the chemical resistance of liver cancer.
The bacterial infection has a significant impact on the human health. With the widespread use of antibiotics, the bacterial resistance has increased significantly, which necessitates the urgent ...identification of novel antibacterial materials. In this study, a hydrogel with an inherent antibacterial ability, self-assembled from a heterochiral peptide C
16
-
D
L
4
L
R
4
, has been reported. The hydrogel demonstrated optimal rheological and injectable properties. It revealed a time-dependent antibacterial activity against Gram-positive
Staphylococcus aureus
and
Bacillus subtilis
as well as Gram-negative
Escherichia coli
and
Shigella sonnei
. After 5 h treatment with the hydrogel, the survival rate of
S. aureus
,
B. subtilis, E. coli
and
Sh. sonnei
bacteria was decreased to 5.9%, 0%, 5.3% and 11.09%, respectively. The chiral nanofibers with a diameter of 15–20 nm in the hydrogel were observed to be conducive to the aggregation of bacteria and destruction of the cell membrane to achieve the antibacterial effect. In addition, the in vitro analysis on the mouse embryonic fibroblasts confirmed the superior biocompatibility of the hydrogel. The results obtained in this study provide the basis for the development of the functional antibacterial hydrogels by the self-assembly of the heterochiral peptides.
Graphical abstract
As a natural polymer, there are a lot of functional groups on the keratin molecular chains, such as carboxyl, amino and hydroxyl groups. In the present study, we used keratin (K) as a multifunctional ...crosslinker and prepared smart nanogels. The nanogels had high loading capacity for drug, while low drug leakage. The surface of the DOX@K/SA-NG is negatively charged and the size was determined to be 432 nm. The nanogels had drug loading capacity (DLC) of 65.2% (w/w) and were capable of triggering drug release upon both pH and reductive (glutathione (GSH)) environment while stable under physiological conditions (pH 7.4 + 10 μM GSH). We evaluated its cancer treatment performance through cell uptake and cytotoxicity experiments, it showed that the prepared DOX@K/SA-NG can effectively inhibit the growth of HepG2 cancer cells.
•High-value utilization of keratin.•Preparation of anti-cancer drug delivery system with high drug loading capacity and low drug leakage.•Preparation and evaluation of feather keratin-based sensitive nanogels with targeting function.
The contactin-associated protein （Caspr） family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the ...Caspr family- CNTNAP1 （Casprl）, CNTNAP2 （Caspr2）, CNTNAP3 （Caspr3）, CNTNAP4 （Caspr4） and CNTNAP5 （Caspr5）, Casprl-5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Casprl participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.
Coumarins are a group of natural compounds commonly found in the families of Rutaceae and Umbelliferae. 7‐Isopentenyloxycoumarin (ISC), auraptene (AUR), and umbelliprenin (UM) belong to ...prenyloxycoumarins (PYCs), which link isopentenyl, geranyl, and farnesyl group at C7 position, respectively. The substituent of 7‐ethoxycoumarin (ETC) is the ethyl group. In this study, UPLC–ESI–QTOF–MS (ultra‐performance liquid chromatography–electrospray ionization–quadrupole time of flight–MS)‐based metabolomics was used to evaluate the in vivo and in vitro metabolism of PYCs. Results showed that ETC produced 10 known metabolites, and ISC was transformed into 17 metabolites in vivo and in vitro, which were undescribed compounds. A total of 35 AUR metabolites, including 34 undescribed metabolites were identified, and 21 metabolites were reported for the first time in UM. The results indicated that hydroxylation and N‐acetylcysteine conjugation were the common metabolic reactions for PYCs. The metabolic rates of ETC, ISC, AUR and UM were 26%, 36%, 81%, and 38%, respectively, in human liver microsome, while they were 24%, 40%, 80%, and 37%, respectively, in mouse liver microsomes. In addition, recombinant cytochrome P450s (CYPs) screening showed that CYP1A1, 2C19, 3A4, and 3A5 were the major metabolic enzymes involved in the formation of hydroxylation metabolites. Together, these results suggest that the isopentenyl group plays an important role in the metabolism of PYCs.
Ru-based electrocatalysts have demonstrated excellent electrocatalytic performance toward hydrogen evolution reaction (HER). However, designing Ru nanoparticles/nanoclusters (Ru NPs/NCs) with ...abundant accessible active sites is challenging. Herein, a selective facile hydrothermal in situ polymerization strategy is described to accurately control the anchoring point of Ru in hollow mesoporous carbon spheres (HMCs) (outer surface, HMCs@Ru; cavity, Ru@HMCs; and pore channels, Ru/S-HMCs). The HER mechanisms of the three catalysts over a wide pH range were revealed by analyzing the loading position, content, dispersion, particle size, and valence state of Ru. HMCs@Ru shows excellent area activity, with overpotentials of 64.3, 2.8, and 78.1 mV at 10 mA·cm
−2
in 0.5 mol⋅L
−1
H
2
SO
4
, 1 mol⋅L
−1
KOH, and 0.5 mol⋅L
−1
phosphate buffer saline (PBS) solutions, respectively. Ru/S-HMCs exhibit high mass activity, with values 43.3, 2.9, and 12.7 times those of Pt/C in alkaline, acidic, and neutral media, respectively, at − 50 mV (vs. reversible hydrogen electrode (RHE)). After 2000 cyclic voltammetry cycles, the performances of HMCs@Ru and Ru/S-HMCs hardly decrease, indicating good stability. The excellent electrocatalytic activity can be attributed to two main factors: (1) the confinement effect, which not only promotes high Ru dispersion but also prevents the leaching of active metal under harsh conditions, and (2) their excellent structural characteristics. The catalyst structure features a large hollow located in the center (~ 160 nm in diameter) and an ultrathin monolayer of mesopores (~ 6 nm) uniformly distributed on the hollow shells, ensuring fast mass diffusion and electron transfer kinetics, as well as complete accessibility of catalytic sites.
Graphical abstract
The tick Ixodes persulcatus is the predominant tick species in Northeastern China, and it is a major vector in transmission of tick-borne diseases. By 16S rRNA Illumina sequencing, we investigated ...the microbiome of I. persulcatus and assessed the variation of the microbiome before and after blood feeding. The prolonged blood meal dramatically altered the composition of the microbiome but did not influence the bacterial diversity. Overall, 373 and 289 bacterial genera were assigned to unfed and fed ticks, respectively. To investigate microbes that were potentially transmitted to vertebrate hosts during a blood meal, we examined the microbiome in rat blood after tick bites. Our data showed that 237 bacterial genera were suspected to be pathogens of vertebrates because they were commonly detected in unfed ticks, fed ticks, and rat blood samples after tick bites. Additionally, the prevalence survey on Borrelia burgdorferi s.l., Ehrlichia chaffeensis, Anaplasma phagocytophilum and Yersinia pestis was performed. We found that B. garinii and B. afzelii are the predominant genospecies of the Lyme disease spirochete in I. persulcatus ticks. This is the first time that the microbial composition in this tick species and in rat blood transmitted via tick bites has been reported. These data may ultimately assist in identification of novel pathogens transmitted by I. persulcatus ticks.
A novel hydrid hydrogel with aggregation-induced emission behavior formed by the self-assembly of Fmoc-phenylalanine (Fmoc-F) and berberine (BBR), which displayed enhanced potodynamic antibacterial ...and anti-biofilm activity, and facilitated the repair of wounds in rats infected with S. aureus.
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•A novel hybrid hydrogel was assembled from Fmoc-F and berberine chloride (BBR).•Aggregation-induced emission behavior was observed for Fmoc-F/BBR hydrogel.•The hydrogel showed enhanced photodynamic antibacterial and anti-biofilm activity.•The hydrogel facilitated the repair of wounds in rats infected with S. aureus.
Bacterial infections are a great threat to public health. The development of materials which prevent biofilm formation, and exhibit antibacterial properties, but are otherwise biocompatible, is a major research goal. In this study, a novel hybrid hydrogel with aggregation-induced emission (AIE) behavior was prepared through the self-assembly of commercial N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine (Fmoc-F) and berberine chloride (BBR). BBR self-assembled into nanoparticles which dispersed throughout the gel network, and endowed the hydrogel with AIE functionality. Fmoc-F/BBR hydrogel displayed enhanced antibacterial and anti-biofilm activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria when used as the active agent in the photodynamic therapy (PDT) process. Additionally, negligible cytotoxicity and low hemolytic activity were displayed. In vivo infection studies showed that Fmoc-F/BBR hydrogel facilitated the repair of wounds in rats infected with S. aureus. Therefore, Fmoc-F/BBR hydrogel provides potential applications in biomedicines, and especially in wound healing.
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