Design, Synthesis, and Biological Evaluation of Dual-Target COX-2/CYP51 Inhibitors for the Treatment of Fungal Infectious Diseases.

The design of novel dual-target (COX-2/CYP51) inhibitors was proposed in the study, and three series of compounds were constructed though the pathway of skeleton screening and combination; their molecular structures were synthesized and evaluated. Most of the compounds exhibited significant antifungal ability. Among them, potential compounds (10a-2, 16b-3) with excellent antifungal and anti-drug-resistant fungal ability (MIC50, 0.125-2.0 µg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds could block the ergosterol biosynthesis pathway by inhibiting CYP51 and influence the internal physiological function of fungal cells, which included the increase of the ROS level, the anomaly of ΔΨm, and the emergence of an apoptotic state. On the other hand, these compounds also effectively showed COX-2 inhibition ability, eliminated the inflammatory reaction of the infected region, and activated the body's immune function. In summary, this study not only provided a novel antifungal drug design pathway but also discovered excellent target compounds.

Generation of particle assemblies mimicking enzymatic activity by processing of herbal food: the case of rhizoma polygonati and other natural ingredients in traditional Chinese medicine.

Processed herbs have been widely used in eastern and western medicine; however, the mechanism of their medicinal effects has not yet been revealed. It is commonly believed that a central role is played by chemically active molecules produced by the herbs' metabolism. In this work, processed rhizoma polygonati (RP) and other herbal foods are shown to exhibit intrinsic phosphatase-like (PL) activity bounded with the formation of nano-size flower-shaped assembly. Via quantum mechanical calculations, an enzymatic mechanism is proposed. The enzymatic activity may be induced by the interaction between the sugar molecules distributed on the surface of the nanoassemblies and the phosphatase substrate via either a hydroxyl group or the deprotonated hydroxyl group. Meanwhile, the investigation was further extended by processing some fresh herbs and herbal food through a similar protocol, wherein other enzymatic activities (such as protease, and amylase) were observed. The PL activity exhibited by the processed natural herbs was found to be able to effectively inhibit cancer cell growth via phosphatase signaling, possibly by crosstalk with kinase signaling or DNA damage by either directly binding or unwinding of DNA, as evidenced by high-resolution atomic-force microscopy (HR-AFM). In this work, the neologism herbzyme (herb + enzyme) is proposed. This study represents the first case of scientific literature introducing this new term. Besides the well-known pharmacological properties of the natural molecules contained in herbs and herbal food, there exists an enzymatic/co-enzymatic activity attributed to the nanosized assemblies.

Serum 25 hydroxyvitamin D levels and affecting factors among preconception fertile women.

BACKGROUND: Recent study found that vitamin D before conception was considered as a potential additional determinant for achieving pregnancy and live births. The study aimed to evaluate the serum 25 hydroxyvitamin D (25(OH)D) levels and its affecting factors among preconception fertile women. METHODS: This cross-sectional study enrolled 410 women aged 22-44 years who attended a preconception genetic counseling clinic from January 2018 to May 2019. Sociodemographic characteristics and reproductive history of women were collected, and height and weight were measured. Serum 25(OH)D concentration was assayed with chemiluminescence immunoassay. Descriptive statistics were used to examine serum 25(OH)D concentration, and socio-demographic characteristics and reproductive history among preconception women. Determinants of vitamin D deficiency and its affecting factors were assessed using χ2 test and logistic regression. RESULTS: Findings showed 84.4% of women had serum 25(OH)D concentration below 20 ng/mL. Women working indoors as well as without a history of childbirth had significantly lower 25(OH)D levels compared with those non-working individuals and having delivered a previous child (both P < 0.05). The 25(OH)D levels were the lowest in winter among that in spring, summer, and autumn (all P < 0.001). Women in winter have significantly elevated OR of 5.00 (95%CI 1.75-14.25) to develop vitamin D deficiency. Seasonal variation in serum 25(OH)D levels was not present in non-working individuals and women aged 31-44 years. CONCLUSIONS: Vitamin D deficiency is common among preconception women especially nulliparous women and working women, which propose to screen serum 25(OH)D on preconception evaluation and emphasize need vitamin D supplements and get sunshine exposure.

Study of Cinobufagin as a Promising Anticancer Agent in Uveal Melanoma Through Intrinsic Apoptosis Pathway.

Uveal melanoma (UM) is the most common primary intraocular carcinoma in adults. Cinobufagin, secreted by the Asiatic toad Bufo gargarizans, is a traditional Chinese medicine, widely used in tumor treatment. Here, we explored the potential antitumor function of cinobufagin and investigated its biochemical mechanisms in UM cells. The antitumor potential of cinobufagin was determined via cell viability, cell cycle, and apoptosis assays. Colony formation assays confirmed that cinobufagin exerted potent antitumor activity in a dose-dependent manner. We found that cinobufagin could induce cell apoptosis and upregulate the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-9 in vivo and in vitro. In addition, after treatment with increased concentrations of cinobufagin, the intrinsic mitochondrial apoptosis pathway was also activated, which was demonstrated by increased cell apoptosis with increased expression of Bad and Bax, decreased expression of Bcl-2 and Bcl-xl, and reduced mitochondrial membrane potential (MMP) in OCM1 cells. Taken together, the results of this preclinical study suggest that cinobufagin can both inhibit cell survival and induce cell apoptosis in a dose-dependent manner in UM cells, which provides new insights into the biochemical mechanism of cinobufagin and its potential as a future chemotherapeutic agent for UM.

Highly Sensitive and Selective Detection of Amoxicillin Using Carbon Quantum Dots Derived from Beet.

In the present work, we synthesized the carbon quantum dots (CQDs) by one step hydrothermal method using the dried beet powder as the carbon source without additional chemical reagents and functionalization. The as-prepared CQDs are quasi-spherical carbon nanoparticles with diameters of 4-8 nm as well as surface functional groups such as carboxyl and hydroxyl groups, and exhibit good water-solubility, biocompatibility, and strong fluorescence. It is confirmed that amoxicillin (AMO) could enhance the fluorescent intensity of CQDs, the I/I0 showed a linear correlation between the intensity of fluorescence and the concentration of AMO in a broad range. These superior properties render a potential application of the CQDs in biomedical.

Dysregulation of YAP by ARF Stimulated with Tea-derived Carbon Nanodots.

YAP is a downstream nuclear transcription factor of Hippo pathway which plays an essential role in development, cell growth, organ size and homeostasis. It was previously identified that elevation of YAP in genomics of genetic engineered mouse (GEM) model of prostate cancer is associated with Pten/Trp53 inactivation and ARF elevation hypothesizing the essential crosstalk of AKT/mTOR/YAP with ARF in prostate cancer. However, the detailed function and trafficking of YAP in cancer cells remains unclear. Using GEM microarray model, we found ARF dysregulates Hippo and Wnt pathways. In particular, ARF knockdown reduced non-nuclear localization of YAP which led to an increase in F-actin. Mechanistically, ARF knockdown suppressed protein turnover of ß-catenin/YAP, and therefore enhanced the activity of AKT and phosphorylation of YAP. Moreover, we found tea-derived carbon dots can interact with ARF in nucleus that may further lead to the non-nuclear localization of YAP. Thus, we reported a novel crosstalk of ARF/ß-catenin dysregulated YAP in Hippo pathway and a new approach to stimulate ARF-mediated signaling to inhibit nuclear YAP using nanomaterials implicating an innovative avenue for treatment of cancer.

[Kinetic study on pyrolysis of psoralen].

In this study, products of psoralen pyrolysis were detected using a solid pyrolysis apparatus and synchrotron radiation vacuum ultraviolet photoionization mass spectrum (SVUV-PIMS). The pyrolytic kinetics of psoralen was also studied by calculating its initial pyrolytic route in quantum chemistry. According to the findings with SVUV-PIMS, three pyrolytic products were observed, CO, C9H6O and C10H6O2. Theoretically, three fragment pathways were calculated for psoralen, in which the major primary decomposition route was de-CO, and the major secondary decomposition reaction was de-CO reaction of de-CO products.