The purpose of this study was to discover novel inhibitors of sirtuin-1(SIRT1) that could be used in the treatment of acute myeloid leukemia(AML).Eight potential SIRT1 inhibitors were identified from 231 511 natural drug-like molecules by virtual screening-based molecular docking and molecular mechanics-generalized Born surface area(MM-GBSA) calculation of binding free energies.Using existing SIRT1 inhibitor molecules as training and test sets, a series of quantitative structure-activity relationship models were established, and the best quantitative structure-activity relationship(QSAR) model was used to predict the IC₅₀ of these 8 potential inhibitor molecules for SIRT1.Subsequently, molecular dynamics simulations were performed to verify the binding mode and stability of these complexes of potential inhibitors and SIRT1 protein.Finally, the activity of these potential SIRT1 inhibitors was verified by cell proliferation assays of OCI-AML2, OCI-AML3 and MV4-11 cells and SIRT1 enzyme activity assays, and it was found that 5 compounds could inhibit AML cell proliferation.Among them, the most active compound, ZINC000001774455, had an IC₅₀ of 2.29 ± 0.09 μmol·L^-1 with OCI-AML2 cells, and at a concentration of 1 μmol·L^-1, the inhibitory ratio of this compound on SIRT1 protein activity was 65.33%.ZINC000001774455 can be used as a lead compound for the development of new AML treatments.

During growth and progression, the microenvironment of tumors suffers a series of abnormal characteristics, which include hypoxia, acid pH, increased oxidative stress, excess glutathione(GSH), as well as certain overexpressed enzymes. Although affect or limit the cancer therapeutic outcomes, these factors provide possible approaches to strategies for cancer detection and novel therapy at the same time. Recently, based on these properties of the tumor microenvironment(TME), various kinds of responsive nano-platforms have been continuously developed and applied in cancer theranostics preliminarily. Thus, this review would introduce the typical features of TME firstly, then detailly summarize the design principles and research progress of corresponding hypoxiaresponsive, pH-responsive, redox-responsive, enzyme-responsive, dual-responsive and multi-responsive nanoplatforms. Finally, the challenges and the perspectives of the TME-responsive nano-platforms are briefly discussed.

With high selectivity and potency, target protein degradation technology has recently emerged as a strategy for drug discovery and design. Proteolysis-targeting chimeras(PROTAC) function as inducers for the degradation of target proteins and are a research focus in drug development. Current research on PROTAC mainly revolves around the rational design of PROTAC molecules, the discovery of new E3 ubiquitin ligase ligands and improvement in drug targeting. In this review, we focus on the PROTAC linker and its effects on the generation of the E3 enzyme-PROTAC-target protein ternary complex from three standpoints: length, binding site and chemical properties. We discuss the influences of the linker on the efficacy and the selectivity of PROTAC molecules.

Natural products and their derivatives are important components of anti-tumor drugs. Currently, anti-tumor drugs derived from natural products which are in clinical practice are mainly conventional cytotoxic or molecularly targeted drugs. Their application is limited by drug-related side effects and drug resistance. Recent studies have shown that anti-tumor natural products often act on multiple targets in tumor cells and in turn interfere with multiple processes in tumorigenesis and development. As tumor is a systemic disease induced by multiple factors, multi-targeted natural products possess unique potential in tumor therapy. However, the targets and mechanisms of the discovered multi-targeted antitumor natural products remain elusive, which limits their further development and application. This review summarized the research progress in the mechanism of action, target identification, and structure optimization of multi-targeted anti-tumor natural products exemplified by a few typical compounds. The research and development of these agents have also been proposed.

Nanoparticles have better applicability in the detection, treatment of cancer and various difficult diseases, but mononuclear phagocytosis system can seriously shorten the time of nanoparticles in vivo circulation, reduce the drug efficacy. The protein crown formed on the surface of the nanoparticle after entering the body can change its surface properties, interfere with the recognition of phagocytes, and thus affect its circulation time in vivo.This article outlines the general composition and formation process of protein crowns. It also summarizes the influence of the physical and chemical properties of nanoparticles, such as particle size, surface charge, hydrophilicity and surface materials on the formation of protein crowns. The protein crown affects the circulation of nanoparticles in vivo, mainly because the adsorbed opsonic protein promotes cell phagocytosis. Therefore, we also introduce the method of using protein crowns to promote the long circulation of nanoparticles in vivo. By designing appropriate physical and chemical properties, surface modification, and directed design of protein crowns, the adsorption of proteins on the surface of nanoparticles can be reduced. Therefore, it can reduce the clearance of nanoparticles in the mononuclear phagocytic system(mainly the phagocytes of the liver and spleen), and achieve the goal of long circulation of nanoparticles in the body.

Drug use during pregnancy is unavoidable. Therefore, it is vitally important for medical workers to help pregnant women take drugs correctly to reduce the incidence of spontaneous abortion, premature birth, and low birth weight. In our study, drug screening model with induced pluripotent stem cells(iPSCs) was used to find some improper drugs which will result in woman's abortion. With 3D culture in vitro, iPSCs can form embryoid bodies(EBs) and cerebral organoids, which simulated in vitro development of early embryos, from inner cell mass to germ-layer differentiation. In the experiment, EBs were exposed to mifepristone(RU486), and three experimental groups were divided randomly. They were control group(without RU486), low-dose group(L-RU486, 10 μg·mL^-1), and high-dose group(H-RU486, 20 μg·mL^-1). After mifepristone exposure, EBs were observed at days 5, 8, and 11, including size of EB, cell apoptosis, and differentiation of germ layers, by using inverted optical microscope, TUNEL assay, and immunofluorescent staining. The results showed that through 3D culture, iPSCs could develop into embryoid bodies, neural rosettes, and finally cerebral organoids. After mifepristone exposure, EBs' sizes were decreased(P < 0.01); the levels of cell apoptosis in EBs were increased after mifepristone exposure(P < 0.01); the development of EBs' germ layer was affected. Mifepristone exposure could inhibit the proliferation of embryonic stem cells, reduce the differentiation of ectoderm(P < 0.01) and promote the development of mesoderm(P < 0.05).In conclusion, iPSCs can be used as a screening model for abortion drug, and EBs' diameter, cell apoptosis, and differentiation changes of the germ layers can serve as criteria of abortion drug screening.

Puerarin(PUE), as an isoflavone component, has a wide range of pharmacological activities, while its poorly aqueous solubility limits the development of solid oral dosage forms. In this study, PUE along with nicotinamide(NIC) were prepared into the coamorphous system by solvent-evaporation method and characterized by powder X-ray diffraction(PXRD), differential scanning calorimetry(DSC) and Fourier transform infrared spectroscopy(FT-IR). In addition, its dissolution behavior and solubilization mechanism were also investigated.PUE-NIC coamorphous was a single homogeneous binary system, with a single glass transition temperature at 35.1 ℃. In comparison to crystalline PUE, during the dissolution process, coamorphous PUE-NIC not only exhibited the "liquid-liquid phase separation"(LLPS) phenomenon, but the formation of A_p type complexation(1∶1 and 1∶2)between PUE and NIC molecules was also verified, which significantly improved the solubility of PUE and prolonged the supersaturation time, and would benefit its absorption.

M701 is a bispecific CD3/EpCAM T-cell engager antibody for the treatment of malignant ascites. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively describe and predict the antitumor effect of M701 in human colorectal cancer xenograft mice. We developed the M701 PK model based on plasma concentration data after i.v. administration. A tumor growth model for human colorectal cancer xenograft was developed to evaluate the antitumor effect of M701. We additionally simulated the inhibitory effect of M701 on tumor volume under different dose regimens based on a PK/PD model. A two-compartment model was developed to predict the PK in human colorectal cancer xenograft mice. The relationship between the M701 concentration and tumor growth inhibition was characterized by a combined Simeoni tumor growth/transit compartment model. The estimated pharmacodynamic parameters were related to the tumor growth characteristics λ₀ (0.212 d^-1) and λ₁ (0.044 7 cm³·d^-1), to the drug potency k₂ (0.071 5 mL·ng^-1·d^-1), and to the kinetics of tumor cell death k₁ (2×10^-5 d^-1). A model visual predictive check showed that both the PK model and the tumor growth model closely fit the observed data. Simulated tumor growth after administration of M701 (0.5 mg·kg^-1 every 6 days and 0.25 mg·kg^-1 every 3 days) could be effectively inhibited. This population PK/PD model of M701 provides insight into the antitumor effect of M701 and supports the further therapeutic development of M701.

A quantitative analytical method based on HPLC coupled with the charged aerosol detector (CAD) for quantitative analysis of multi-components with a single marker (QAMS) was established for simultaneous determinations of astragaloside Ⅰ, astragaloside Ⅱ, astragaloside Ⅳ, calycosin-7-O-β-D-glucoside, formononetin and 7, 2'-dihydroxy-3', 4'-dimethoxyisoflavan in Astragalus membranaceus. The separation was performed on an Agilent SB-C18 (150 mm×4.6 mm, 3.5 μm), with gradient elution using the mobile phase consisting of 0.05% formic acid solution and 0.05% formic acid acetonitrile at the flow rate of 1.0 mL·min^-1. The column temperature was 35 ℃, and the injection volume was 20 μL. For CAD, the drift tube temperature was at 50 ℃. The contents of six components in A. membranaceus were determined by both external standard method (ESM) and QAMS, and then were compared. The results showed that chromatographic peaks were separated well and the linear ranges of astragaloside Ⅰ, astragaloside Ⅱ, astragaloside Ⅳ, calycosin-7-glucoside, formononetin and 7, 2'-dihydroxy-3', 4'-dimethoxyisoflavan were 0.113-2.250 mg·mL^-1, 0.012-0.240 mg·mL^-1, 0.004-0.080 mg·mL^-1, 0.065-1.300 mg·mL^-1, 0.005-0.100 mg·mL^-1 and 0.007-0.150 mg·mL^-1, respectively. The content ranges of astragaloside Ⅰ, astragaloside Ⅱ, astragaloside Ⅳ, calycosin-7-glucoside, formononetin and 7, 2'-dihydroxy-3', 4'-dimethoxyisoflavan were 0.306-0.922 mg·g^-1, 0.053-0.183 mg·g^-1, 0.015-0.092 mg·g^-1, 0.069-0.823 mg·g^-1, 0-0.098 mg·g^-1 and 0.020-0.107 mg·g^-1 in 20 batches of A. membranaceus, respectively. Using astragaloside Ⅱ as an internal reference, the relative correlation factors of astragaloside Ⅰ, astragaloside Ⅳ, calycosin-7-O-β-D-glucoside, formononetin, and 7, 2'-dihydroxy-3', 4'-dimethoxyisoflavan were calculated as 0.561, 0.835, 0.299, 0.796, and 0.799, respectively. The results were compared with those obtained by the external standard method to verify the feasibility, rationality and repeatability of QAMS method, and there was no significant difference in assay results between the two methods. In conclusion, the QAMS method is accurate and feasible, and could be used to determine the contents such as astragaloside Ⅰ, astragaloside Ⅱ, astragaloside Ⅳ, calycosin-7-glucoside, formononetin and 7, 2'-dihydroxy-3', 4'-dimethoxyisoflavan, and it can be used for quality control of A. membranaceus.

We investigated the inhibitory effect and mechanism of action of bruceantin (BCT) on the proliferation, invasion and migration of non-small cell lung cancer (NSCLC) cells. The cytotoxic activity of BCT was measured by MTT assay; a colony forming assay, wound healing assay, and a Transwell assay were used to investigate the anti-proliferative, anti-migration, and anti-invasion effects, respectively; immunoblotting and RT-qPCR were used to detect the expression of related proteins, miRNA, and mRNA, respectively, that were involved in cell proliferation, migration, and invasion. Two gene prediction websites were used to predict the downstream target gene of miRNA. Our results show that BCT has a potent cytotoxic effect on NSCLC cell lines, with a half maximal inhibitory concentration (IC₅₀) of BCT against H1299, PC-9, and A549 of 0.12 ± 0.02, 0.31 ± 0.20, and 2.07 ± 0.70 μmol·L^-1, respectively. When H1299 cells were treated with 0.03, 0.15, and 0.75 μmol·L^-1 BCT for 24 h, the proliferation, migration, and invasive ability were inhibited in a concentration-dependent manner. It is worth noting that the expression level of miRNAs related to cell migration and invasion, such as miR-29a-3p, miR-21-3p, miR-183-5p, and miR-34b-5p increased with the concentration of BCT, especially for miR-29a-3p. Using the two gene prediction websites, we predict that integrin β1 (ITGB1) may be the target gene of miR-29a-3p; immunoblot results further show that a variety of proteins related to cell proliferation, migration, and invasion, such as various proteins of the integrin family, β-catenin, p-Src, and vascular endothelial growth factor, all decreased in a concentration-dependent manner, among which the reduction of ITGB1 protein was the most obvious. RT-qPCR results showed that there was no change in ITGB1 mRNA expression. We speculate that BCT might inhibit the expression of ITGB1 protein by up-regulating miR-29a-3p independent of its mRNA level. The in-depth mechanism needs to be further explored. This study suggests that BCT has the potential for further development in the treatment of NSCLC.