Reprogramming of metabolism is one of the most critical features in tumorigenesis and tumor growth. Many types of cancer show an increased demand for specific amino acids, rely on exogenous supplies, or alter amino acid metabolic pathways, leading to changes in corresponding amino acid levels to meet the need of tumorigenesis. Therefore, if the level of tumor growth-dependent amino acids can be effectively controlled, a new treatment strategy can be developed from the perspective of cell metabolism. At present, remarkable progress has been made in this field. This paper outlines the amino acid metabolic pathways closely related to tumorigenesis and tumor growth, and summarizes the corresponding regulatory mechanisms and active molecules. Finally, the direction of the field is discussed and prospected for future development.

To screen the antithrombotic effective components group of Trichosanthes extract, and to verify its pharmacodynamics and analyze its mechanism, the HPLC fingerprint of Trichosanthes extract (0.09, 0.45, 0.9 g·kg^-1) was established, and the pharmacodynamic indexes of antithrombosis in rats with aspirin (0.01 g·kg^-1) as positive control group were determined (the animals used in this experiment were approved by the Medical Ethics Committee of Wannan Medical College). The antithrombotic spectrum-activity relationship of Trichosanthes extract was studied and the effective antithrombotic ingredients group was screened by grey relational analysis. The monomer compound mixed solution (0.006, 0.03, 0.06 g·kg^-1) was prepared according to the content of each component in the active component group, and the pharmacodynamics and action mechanism were studied to verify the correctness of the spectrum-effect relationship. The correlation between the 22 components of Trichosanthes extract and antithrombotic efficacy was different and showed dose-effect relationship. Cytosine, uracil, guanine, hypoxanthine, xanthine, adenine, guanosine, and adenosine are the main antithrombotic components of Trichosanthes extract. The ratio of cytosine, uracil, guanine, hypoxanthine, xanthine, adenine, guanosine and adenosine was 3:12:10:5:2:8:13:14. Compared with the model group, the thrombus dry weight of each effective components group could be effectively reduced (P < 0.01 or P < 0.05), but there was no significant difference between each effective components group and the Trichosanthes extract group. Compared with the model group, the TXB₂ content in group (0.06 g·kg^-1, 0.03 g·kg^-1) could be effectively reduced (P < 0.01 or P < 0.05), and the content of 6-keto-PGF_1α could be increased in each group (P < 0.01), and the TXB₂/6-keto-PGF_1α tended to be normal and showed a dose-effect relationship. The effect was better than that in the Trichosanthes extract group (0.45 g·kg^-1) (P < 0.01). The effective ingredients group has a good antithrombotic effect, its mechanism is to inhibit platelet aggregation and improve vascular endothelial function.

This study was designed to explore the interventional mechanism involving "multi-components, multi-targets and multi-pathways" of Gu-Chang-Zhi-Xie pills (GCZX) for treatment of irritable bowel syndrome (IBS) using pharmacological network technology. Firstly, 96 active ingredients from GCZX pills were screened by ADME parameter filtration and chemical space principal component analysis, and the targets of anti-IBS function were predicted using PharmMapper online database. Secondly, AutoDock Vina was used to validate the docking between the active ingredients and predicted disease targets, and to establish the corresponding relationship between "pharmacodynamic molecules and target proteins". Finally, the target elements were mapped into the KEGG biological pathway by CluoGO plug-in, which further elucidates the potential relationship between the key targets and the mechanism of action of Gu-Chang-Zhi-Xie pills for treatment of IBS. The results showed that most of the top 11 key pharmacodynamic molecules were isoquinoline alkaloids, which mainly acted on inflammatory or pain targets, with different degrees of anti-inflammatory and analgesic effects. A total of 39 key targets were identified, including TPH1, TNF-α, IL-6, IFN-γ, MAO-A and IL-10. These targets were mapped to 29 KEGG pathways, of which the P-value of 5-HT signaling pathway was the smallest. Therefore, the pharmacodynamic molecules mainly act on 6 core targets and may play a major role in the regulation of 5-HT signal synthesis or transport pathway. This study sets an example for drug development and mechanistic investigation using innovative technology.

Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke, especially after thrombolytic therapy. This event is associated with increased morbidity and mortality. Tissue plasminogen activator (t-PA), the only FDA proved drug for breaking blood clots, is underutilized in ischemic stroke, because of its limited therapeutic window and hemorrhagic complications. Due to the lack of clear understanding of the pathological mechanism, there are no effective drugs to decrease the incidence of HT. Pinocembrin is a natural flavonoid compound and has neuroprotective effects in animal ischemic stroke models. In this study, we investigated the role of pinocembrin in t-PA thrombolysis-induced HT in rat thromboembolic stroke model. t-PA was administrated 6 h after ischemia and pinocembrin (5, 10 and 20 mg·kg^-1) was given 5 min before t-PA administration. Infarct volume, neurological score and hemoglobin content were evaluated at 24 h after ischemia. Evans blue leakage was used to detect blood-brain barrier (BBB) permeability. All procedures were approved by the Institutional Animal Care and Use Committee of the Peking Union Medical College. The results showed that treatment with t-PA at 6 h after ischemia aggravated brain injury and increased the risk of HT, with infarct volume and brain water content reached 39% and 83.4%, respectively. Pretreatment with pinocembrin decreased the infarct volume and brain water content to 28.5% and 80.3%, and improved neurological function. In addition, the combined application of pinocembrin with t-PA reduced hemoglobin content and Evans blue content in brain tissue by 50% and 40%, indicating that pinocembrin could protect the BBB permeability and reduce the occurrence of HT. Among these doses, 10 mg·kg^-1 is most effective. In conclusion, our results demonstrate that the combination of pinocembrin with t-PA protects against cerebral ischemia, reduces the occurrence of HT induced by t-PA thrombolysis. Thus, pinocembrin may be a potential therapeutic drug for t-PA induced HT.

Covalent tyrosine kinase inhibitors (TKIs) can inhibit the signaling pathway of tumor cells by covalent binding with cysteine residues of target proteins, which has the advantages of high potency, extended duration of action and overcoming drug resistance. In this article, we will review the metabolism and pharmacokinetics of some covalent TKIs. Currently, the covalent TKIs approved by US food and drug administration (FDA) are afatinib, neratinib, dacomitinib, osimertinib, ibrutinib and acalabrutinib. Pyrotinib have been approved by National Medical Products Administration (NMPA) to reach the market recently. Covalent TKIs can covalently bind with plasma proteins, especially human serum albumin, thus effected the pharmacokinetics of these drugs.

As a part of novel drug delivery carriers, peptides have diverse biological activities, low immunogenicity and good biocompatibility. In recent years, studies on the delivery carriers modified by peptides have attracted much attention. Among them, the peptides with acid sensitivity can change their secondary structures under slightly acidic microenvironment of the tumor or in lysosome. Therefore, the carriers made or modified by acid-sensitive peptides can specifically release the loaded drug in the tumor tissue, enhance the cell internalization of drugs and improve its therapeutic effects. In accordance with acid-sensitive peptides studied, the side chains, number of polar residues, sequence and secondary structure of the peptides might be involved in the acid sensitivity. In this review, we summarize the acid-sensitive peptides from recent literatures, analyze the connection between the structure and the acid sensitivity, and focus on the mechanism and application of acid-sensitive peptides in drug delivery. This provides the basis for further development and utilization for acid-sensitive peptides for efficient drug delivery.

Disulfiram (DSF) is a traditional anti-alcohol drug, but it was recently found that DSF has strong inhibitory effect on the growth of a variety of cancer cells. However, its clinical application is greatly limited due to its poor solubility, instability in gastrointestinal tract and short plasma half-life. In this study, DSF is fabricated into nanosuspensions with the aim of trying to solve these problems. DSF nanosuspensions (DSF-NSps) were prepared by the anti-solvent precipitation method under ultrasonication, and the suitable stabilizer was screened according to the size, polydispersity index (PDI), and zeta potential of the resultant nanosuspensions, along with their particle size change during the storage at room temperature. The particle size, PDI, and zeta potential of DSF-NSps were determined using dynamic light scattering method, while the morphology of DSF-NSps was observed by transmission electronic microscope (TEM). The stability of DSF-NSps in media was examined according to their particle size change in different physiological media. The concentration of DSF was measured by HPLC assay. The in vitro drug release was evaluated on basis of dialysis. MTT assay was employed to evaluate the in vitro cytotoxicity of DSF-NSps against cancer cell lines. The 4T1 tumor-bearing mouse model was used to evaluate the in vivo therapeutic efficacy of DSF-NSps. All the animal experiments were acquired according to the Regulations for Animal Experiments and Guidelines for Ethical as defined by Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College. As a result, the combinational use of soyabean lecithin (SPC) and D-alpha tocopherol acid polyethyene glycol succinate (TPGS) was determined to best stabilize DSF-NSps when the ratio of DSF-SPC-TPGS was 24:20:4 (weight ratio), with small particle size and good storage stability. The resultant DSF-NSps showed a regular spherical morphology and drug loading content of (45.36 ±2.09)%, with average particle size of 175.00 ±0.75 nm, PDI of 0.24 ±0.07 and zeta potential of -14.3 mV. DSF-NSps displayed good particle size stability in a variety of biological media including phosphate buffer saline, normal saline, 5% glucose, artificial gastric fluid, artificial intestinal fluid and plasma, which would meet the demand of both intravenous and oral administration. The in vitro study demonstrated that nano-encapsulation greatly increased the stability of DSF in aqueous media, DSF-NSps exhibited sustained release of the encapsulated drug and significantly inhibited 4T1 cells compared to free DSF (IC₅₀, 1.07 vs 5.53 μg·mL^-1, P < 0.01). DSF-NSps showed a good dose-response relationship on the 4T1 tumor-bearing mice with the tumor inhibition rates at the three doses being 80.22%, 75.14% and 66.10%, all higher than that of paclitaxel injections (55.01%, P < 0.05). The in vivo biodistribution study displayed that DSF-NSps were mainly distributed into liver, spleen and tumor. In sum, disulfiram nanoparticles could be expected to provide an effective anti-cancer drug for the treatment of breast cancer.

IMB5046 is a newly discovered nitrobenzoate functioning as a microtubule inhibitor. Here we report its synthesis and in vitro anti-angiogenic activity. IMB5046 was synthesized by conjugation of 2-morpholin-4-yl-5-nitrobenzoic acid with 4-(methylthio)benzyl alcohol via two-step reactions. The structure of the end product was verified using ¹H NMR and HR-MS spectroscopy. The effect of these compounds on cell proliferation was determined using MTT assay, and their impact on cytoskeleton was investigated using fluorescence assay. Flow cytometry was performed to examine the effect of IMB5046 on cell cycle. Cell wound scratch assay and Transwell assay were performed to examine cell migration. Endothelial tube formation assay was used to evaluate the anti-angiogenic activity of IMB5046. The results indicated that IMB5046 induced endothelial cell contraction and microtubule depolymerization, and inhibited the proliferation of endothelial cells and tumor cells, while two raw materials showed no obvious effects. IMB5046 arrested cell cycle at G₂/M phase, even at low-cytotoxic concentrations it significantly inhibited the motility of endothelial cells. IMB5046 inhibited the tube formation of endothelial cells according to the number of tubes and junctions. In conclusion, IMB5046 is a promising microtubule-targeting drug with anti-angiogenic activity.

This study aimed to evaluate the antioxidant activities of Scutellaria baicalensis Georgi flowers by measuring the scavenging activity of hydroxyl radical and superoxide anion radical. Aging of rats was induced by D-galactose and protective effects of Scutellaria flower extract (SFE) at different doses were evaluated by locomotor activities. To explore the mechanism of SFE, metabolomic technique combined with multivariate statistical methods was used to analyze the profile of metabolites from rat serum and quantify the levels of glutamine and glutamate in the serum. All research procedures were approved according to the Committee on the Ethics of Animal Experiments of Shanxi University. The results showed that high-dose of SFE had antioxidant activity in vitro, and could ameliorate the aging behavior of rats. A total of 9 potential biomarkers related to aging were found, pointing to the involvement of 7 metabolic pathways.

The purpose of this study is to further explore the effects of SI-4650, a newly discovered small molecule inhibitor of spermine oxidase (SMO) in our laboratory, on proliferation and migration of human osteosarcoma 143B cells and its underlying molecular mechanism. Chemiluminescence and high performance liquid chromatograph were used to analyze the effect of SI-4650 on SMO activity in 143B cells. DCFH-DA-staining/FCM was used to analyze the accumulation of cellular reactive oxygen species (ROS), whereas MTT and FCM were used to detect proliferation and cell cycle. Transwell culture and Western blot were used to analyze the expression levels of migration-related proteins. PI/FITC-Annexin V/FCM, fluorescence microscopy and Western blot were used to analyze apoptosis and autophagy. Our results showed that SI-4650 could significantly decrease SMO activity, inhibit cell proliferation or migration, and induce a S-phase cell cycle arrest in 143B human osteosarcoma cells. The mechanism may be related to interfering with polyamine metabolism, activating mitochondrial-mediated apoptosis and causing autophagic death. These results suggest that SI-4650 has the potential for clinical use in treatment of osteosarcoma.