This research explored the synergistic effects and the mechanism of parthenolide (PTL) and vorinostat (suberoylanilide hydroxamic acid, SAHA) on the proliferation of A549 non-small cell lung cancer cells. The combination effect of PTL and SAHA was detected by cell counting kit-8 (CCK-8) and colony formation assays. Scratch test was performed to detect cell migration. Annexin V-fluorescein isothiocyanate isomer/propidium iodide (FITC/PI) flow cytometry and Western blot analyses were used to determine cell apoptosis and its mechanism. The results showed that combination of PTL and SAHA inhibited the proliferation and migration of A549 with a synergistic effect compared to the single-drug groups. The combination of PTL and SAHA had synergistic effect to induce cell apoptosis by regulating p53 and c-myc pathways, and affected the expression levels of poly ADP-ribose polymerase (PARP), cysteinyl aspartate specific proteinase (caspase)-9, and caspase-3. Taken together, this study shows that combination of PTL and SAHA has synergistic effect, induces cell apoptosis and inhibits A549 proliferation, which is likely to be a novel strategy for the treatment of non-small cell lung cancer.

Tanshinones and salvianolic acids are important materials in the treatment of coronary heart disease, myocardial infarction, hypertension, hyperlipidemia, stroke and others illnesses. In recent years, with the development of genomics, transcriptome, metabolomics and bioinformatics, many advances have been made in the biosynthesis and transcriptional regulation of tanshinones and salvianolic acids. This paper summarizes these advances and suggests further study on the downstream synthesis pathways and transcriptional regulatory mechanisms to reveal new molecular mechanism of synthesis, transport, regulation and modification. Additionally, we discuss the design and construction of new biological pathways to increase the expression of biosynthesis genes and the production of secondary components, is a newly developing research field.

Drug metabolites in the systemic circulation can be closely related to the safety or efficacy of drugs, so it is necessary to evaluate the pharmacokinetics of both the parent drug and its major metabolites in plasma. Bisthianostat, a novel histone deacetylase (HDAC) inhibitor, is currently under development. An LC-MS/MS method was developed and validated for the simultaneous determination of bisthianostat and its hydrolyzed N-hydroxyamide metabolite M351 in human plasma to evaluate their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes and endogenous substances were separated on a Waters BEH C₁₈ column (2.1 mm×50 mm, 1.7 μm). The mobile phase consisted of acetonitrile and 5 mmol·L^-1 ammonium acetate (containing 0.2% formic acid, v/v) for gradient elution. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 367.1→235.0 for bisthianostat, m/z 352.1→207.0 for M351, m/z 371.1→235.0 for d₄-bisthianostat, and m/z 357.1→208.0 for d₅-M351. The method was linear over a concentration range of 2.00-2000 ng·mL^-1 for bisthianostat and 4.00-4 000 ng·mL^-1 for M351. The results of quality control samples showed that the intra-and inter-day precision were no more than 6.2% for bisthianostat and 6.8% for M351. The accuracy ranged from -1.1% to 4.3% for bisthianostat and -0.5% to 4.9% for M351. The pharmacokinetic results show that after a single oral administration of 100 mg bisthianostat, the time to peak (t_max) of M351 in the plasma of three patients with tumors was significantly longer than that of the parent drug (t_max was 4.00 h and 0.67 h, respectively), and the C_max and plasma exposure of M351 were about 1.7 times and 11 times higher, respectively, than that of the parent drug. This clinical trial was approved by the society of ethics and conducted in Renji Hospital, Shanghai Jiaotong University School of Medicine.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CL^pro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this paper, we report the validation and use of bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening for SARS-CoV-2 virus 3CL protease inhibitors. The results show that the method is able to monitor the cleavage efficiency of 3CL protease with good reproducibility (Z' factor is 0.59), and is consistent with antiviral activity analysis in cell culture. This work demonstrates that this method can be applied to the screening and evaluation of 3CL protease inhibitors, providing a powerful tool for the development of new drugs.

Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in several diseases. Under the normal physiological conditions, only about 0.5% of endothelial cells (ECs) undergo mitosis, while the most ECs are in a resting state. Angiogenesis is a dynamic process in which ECs shift from resting to activated state, including three basic steps:① excessive vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), platelet-derived endothelial growth factor (PDGF) and other pro-angiogenic factors secreted by ECs can promote the germination of ECs in the original blood vessels; ② the sprouts are continuously elongated through the proliferation of ECs and the degradation and migration of basement membrane. At this time, the ECs present two phenotypes with filamentous feet and strong proliferation ability; ③ the buds are continuously elongated to form a tubular structure and connect with adjacent blood vessels, and the junction is wrapped by wall cells and basement membrane to form new blood vessels. Nowadays, angiogenesis has become a target for clinical treatment of multifarious diseases. On one hand, anti-angiogenesis is used to treat various diseases with excessive angiogenesis, such as cancer, atherosclerosis, and diabetic retinopathy, etc. On the other hand, the diseases caused by insufficient angiogenesis, including myocardial infarction, myocardial ischemia/reperfusion injury, stroke, wound long-term healing and other ischemic diseases can be improved by pro-angiogenesis therapy. Large numbers of researches have shown that many active ingredients of traditional Chinese medicine can effectively treat the previously mentioned diseases by regulating angiogenesis in different ways. Therefore, the anti-and pro-angiogenesis effects of some active ingredients derived from traditional Chinese medicine and their mechanism were summarized in this manuscript, arming to provide theoretical basis for the development of new drugs for the treatment of angiogenesis-related diseases.

Snake bite is a common acute and severe disease in tropical and subtropical regions, and its public health importance has been largely neglected. Snake venom is a complex mixture of active proteins, polypeptides, and other toxins. Many of these components can target multiple ion channels, cell receptors, and membrane transporters. Compared with traditional small molecule drugs, the proteins and polypeptides from snake venom have stronger specificity and affinity to targets and are especially suitable for novel drug design. The current studies show that snake venom and its components have great potential for development as leading compounds of new drugs. In this paper, the recent advances in main components, toxic effects, and detoxification strategies of snake venom, as well as its pharmacological activities and medical application are reviewed. The aim is to provide reference for clinical diagnosis and treatment of snake bite and development of new drugs based on snake venom.

Breast cancer is the most common malignant tumor in women worldwide. In breast cancer tumor tissues, a variety of targets related to the occurrence and development of breast cancer have been observed, and many drugs have been used in clinical applications for these targets. However, most of these drugs are small molecule inhibitors. With the long-term use of these drugs, acquired drug resistance often occurs in breast cancer patients. To overcome the drug resistance, the development of more efficient drugs is highly desirable in the treatment of breast cancer. Proteolysis targeting chimera (PROTAC) technology is a new kind of targeted protein degradation technology, which has shown broad prospect of applications in the field of drug development. The use of PROTAC technology to target the degradation of relevant targets in breast cancer has become a feasible strategy for breast cancer treatment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and cartilage destruction. An imbalance in macrophage polarization is closely related to the occurrence and development of RA, including a central role for M1 macrophages in promoting inflammation and bone destruction in the cytokine network environment of RA. It is a remarkable fact that the abnormal immune-microenvironment in RA patients promotes the metabolic reprogramming of macrophages, which disrupts the dynamic balance of M1/M2 by regulating the polarization of macrophages, leading to a persistent tissue inflammation. Using drugs to inhibit M1 macrophage polarization or induce M2 macrophage polarization is expected to be an ideal strategy for drug development for RA treatment. This review summarizes the effects of metabolic reprogramming of macrophages on polarization phenotype and the metabolism-related signaling pathways in the RA microenvironment, and provides references for the development of RA drugs that can target macrophage metabolism.

Ursodeoxycholic acid (UDCA) is an essential drug for the treatment of cholestatic liver diseases. As the most important representative of endogenous drugs, the metabolism and disposition of UDCA in human is characterized by both host-gut microbial co-metabolism and hepato-billilary-intestinal circulation. These distinct metabolic and pharmacokinetic features have brought great challenges into the bioequivalence (BE) evaluation of UDCA generic formulations. These challenges include not only biopharmaceutical problems derived from the unique physiochemical properties of amphiphilic molecules and the large single dose, but also the drug metabolism and pharmacokinetic problems associated with endogenous metabolism, long terminal half-life, high inter-and intra-individual variations, as well as accurate determination of UDCA and its metabolites. This review summarized academic and industrial literatures about the clinical pharmacokinetics and endogenous metabolism of UDCA. Current guidelines and technical challenges of UDCA BE studies were extensively discussed. Knowledge summarized in this review is expected to provide valuable reference for the development of UDCA generic formulations.

Metabonomics techniques were used to investigate the mechanism and metabolic pathways of total extract of Amygdalus mongolicus against renal fibrosis in rats. Rats were randomly divided into a model group (MOD), a sham surgery group (SDG), a benazepril hydrochloride-treated group (BHT) and three groups treated with the total extract of Amygdalus mongolicus:low-dose group (TOT-L), middle-dose group (TOT-M) and high-dose group (TOT-H), with 10 rats in each group. The rats were given intragastric administration for 3 weeks and kidney and blood samples were taken. Pharmacodynamic studies and ultra performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC-Q-TOF/MS) analysis were used to show that the total extract of Amygdalus mongolicus has an anti-fibrotic effect in rats. Compared with the MOD group, rats in the TOT-L, TOT-M and TOT-H groups showed a reversal in 67, 69, and 70 biomarkers, respectively, and shared 62 biomarkers. Reversal was observed for 7 key biomarkers related to renal fibrosis, including S-adenosy-L-methioninamine, ornithine, diketogulonic acid, and others, and changes in 5 metabolic pathways, including arginine and proline metabolism, pentose and glucuronate interconversions. These results give evidence of the metabolic pathways and the mechanism of action of Amygdalus mongolicus to prevent renal fibrosis in rats. The animal experiments were approved by the Medical Ethics Committee of Baotou Medical College (No. 20190314).