Latest ArticlesSelective activation or inhibition of the angiotensin Ⅱ type 2 (AT2) receptor can cause vasodilation, decrease cell proliferation, promote neurite outgrowth and block neuronal excitability. The AT2 receptor can be used as a potential drug target for the treatment of cardiovascular diseases, fibrosis, inflammation, neuronal diseases and tumors. Research and development of new drugs that selectively act on the AT2 receptor and the mechanism of intracellular signal transduction involving the AT2 receptor is a challenging but worthy endeavor. We review research progress on the AT2 receptor and compounds that act on the AT2 receptor, along with structure-activity relationship analysis, to provide reference and guidance for further research in this field.
Indoleamine 2, 3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the degradation of tryptophan to kynurenine. IDO1 is highly expressed in some tumor tissues. IDO1 can deplete tryptophan in tumor microenvironment, inhibit T cell function, and mediate the immune escape of tumor cells. Thus, IDO1 is considered a potential target of tumor immunotherapy. Currently, there are several IDO1 inhibitors in clinical research studies. The mechanism of IDO1-mediated tumor immune escape and the structure of IDO1 inhibitors are summarized in this review.
With a deepening understanding of cancer treatment, immune checkpoint inhibitors are recognized widely as a novel fundamental remedy for various malignancies with effectiveness and safety. With the development of pharmacometrics, model-informed drug development (MIDD) has emerged to accelerate the process of clinical research for new drugs and improve the accuracy of decision-making in new drug research, especially for immune checkpoint inhibitors. As a typical illustration, the research development of pembrolizumab is presented in this review to highlight the application of MIDD, which may provide a reference for the development of other new antitumor drugs.
Biphasic dissolution test, consisting of immiscible aqueous and organic phase, is an in vitro dissolution method that simultaneously measures the dissolution and partition of drugs. Due to the advantages of simulating in vivo absorption and overcoming the influence of surfactants on dissolution, it has been widely used to evaluate the poorly soluble drugs in vitro dissolution. Based on the relevant research in this field in recent years, this review summarizes the history, dissolution device, theoretical model and application of the biphasic dissolution test. Finally, the prospects in the development of biphasic dissolution test are also outlined.
Multi-template molecularly imprinted solid phase extraction not only has the advantages of high selectivity, large adsorption capacity, easy preparation, reuse and low environmental pollution, but also can realize the enrichment and separation of many kinds of compounds. It has attracted wide attention in the extraction and separation of traditional Chinese medicine components. This study summarizes the latest development of multi-template molecularly imprinted solid phase extraction. At the same time, based on the classification of active components of traditional Chinese medicine (flavonoids, alkaloids, phenylpropanol, terpenes, etc.), the latest application of multi-template molecular imprinting solid phase extraction in multi-component separation of traditional Chinese medicine was reviewed, with a view to better application of multi-template molecularly imprinted polymer in active multi-component extraction and separation of traditional Chinese medicine and provide reference for the material basic research of the efficacy of traditional Chinese medicine.
Blood-brain barrier (BBB) is the most challengeable obstacle for brain-targeted drug delivery. The combination of focused ultrasound (FUS) and microbubbles provides a new way for brain-targeted drug delivery across BBB based on the cavitation effect. This review briefly described the recent research of FUS combined with microbubbles to enhance the BBB permeability for brain-targeted drug delivery. The contents included the FUS mechanism, the types of the commercial microbubbles, shell materials, inner gas and preparation techniques of microbubbles, the opening mechanism of FUS with microbubbles, and the safety consideration. FUS combined with microbubbles may be the effective strategy to improve the BBB permeability for brain-targeted delivery, which could provide references for the clinical applications.
This study investigated the mechanism by which baicalein protected PC12 cells from Aβ25-35-induced injury. PC12 cells were treated with Aβ25-35 (20 μmol·L-1) and the ability of baicalein to prevent apoptosis was investigated by monitoring changes in cell morphology, Hoechst 33342 staining, and measurement of inflammatory factors. Western blotting was used to detect the expression of the apoptosis-related proteins cysteinyl aspartate specific proteinase-3 (caspase-3), cleaved cysteinyl aspartate specific proteinase-3 (cleaved caspase-3), proteins involved in the Janus kinase 2/signal transducer and activator of transcription 1 (JAK2/STAT1) pathway, and downstream inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The results show that baicalein (80 μmol·L-1) can significantly inhibit apoptosis and the release of inflammatory factor IL-8 and TNF-α in Aβ25-35-treated PC12 cells. Western blotting results showed that baicalein can inhibit the phosphorylation of JAK2 and STAT1 and decrease the expression of downstream iNOS and COX-2, thereby inhibiting the JAK2/STAT1 signaling pathway and preventing Aβ25-35-induced PC12 cell damage.
This study investigated the mechanism by which icaritin (ICT) inhibits exosomes-induced lung metastasis of B16BL6 mouse melanoma cells. The culture supernatant of B16BL6 cells was collected for extraction of exosomes by ultracentrifugation and their characterization by transmission electron microscopy and Western blotting. Exosomal protein was quantified by BCA. A wound-healing assay was used to determine the effect of ICT on the migratory ability of B16BL6 cells induced by exosomes. After establishing an experimental melanoma lung metastasis model in C57BL/6 mice, we used H & E staining to study the ability of ICT to inhibit exosomes-induced melanoma metastasis. Animal experiments were approved by the Ethics Committee of Nanjing University of Chinese Medicine. ELISA and immunofluorescence were used to detect pro-inflammatory factors interleukin 6 (IL-6), S100 calcium-binding protein A8/A9 complex (S100A8/A9), serum amyloid A (SAA) and fibronectin in metastatic tumors. The expression of metastatic tissue-related proteins stimulator of interferon gene (STING), phospho-STING (p-STING), TANK-binding kinase 1 (TBK1) and phospho-TBK1 (p-TBK1) was detected by immunohistochemistry or Western blotting. The results showed that the particle size of exosomes was 149.33±2.68 nm, the polydispersity index (PDI) was 0.192±0.02, the zeta potential was -32.22±0.50 mV, and the particles had classic tea tray-like membrane structure under TEM. The protein concentration of exosomes was measured to be 838.66±62.14 μg·mL-1. The results of the cell scratch test showed that ICT can inhibit exosomes-induced migration of B16BL6 cells at a concentration of 5, 10, and 20 μmol·L-1. In vivo experimental results also showed that ICT can inhibit exosomes-induced metastasis of melanoma to the lungs and can significantly inhibit the expression of pro-inflammatory factors S100A8/A9, SAA and IL-6 in lung tissue, and inhibit the expression of p-STING and p-TBK1 in metastatic lung tissue. Taken together, these results indicated that ICT can significantly inhibit exosomes-induced tumor metastasis, and the inhibition is related to the inactivation of STING in metastatic foci.
Sempervirine, a yohimbane-type alkaloid isolated from Gelsemium elegans, was found to significantly inhibit the cellular proliferation of U251 cells in vitro and in vivo in a dose-dependent manner. U251 cells were treated with 0-16 μmol·L-1 of sempervirine for 24, 48 or 72 h. An MTT assay and clone formation assay were used to investigate cell survival and clone formation. Hoechst staining and Annexin V-FITC/PI staining were used to measure cell apoptosis. The expression of PI3K, AKT, p-AKT, Bax, Bcl-2, caspase-3 and cleaved caspase-3 was determined by Western blot analysis. The antitumor effect of sempervirine in vivo was investigated by inoculating nude mice with U251 cells. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Fujian Medical University (Fujian, China). The results show that sempervirine significantly inhibits the proliferation and induces the apoptosis of U251 cells, promotes cleavage of caspase-3, down-regulates the protein expression of PI3K and Bcl-2/Bax, and inhibits phosphorylation of AKT in vitro. Intraperitoneal injection of 4 or 8 mg·kg-1·day-1 of sempervirine inhibits U251 cells tumor growth in the xenograft nude mice, and tumor weight decreased by 44.76% and 61.26%, respectively. Our study shows that sempervirine significantly inhibits the proliferation of U251 cells in vitro and in vivo, laying a foundation for further research and development of its anti-glioma effect.
Dengue virus (DENV) is the most rapidly transmitted mosquito-borne pathogen, which is the main cause of seasonal outbreaks of dengue fever and dengue hemorrhagic fever in tropical and subtropical regions, and may cause serious life-threatening diseases. There is an urgent need to develop effective vaccines or antiviral therapies. In this paper, we found that a podocarpane-type diterpenoid, (3α, 5β, 10α)-13-methoxypodocarpa-8, 11, 13-triene-3, 12-diol (MPTD), isolated from the stems and leaves of Aleurites moluccana, showed good effect against DENV. The anti-DENV activity of MPTD against four different DENV serotypes was studied by plaque assay. The cytotoxicity of MPTD in Vero and Huh7 cells was tested by MTT assay. qRT-PCR and Western blot assays were used to investigate the anti-DENV activity of MPTD at RNA and protein levels, respectively. The results showed that MPTD greatly reduced the virus titer in DENV infected Vero cells, and its 50% effective concentration (EC50) for DENV (1-4) were 2.72±0.39, 10.99±5.18, 18.72±0.21, and 0.48±0.28 μmol·L-1, respectively. The results showed that MPTD inhibits DENV RNA level and the expression of E protein. In addition, MPTD may inhibit the early stage of DENV replication and exert antiviral activity. Further studies showed that the inhibitory effect of MPTD against DENV infection is not targeting the viral entry stage. Therefore, MPTD has a significant anti-dengue virus effect, and is an anti-DENV compound with potential application value.
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