Latest ArticlesThe bone marrow microenvironment, also known as the bone marrow niche, plays a critical role in maintaining the functions of hematopoietic stem cells. Under physiological conditions, various bone marrow cells regulate each other to sustain hematopoietic homeostasis. However, bone marrow cells gain abnormal function under pathological conditions to cause and promote the occurrence of leukemia and induce drug resistance. Recent findings indicate that abnormal proliferation and differentiation are not the sole reason to cause leukemia. Different types of bone marrow cells also induce intercellular adhesion, abnormally secrete cytokines and chemokines, accelerating leukemia's progress. This article reviews the multiple signaling pathways that regulate the formation and progress of leukemia bone marrow niche, such as C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 signaling pathway, et al. It emphasizes that targeting leukemia bone marrow niche is a vital strategy for improving the leukemia treatment.
Over the past three decades, more and more antisense drugs have been approved for marketing or clinical trails. Antisense technology has become the focus of pharmaceutical research due to its unique advantages in treating diseases and strong clinical development potential. There is a big difference from traditional small molecule chemical drugs, and macromolecular protein biological drugs. Antisense drugs are a very independent drug form. Antisense drugs were initially used to treat diseases with single gene mutations, but recently they have gradually begun to be used for the treatment of common diseases. Rational antisense drug design is crucial for disease treatment based on genetics. This paper reviews the latest progress in the field of action mechanism, chemical modification and delivery strategy of antisense drugs, and analyzes the current intractable problems. It is believed that with the resolution of these problems, the research of antisense drugs can reach a new level.
Glioblastoma (GBM) is the most common primary brain tumor, which is prone to recurrence and metastasis with poor prognosis. In recent years, immunotherapy has prolonged the survival of patients with GBM, providing a new option for the treatment of GBM. Target selection is very important for immunotherapy. Epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) is highly expressed on the surface of GBM cells in some patients, and EGFRvⅢ was not expressed in normal tissues. EGFRvⅢ are pivotal for the occurrence and progression of GBM, various targeted therapy including immunotherapy is promising to improve the efficacy of GBM. Currently, there are various approaches to target EGFRvⅢ, including humanized monoclonal antibodies, adoptive cell therapies and therapeutic vaccines. In this review, we focus on the preclinical and clinical findings of targeting EGFRvⅢ for GBM.
This study investigated the inhibitory effect and mechanisms of cryptotanshinone (CPT) on tamoxifen resistant cell MCF7-TAMR. The inhibitory effect of CPT on the viability of MCF7-TAMR cells was evaluated using the MTT assay. We found that CPT significantly inhibited the growth of MCF7-TAMR cells in a dose- and time-dependent manner. The half inhibitory concentration (IC50) is 15.14 ± 2.82 μmol·L-1 at 24 h. CPT induced cell cycle arrest of MCF7-TAMR cells at G0/G1 phase, and promoted apoptosis of MCF7-TAMR cells by upregulating intracellular levels of reactive oxygen species (ROS). Transwell results showed that CPT significantly inhibited the migration of MCF7-TAMR cells. Furthermore, CPT decreased the CD24-/lowCD44+ cell population in MCF7-TAMR cell-derived microspheres. Western blot results showed that CPT effectively inhibited the phosphorylation of estrogen receptor α (ER-α), and reduced the expression of phosphatidylinositol 3-kinase (PI3K-p85), serine-threonine protein kinase (Akt) and multidrug transporter ATP-binding cassette superfamily G member 2 (ABCG2). These results showed that CPT can induce cell apoptosis, cause cell cycle arrest, inhibit cell migration and inhibit ER-α phosphorylation, inhibit PI3K/Akt signaling pathway, reduce the number of CD24-/lowCD44+ cells and the expression of ABCG2, overcome cell drug resistance.
The carbamoyl phosphate synthase 1 (CPS1) enzyme is involved in the first phase of the urea cycle, providing a prerequisite molecule for pyrimidine synthesis, as well as promoting tumor cell proliferation and growth. Studies have found that CPS1 is highly expressed in a variety of tumors, including colorectal cancer, lung cancer, etc. and its overexpression is related to the poor prognosis of tumors. Thus, small molecules targeted to inhibit the function of CPS1 in tumors may provide therapeutic benefits for cancer patients who overexpress CPS1. In this study, the function of CPS1 was investigated in vitro, and we found that overexpression of CPS1 can enhance the migration ability of colorectal cancer cells HCT15. Here, based upon the existing crystal structure, combined with high-throughput virtual screening, we obtained 8 candidate small molecule compounds. In vitro activity evaluation, we found that compound 3 has good anti-HCT15, HCT116 cell proliferation activity (HCT15, IC50, 7.69 ± 1.10 μmol‧L-1, HCT116, IC50, 13.53 ± 0.46 μmol‧L-1). Subsequently, molecular docking and molecular dynamics (MD) simulation analysis showed that, compound 3 could target and inhibit the activity of CPS1. In vitro studies showed that compound 3 could inhibit the migration of HCT15 cells, as well as induced cell cycle arrest and apoptosis. Taken together, this study found that compound 3 is a potential small molecule inhibitor that targets CPS1, which provides the experimental basis and theoretical basis for the development of targeted intervention small molecule therapeutic drugs. Based upon the chemical structure of compound 3, we will shed new light on further optimizing its activity and therapeutic potential, which may provide a therapeutic benefit to the patients with CPS1-related tumors.
One undescribed diterpenoid acid and six compounds were isolated from the 95% ethanol fraction of Pinus kesiya var. langbianensis (A.Chev.) Gaussen ex Bui resin by using various chromatographic methods, including MCI Gel, Sephadex LH-20, ODS, silica gel and semi-preparative HPLC. The planar structures were identified by spectroscopy methods (1D, 2D NMR, UV, IR, MS, etc.), and the absolute configuration of the new compound was determined by ECD calculation. Compound 1 is a new compound, and compounds 2, 5-7 were isolated from Pinus kesiya var. langbianensis (A.Chev.) Gaussen ex Bui for the first time.
Ten compounds were isolated from the 95% ethanol extract of the whole plant of Gerbera piloselloides by silica gel column chromatography, MCI column chromatography and semi-preparative HPLC methods. Their structures were identified on the basis of physicochemical properties, spectral data (UV, IR, MS and NMR), circular dichroism (CD) spectra and single crystal X-ray diffraction analysis as 3′R-gerpilosecoumarin A (1a), 3′S-gerpilosecoumarin A (1b), gymnastone (2), gerberinside (3), divaricataester C (4), luteolin (5), caffeic acid methyl ester (6), ethyl chlorogenate (7), 6-(β-D-glucopyranosyloxy)-7-methoxy-5-benzoranpropanoic acid methyl ester (8) and glucozaluzanin C (9). Among them, new compounds 1a and 1b were new compounds and optical enantiomers, which were obtained by chiral resolution, and their absolute configurations were determined by quantum chemical calculation ECD. Compounds 1 and 1a/1b significantly increased the survival of IEC-6 in rat small intestinal crypt epithelial cells after LPS injury.
A series of tacrine-phenol-bifendate hybrids (7a-7e, 8a-8e) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs) with low hepatotoxicity. All the compounds had potent ChEs inhibitory activity with half-inhibitory concentration (IC50) values at the nanomolar range. Compound 8d exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC50 value of 156.39 nmol·L-1 and compound 7b showed the most potent inhibition for butyrylcholinesterase with IC50 value of 16.33 nmol·L-1. Kinetic and molecular modeling studies showed that 8d targeted both the catalytic active site and the peripheral anionic site of AChE. In addition, these compounds showed low toxicity to hepatocytes, and compound 8d did not increase the level of reactive oxygen species in HepG2 cells.
Innate immune system, a non-specific defense system formed after birth, is body's first line of defense against pathogens. Innate immunity also plays a key role in the tumor immunosurveillance. With the clinical success of cancer immunotherapy, the regulatory mechanism of innate immune cells in antitumor response has begun to draw increasing attention. Recently, it has been recognized that metabolic regulation plays a vital role in innate immunity, in particular in the tumor microenvironment where the metabolic reprogramming in cancer increases the complexity of immunometabolism yet also provides therapeutic vulnerabilities. This review summarizes the recent progress in understanding the metabolic regulation of the innate immune response. We discuss how metabolites of glucose, amino acids, lipid and nucleotide metabolism regulate the function of innate immune cells. We pay the special attention to the metabolic crosstalk between immune cells or tumor-immune cells in the tumor microenvironment. With the review, we hope to get a better understanding of metabolic regulation of antitumor immunity and provide basis for metabolism-targeted immunotherapy.
Ultra-high performance liquid chromatography coupled with quadrupole/time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS/MS) has been used to detect the metabolites of schaftoside in plasma, bile, urine and feces of mice after oral administration. The study was approved by the Experimental Animal Ethics Committee from Xuzhou Medical University (No. XZMULL201612024). Compounds were identified by analyzing their high-resolution mass spectrometry data, mass spectra, and comparison with reference substances and the literatures. The parent compound and 29 metabolites were detected in the plasma, bile, urine and feces samples of mice. The main metabolic pathways of schaftoside in mice include deglycosylation/glycosylation, hydroxylation/dehydroxylation, hydrogenation, methylation, acetylation, sulfation, and glucuronidation. This study provides references for the material basis of schaftoside in vivo.
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