ABSTRACT
BACKGROUND: Gastric cancer (GC) is one of the top 10 malignant tumors worldwide and poses a great threat to human life and health, the prevention and treatment of which has become the focus and difficulty of medical research. With its unique advantages, traditional Chinese medicine (TCM) is widely used in the prevention and treatment of postoperative recurrence and metastasis of GC as well as the improvement of patients' quality of life. The aim of this study is to elucidate the curative effect and the underlying mechanism of Yiqi Huayu Jiedu (YQHYJD) decoction. METHODS/DESIGN: This is a prospective, multicenter, randomized controlled trial continuing 3 years. Two hundred ninety-eight eligible patients will be randomly divided into 2 groups, the chemotherapy combined with placebo and the chemotherapy combined with YQHYJD group at a ratio of 1:1. All patients will receive the treatment for 6 months and follow up for 3 years. The primary outcomes are disease-free survival, and 1-year, 2-year, 3-year progression-free survival rate, while the secondary outcomes are tumor makers, TCM syndrome score, quality of life score, overall chemotherapy completion rate, intestinal flora diversity test, immune function (T, B lymphocyte subsets and NK cells) test. The Security index includes blood, urine and stool routine, electrocardiogram, liver function (ALT), and renal function (BUN, Scr). All of these outcomes will be analyzed at the end of the trial. DISCUSSION: This research will provide the valuable evidence for the efficacy and safety of Yiqi Huayu Jiedu decoction in postoperative GC. Furthermore, it will be helpful to form a higher level of evidence-based medical basis for TCM in the treatment of GC recurrence and metastasis. TRIAL REGISTRATION: ChiCTR2000039038.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Stomach Neoplasms/drug therapy , Biomarkers, Tumor/analysis , Chemotherapy, Adjuvant , Disease-Free Survival , Gastrointestinal Microbiome , Humans , Multicenter Studies as Topic , Neoplasm Metastasis/prevention & control , Neoplasm Recurrence, Local/prevention & control , Progression-Free Survival , Quality of Life , Randomized Controlled Trials as Topic , Stomach Neoplasms/surgeryABSTRACT
Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
Subject(s)
Apoptosis/drug effects , Autophagic Cell Death/drug effects , Benzylisoquinolines/pharmacology , Calcium/metabolism , Neoplasms/pathology , Ryanodine Receptor Calcium Release Channel/metabolism , Cell Line, Tumor , Drugs, Chinese Herbal , Humans , Neoplasms/metabolismABSTRACT
The rhizome of Anemarrhena asphodeloides Bge. is commonly used as an herbal medicine in China. In this study, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) was used, in both negative and positive ion modes, to comprehensively analyze the chemical constituents of A. asphodeloides. From the intact precursor ions, MS/MS fragmentation information, and previous reports, we identified 89 compounds. These compounds included 8 cyclic peptides, 11 flavones (9 xanthones), 45 steroidal saponins, 15 fatty acids, 3 lignans, and 7 other compounds. Dimer xanthones and cyclic peptides are reported for the first time in A. asphodeloides. The analytical method we have developed is simple, reliable, and effective. The results provide comprehensive information on the metabolite profile of A. asphodeloides, which may benefit the quality control and further utilization of A. asphodeloides.
Subject(s)
Anemarrhena/chemistry , Chromatography, High Pressure Liquid/methods , Plant Extracts/analysis , Plant Extracts/chemistry , Rhizome/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Saponins/analysis , Xanthones/analysisABSTRACT
Two new alkaloids, named stenine A (1) and stenine B (2), along with the known compounds neostenine (3), stenine (4) and neotuberostemonine (5), were isolated from the roots of Stemona sessilifolia. Their structures were elucidated by 1D- and 2D-NMR spectra and X-ray single-crystal diffraction experiment. Anti-acetylcholinesterase (AChE) activity of compounds 1-5 were also tested. Compounds 2 and 4 showed significant anti-acetylcholinesterase activities, with IC50 values of 2.1±0.2 µM and 19.8±2.5 µM, resp. The mode of AChE inhibition by Compound 2 (the most potential AChE inhibitor) was reversible and competitive. In addition, molecular modeling was performed to explore the binding mode of compound 2 with AChE.
Subject(s)
Acetylcholinesterase/metabolism , Alkaloids/pharmacology , Cholinesterase Inhibitors/pharmacology , Plant Extracts/pharmacology , Stemonaceae/chemistry , Alkaloids/chemistry , Alkaloids/isolation & purification , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/isolation & purification , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Plant Extracts/chemistry , Plant Roots/chemistryABSTRACT
AIMS: Inhibition of acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease (AD). Many plant derived alkaloids (such as huperzine A, galanthamine and rivastigmine) are known for their AChE inhibitory activity. The aim of the present work was to isolate and identify new AChE inhibitors from Holarrhen antidysenterica. MAIN METHODS: These compounds were tested for AChE inhibiting activity by the Ellman's method in 96-well microplates. In addition, molecular modeling was performed to explore the binding mode of inhibitors 1-5 at the active site of AChE, and the preliminary structure-activity relationships (SARs) were discussed. KEY FINDINGS: In the course of searching for AChE inhibitors from herb medicines, the total alkaloidal extract from the seeds of H. antidysenterica was found having potent AChE inhibitory activity with an IC(50) value of 6.1 µg/mL. Further bioactivity-guided chromatographic fractionation afforded five steroidal alkaloids, conessine 1, isoconessimine 2, conessimin 3, conarrhimin 4 and conimin 5. All the isolated compounds, except for 2, showed strong AChE inhibiting activity with IC(50) values ranging from 4 to 28 µM. The most active inhibitor is compound 3 with an IC(50) value of 4 µM. The mode of AChE inhibition by 3 was reversible and non-competitive. SIGNIFICANCE: The results suggest that these alkaloids could be potential candidates for further development of new drugs against AD.