Latest ArticlesEllagic acid is ubiquitous in plants and is considered as a potential candidate for antioxidant and antineoplastic drugs. However, ellagic acid has poor solubility and precipitates easily even after initial solubilization. Improvement of its bioavailability has been a concern of pharmaceutical industry. It was found that storage in Sanlejiang oral liquid at low temperature keeps its stability. Ellagic acid is anomalous in a way that is easily soluble at low temperatures but precipitates at high temperatures. In order to reveal the mechanism of this phenomenon and develop precipitation prevention and control strategies, ellagic acid in Sanlejiang oral liquid was stored at high, medium and low temperatures for three months. The changes of composition and phase state of the whole system during storage were systematically tracked and studied by means of precipitation amount or morphology, HPLC chemical profile of supernatant versus precipitates, and comprehensive characterization of physical phase state. The results show that the amount of precipitation at low temperature is only 1/3 of that at normal room temperature. As the temperature rises, the sedimentation increases sharply. HPLC analyses of supernatant versus precipitates revealed that ellagic acid precipitation originated from two ways:chemical degradation and physical deposition. The chemical sedimentation is related to the hydrolysis of tannins under acidic condition, forming chebulagic acid and corilagin. Physical sedimentation is related to the decrease of the association degree and viscosity of polyphenol colloids when temperature rises. This study elucidated the stability mechanism of ellagic acid in liquid preparations of TCM, and provided the mechanistic basis for efficient utilization and solution prepartion of ellagic acid.
The molecular identification of Ophiocordyceps sinensis and its adulterants was carried out by real-time fluorescent PCR with TaqMan probe. Genomic DNA was extracted from 100 samples of Ophiocordyceps sinensis and its adulterants. MEGA 7.0 software was used for comparative analysis to define the variable sites between Ophiocordyceps sinensis and its adulterants according to the internal transcribed spacer (ITS) region of ribosomal DNA (rDNA). A set of specific primers and TaqMan probe were designed using Primer Premier 6.0 software, and sensitivity and specificity studies were performed on two different real-time fluorescent PCR systems (Genesig q16 and Bio-Rad CFX96). The sensitivity study showed that the detectable DNA template concentration of Ophiocordyceps sinensis for the real-time fluorescent PCR was 0.016 ng·μL-1 in the Bio-Rad CFX96 system and 15.527 ng·μL-1 in the Genesig q16 system, respectively. Meanwhile, this method had good specificity for Ophiocordyceps sinensis on Genesig q16 and Bio-Rad CFX96 systems, so Ophiocordyceps sinensis could be clearly distinguished from Ophiocordyceps nutans, Cordyceps gunnii, Cordyceps militaris, Cordyceps cicadae, Cordyceps liangshanensis, Cordyceps gracilis. Our results indicate that real-time fluorescent PCR with TaqMan probe can be used to accurately identify Ophiocordyceps sinensis from its adulterants. This provides a technical method that has wide applications for market management and quality control of Chinese materia medica.
Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis and production of essential lipid-derived molecules. There is increasing evidence that hepatitis C virus (HCV) has co-evolved due to its lack of lipid biosynthetic pathways to utilize host lipid metabolic pathways to establish a suitable environment for virus proliferation and obtain the necessary components, eventually promote the assembly and transportation of virus. In this review, we outline the relationship between HCV life cycle and lipid droplet biosynthesis and metabolism, with the aim to discover potential antiviral targets for development of new therapeutic interventions.
Ferroptosis is a novel type of regulated cell death with morphology, biochemistry and mechanisms differing from traditional cell death types such as apoptosis, necrosis and pyroptosis. The regulatory mechanisms of ferroptosis mainly involve iron metabolism, amino acid metabolism and lipid metabolism. It has been found that ferroptosis plays a key role in the pathogenesis of diseases including neurodegenerative diseases, malignant tumors and ischemic reperfusion injury. Parkinson's disease (PD) is one of the most common neurodegenerative diseases and its etiology and pathogenesis remains unclear. Recent studies revealed that ferroptosis might be involved in the pathogenesis of PD, as evidenced by high iron content, depletion of reduced form of glutathione and elevated levels of lipid peroxides detectable in the midbrain of PD patients. Both in vitro and in vivo models of PD have shown that some ferroptosis inhibitors have the ability of attenuating the symptoms and one iron chelator is undergoing a clinic trial. We here summarize the mechanisms of ferroptosis and its association with PD, in an effort to suggest potential novel targets for therapies of PD.
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.
Pyrrolizidine alkaloids (PAs) are a class of hepatotoxic compounds that are largely found in plants. "Zicao" is one of the most commonly-used Chinese herbal medicines from multiple sources, owing to its anti-inflammatory and wound healing effects. However, many studies have shown that this herb and its relative species contain hepatotoxic PAs. These PAs may cause hepatic sinusoidal obstruction syndrome following metabolic activation, and are therefore considered as potential toxic substances. Even though the toxicity of "Zicao" in clinical use has not been reported, the existence of PAs will undoubtedly post a threat for its safety in long-term use. It has now become the focus of many researchers to disclose and prevent its potential risk of intoxication. This review summarizes recent progress and key scientific evidence found in the research of pyrrolizidine alkaloids from "Zicao" and its relative species, including their metabolic toxicity. We comment on the need of future studies, such as providing a reference or guidance for safety evaluation of this medicinal herb in clinical practice.
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.
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.
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.
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