Latest ArticlesThe adenosine triphosphate (ATP) liposome, prepared with the methods of film dispersion and ion-pairing was evaluated for its therapeutic effect on hypoxic brain damage. The appropriate formulation is adenosine disodium triphosphate, hexadecyl trimethyl ammonium bromide, soybean phospholipid, cholesterol with mass ratio of 1:1.98:8:3. The encapsulation efficiency of ATP liposome was (81.50 ±0.82) % and the loading efficiency was (6.79 ±0.07) %. In vitro release test and rheology test were conducted to investigate the physicochemical properties of ATP liposomes and empty gels respectively. The blank methylcellulose gel, followed with ATP liposome and ATP aqueous solution added to the methycellulose gel, were used for nasal administration in mice respectively. All experiments were approved by the Ethics Committee for Experimental Research in Academy of Military Medical Sciences. After 9 days of continuous administration, ATP liposome hydrogel increased the values of red blood cells and hemoglobin (P < 0.01) compared to ATP hydrogel and blank gel. And the ATP liposome hydrogel significantly increased the standard hypoxia tolerance time in mice compared to ATP hydrogel and blank gel after 13 days of nasal administration (P < 0.05). The immunohistochemical staining of mice hippocampus for the proapoptotic gene p53 showed that ATP liposome hydrogel was capable of protecting brain tissue in hypoxia. It is indicated that the prophylactic administration of ATP liposome nasal gel can significantly improve the hypoxia tolerance of mice, and the ATP liposome nasal gel was proved to be a promising anti-hypoxia preparation.
Although noninvasive trachea cannula is a common technique in clinic, this technique is hard to be applied in mice. It is even more difficult to perform the repeated noninvasive trachea cannula on the same mouse due to the throat injury. Here we report an effective, rapid and easy method to perform the noninvasive intubation on mice. This method can effectively be applied to many pharmacological and other related studies. In addition, this strategy can protect the mouse from physical injury caused by operative procedure. All procedures involving animal treatment were approved according to the Committee on the Ethics of Animal Experiments of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In alliance with lung function measurement system, we detected the normal lung function values and presented the lung function development curves of mice of different age. We found that the lung function of mice was matured at 8 weeks old or at the body weight of 18-20 g. In addition, we constructed the mouse model of multiple bleomycin induced pulmonary fibrosis by using this method and illustrated that the trachea cannula is more efficiency than nasal inhalation. Using this method, we have confirmed that the immune microenvironment in lung tissue of multiple bleomycin model is distinct from that of single bleomycin induced pulmonary fibrosis model. Thus, this method is a reliable and safe strategy for the pharmacology study.
Our previous report demonstrated puerarin protected β cells by up-regulating the expression of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R). However, whether the anti-diabetic effects of puerarin in vivo depend on GLP-1R activation has not been clarified. In this study, the GLP-1R agonist exendin-4 (Ex4) and the GLP-1R antagonist exendin 9-39 (Ex9-30) were used. Type 2 diabetes was induced in C57BL/6J mice by a high fat diet (HFD) and divided into the following groups: control, HFD, HFD/puerarin (300 mg·kg-1·d-1), HFD/puerarin/exendin 9-39 (Ex9-39: 10 nmol·kg-1·d-1), and HFD/puerarin/exendin-4 group (Ex4: 10 nmol·kg-1·d-1). Animal experiments were approved by the Research Animal Care Committee of Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine (AEWC-025). Puerarin was administered orally, Ex9-39 and Ex4 were administered by intraperitoneal injection for 10 days. Compared with HFD group, after 10-day treatment, the fasting blood glucose and oral glucose tolerance test (OGTT) of diabetic mice were effectively improved by puerarin (P < 0.05). Meanwhile, serum insulin levels were increased by puerarin, and levels of glucagon, triglycerides, and total cholesterol were significantly reduced (P < 0.05). Importantly, Ex4 significantly enhanced the anti-diabetic effects of puerarin in HFD mice, while Ex9-39 markedly inhibited the effects of puerarin (P < 0.05), which indicates that the effects of puerarin depend on GLP-1R activation. Furthermore, results of Western blotting of liver tissue showed puerarin effectively activated AKT and inhibited FOXO1, which relied on GLP-1R activation as well. Taken together, our findings demonstrate that puerarin ameliorates glucose homeostasis in HFD mice and is dependent on GLP-1R activation. This study provides experimental support for the potential application of puerarin.
The aim of this study was to identify the anti-inflammatory markers of Zhachong shisanwei pills (ZC-13) and characterize their mechanisms. UPLC/Q-TOF-MS combined with an NF-κB dual fluorescence reporter gene system and NO content detection were utilized to identify the anti-inflammatory bioactive substances in ZC-13. Network pharmacology and bioinformatics methods were used to predict the main targets and pathways of these anti-inflammatory markers, and to verify the main anti-inflammatory pathways of costunolide. Results showed that in ZC-13, four kinds of markers related to NF-κB inhibition were identified: gallic acid, ellagic acid, liquiritin apioside, glycyrrhizic acid, and four kinds of markers related to NO release inhibition were found: gallic acid, liquiritigenin, costunolide, and dehydrocostus lactone. The above components exert anti-inflammatory activities mainly through the regulation of PDK1 (3-phosphoinositide-dependent protein kinase 1), MAPK14 (mitogen-activated protein kinase), GSK3β (glycogen synthase kinase-3β) and other anti-inflammatory-related targets, and further adjust the PI3K-AKT (phosphoinositide 3-kinase- protein kinase B), MAPK, mTOR (mammalian target of rapamycin) pathways. Among them, costunolide can inhibit AKT phosphorylation and NF-κB nuclear transfer. The above results identified the anti-inflammatory markers and possible mechanisms of ZC-13, and provide a theoretical basis for standardizing the clinical application and quality of ZC-13.
More and more clinical evidence shows that patients with Coronavirus Disease 2019 (COVID-19) died due to severe complications such as acute respiratory distress syndrome and multiple organ failure due to the aggravation of the disease in the later period, and the main cause of the aggravation is "cytokine storm". There is no specific drug for the treatment of severe COVID-19 patients. Although western medicine can improve some symptoms, it leaves a large sequela, while traditional Chinese medicine plays an important role in this outbreak. In this paper, based on the clinical reported cytokines storm-related indicators, the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was used to mine and screen the traditional Chinese medicines acting on these cytokines based on the theory of "damp toxin invading the lung". It was found that 19 cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), granulocyte-macrophage colony stimulating factor (GM-CSF) and so on, were closely related to COVID-19, and 22 traditional Chinese medicines such as Ephedrae Herba, Glycyrrhizae Radix Et Rhizoma and Lonicerae Japonicae Flos acted on these cytokines, so as to provide certain reference for the reasonable choice of prescription and addition or modification of drugs for COVID-19 patients in the middle and late stage of Chinese medicine clinical treatment.
Acid-sensing ion channel 1a (ASIC1a) is an ammonia-chlorine-sensitive ligand-gated ion channel, and is widely distributed and expressed in the central and peripheral nervous systems. In a physiological environment, cells maintain a stable pH value around 7.0-7.5 through various transport modes of H+. During the occurrence of some pathological conditions such as allergic asthma, nephritis, arthritis, enteritis, acute lung injury, and other inflammatory diseases, the anaerobic glycolysis of tissue produces H+ accumulation of lactic acid and ATP hydrolysis, resulting in tissue acidification and body fluids. The pH value drops sharply to around 4.0-6.0, which further activates ASIC1a, causing a sharp deterioration of the inflammatory disease. In recent years, targeting ASIC1a may be a potential treatment strategy. This review briefly summarizes the role of ASIC1a in inflammatory diseases and discusses the research progress of ASIC1a in inflammatory diseases.
This study was performed to determine the metabolic profile of a new illicit drug, PX-2, in human liver microsomes. Q Exactive™ HF Quadrupole-Orbitrap LC-MS (LC-QE-HF-Orbitrap-MS) was employed to determine the metabolic sites and pathways of phase Ⅰ and phase Ⅱ metabolism. PX-2 was added to a microsomal incubation model to simulate human hepatic metabolism. The results showed that a total of 18 phase Ⅰ metabolites and 3 glucuronidated phase Ⅱ metabolites were generated, with the main metabolic pathways of phase Ⅰ metabolism including amide hydrolysis, fluoropentyl oxidative defluorination, benzyl hydroxylation, and carbazole ring hydroxylation. Based on the type and sites of metabolism, phase Ⅰ metabolites M1.1 (amide hydrolysis), M4.1 (carbazole cyclic hydroxylation), and M3.1 (oxidative defluorinative hydroxylation) are proposed to be potential poisoning markers. The results of this study provide a basis for identification of related drugs and establishment of testing methods in biological samples.
Small molecular drugs with large ring structure have recently attracted the attention in medicinal chemistry, the reason is their advantages in improving pharmacological activity and selectivity, and in satisfying drug-like properties. The macrocyclic structure takes into account both the microscopic structure for binding to targets and the macroscopic properties required by the pharmacokinetics. Although macrocyclic drugs historically originated from natural products, in recent years, they have been successfully designed, expanded the chemical space of traditional small molecules, and, to some extent, broken through the well-known the Role of Five in drug innovation. In addition, macrocyclic molecules also pave the path for developing drugs for non-druggability targets and for interfering with protein-protein interaction. This article focuses on the molecular design of macrocyclic drugs with some successful examples, concisely discusses structural optimization of a few macrocyclic natural drugs, and briefly describes stapled peptides in medicinal chemistry.
In this study the blending process of Qingyan tablets was simplified and simulated, and near infrared spectroscopy was used to monitor the blending process of several raw materials in different particle size systems to explore the influence of particle size on the blending end-point. Five blended batches with different particle sizes were designed in this experiment and the near infrared spectra of the blended samples were collected. Partial least squares regression (PLSR) models of the contents of Platycodonis Radix, Fructus Chebulae, borax, Hanshuishi and microcrystalline cellulose were developed. A quantitative model was applied to determine the blending end-points of three separate batches of blends with different particle sizes. The moving block of standard deviation (MBSD) was used as a qualitative method for determination of the blending end-point. The results show that the smaller the particle size of the materials, the shorter the time to reach the blending end-points, and with more accurate model predictions. In addition, although the MBSD method is convenient and fast without modeling, the results of blending end-point determination were not as accurate as PLSR method. This approach allowed us to determine the blending end-point of Qingyan tablets.
MicroRNAs (miRNAs) are a class of non-coding single-stranded RNAs involved in the regulation of gene expression found in a wide variety of eukaryotic cells and viruses. Recent studies have shown that some plant-derived miRNAs, which can stably exist in blood, tissues, and organs of animals, play a role in regulating the expression of different target proteins. In this review, we intend to sort out the mechanism of plant miRNA regulation based on the current research, and discuss its application prospects in the mining of miRNA active components of traditional Chinese medicine, small nucleic acid drug development, and drug development using plants as carriers. This can be beneficial to deepen the understanding of plant miRNA regulation, as well as the pharmacological mechanism and biological function of medicinal plants, thus providing new ideas for the prevention or treatment therapies towards human diseases.
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