Latest ArticlesAutoimmune disease refers to a series of diseases caused by the body's immune response to autoantigens leading to autologous tissue damage. The examples include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and psoriasis, etc. Janus kinases (JAKs) are a class of non-receptor tyrosine kinases that are essential signaling mediators in the signal transduction and expression of the inflammatory cytokines, which are closely related to the occurrence and development of the autoimmune diseases. Studies have shown that the inhibitors targeting JAK can exert anti-inflammatory and immuno-modulatory pharmacological activities by modulation of the cell signaling pathways related to the inflammatory cytokines. In this paper, the literature about small-molecule drugs targeting JAK on autoimmune diseases in recent years are summarized to provide valuable information for the research and development of drugs.
Signal transducer and activator of transcription 3 (STAT3) is a kind of signal transduction protein involved in cell proliferation, differentiation, apoptosis and other important physiological processes in response to a large number of cytokines and growth factors in cells. It has been shown that constitutive activation of STAT3 is closely associated with oncogenesis and tumorigenesis. Inhibition of aberrant STAT3 signaling has been one of promising strategies for the development of anti-neoplastic therapeutics. The review summarizes the latest progress of STAT3 inhibitors in recent years from the perspective of targeting N-terminal domain, DNA binding domain, SH2 domain and C-terminal transactivation domain of STAT3.
Saponins are important components in traditional Chinese medicine (TCM) with significant biological activities, which could be divided into triterpenoid saponins and steroidal saponins according to structures of the aglycone skeletons. This article reviews the in vivo metabolic pathways of some typical natural saponins such as ginsenosides, licorice saponins, saikosaponins, timosaponins and diosgenin glycosides. Saponins often show poor absorbance after oral administration. The in vivo metabolism of saponins generally contain two steps. These compounds usually undergo hydrolysis in stomach and gut. Then they are absorbed into blood and metabolized in liver. The secondary glycosides and the aglycones produced in gastrointestinal tract often show higher bioavailability and better bioactivity, while downstream metabolites in liver are mainly produced by phase Ⅰ metabolism. Clarification of the in vivo metabolism of bioactive saponins is helpful for the understanding of the effective ingredients in TCM, as well as the discovery of new drugs from natural products.
Nano-drug delivery systems (nano-DDS) are the hotspots of new drug delivery systems, which have many advantages, such as sustained and controlled release, targeting delivery. Traditional pharmacokinetics are difficult to predict the efficacy of drugs in vivo sometimes. It is urgently needed to extend the traditional pharmacokinetics studies to the cell/subcellular level and perform cell pharmacokinetic studies. The study on the pharmacokinetics of nano-DDS helps us to elucidate the mechanism of the actions of them in cells and guides us to design and develop nano-DDS more reasonably. This article summarizes the research content and methods on the cellular pharmacokinetics of nano-DDS, in order to provide an important reference for the early stage design of nano-DDS.
Chemotherapeutic agents along with other treatments, such as chemotherapy and radiotherapy, have made significant contributions to cancer therapy, however multidrug resistance (MDR) in tumor remains an important developmental barrier to efficient chemotherapy. In recent research, there is increasing evidence that nitric oxide (NO) has the potential to overcome MDR. Unlike other chemosensitizers that ameliorate MDR but are potentially toxic, NO is endogenous and biocompatible molecule, which makes it even more promising as a cancer therapeutic. Nanoparticle-based drug delivery systems not only facilitate the delivery of multiple therapeutic agents, but also promote the avoidance of MDR, which are promising to both efficient delivery of NO and anti-cancer drugs in combination. Therefore, this review will discuss the mechanisms how NO reverse MDR and the recent advances in the application of NO functionalized nanoparticles for anticancer drug delivery.
As a living cell product, chimeric antigen receptor (CAR)-T cell therapy displays multiple characteristics including the diversity of raw materials, the complexity of manufacturing process and the complementarity of quality control set. Pharmaceutical research and evaluation of CAR-T cell therapy are fundamentally different from small molecule and macromolecular recombinant proteins. Chemistry manufacturing and controls (CMC) review of investigational new drug (IND) submission for CAR-T therapy should especially pay attention to above unique characteristics and focus on potential risks to ensure clinical safety. Based on questions and concerns from recent CMC review practice and workshop on CAR-T cell therapy IND application, the critical points to consider for CMC study is proposed, and questions related to supplementation are also discussed in this review to accelerate the clinic translation of CAR-T therapy.
In this article, we exogenously administered glucocorticoids to rats, observed changes in the structure and function of gap junctions in the prefrontal cortex (PFC) and studied the effects of glucocorticoid receptor (GR) inhibitor mifepristone on these changes. Subcutaneous injection of corticosterone (CORT) was used to increase glucocorticoid levels in rats, intragastric administration of mifepristone antagonist GR. Sucrose preference test was conducted to evaluate anhedonia. Dye transfer assay and electron microscopy were used to analyze the function and ultrastructural changes of gap junctions in astrocytes of PFC. Immunofluorescence was used to detect the expression of connexin 43 (Cx43). Animals exposed to CORT showed behavioral deficits in sucrose preference test, exhibited significant decreases in diffusion of gap junction channel-permeable dye and abnormal gap junctional ultrastructure, as well as reductions in Cx43 puncta density in the PFC. The behavioral and cellular alterations induced by CORT were reversed or blocked by treatment with the GR antagonist mifepristone. The results suggest that mifepristone can improve the gap junction function and structural damage of astrocytes in the PFC of depressive rats induced by CORT. In conclusion, the activation of the GR receptor may contribute to gap junction dysfunction in the PFC.
The study aims to explore the effects of N-p--chlorobenzenesulfonyl-4-amino salicylic acid on the dextran sodium sulfate (DSS)-induced ulcerative colitis in mouse. A total of 60 BALB/c mice were randomly divided into 6 groups (n=10):control group, DSS model group, 5-amino salicylic acid (5-ASA) group, and administration groups (N-p--chlorobenzenesulfonyl-4-aminosalicylic acid) 10, 20, 40 mg·kg-1. Model group were induced by drinking 4% (w/v) DSS solution for 7 days and normal water for the next 3 days. The positive group and drug group mouse were given 5-ASA (40 mg·kg-1) and N-p--chlorobenzene sulfonyl-4-amino salicylic acid (10, 20, 40 mg·kg-1) by gavage respectively. During the experiment, changes in body weight, bloody stool, fecal character and mental status were observed daily. Damage and repair of the colon mucosa and the pathological changes of important organs were observed by hematoxylin and eosin (HE) staining. Expression of inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), macrophage inflammatory protein 2 (MIP-2), myeloperoxidase (MPO) in serum were detected by ELISA. The results showed that bloody stools and diarrhea emerged on the 4th day after model establishment in model mice. The number of bloody mice rose to ten, and blood and diarrhea began to appear in the administration group on the 7th day. Mental status was poor and body weight decreased significantly in model group since the 4th day, and the situation was improved in the administration group and 5-ASA group. Colons in the administration groups (10, 20, 40 mg·kg-1) were longer than those in the DSS model group. In the DSS model group, the colonic mucosa and submucosa of mice exhibited severe inflammatory cell infiltration, various degrees of necrosis, proliferation. In the middle dose group (20 mg·kg-1), the situation has improved slightly and the colonic mucosa showed mildly chronic inflammation and a small amount of inflammatory cells infiltration. The high dose group (40 mg·kg-1) showed normal colon mucosal, relatively complete epithelial structure and few inflammatory cell infiltration. The levels of IL-1β, IL-6, TNF-α, MIP-2 and MPO in the serum of mice were lower in the administration group (40 mg·kg-1) than in model group. Therefore, N-p--chlorobenzenesulfonyl-4-amino salicylic acid might be a feasible treatment for DSS-induced UC.
The mechanism of leukocyte elevation activity of Lvjiao Buxue granules was studied by establishing the active components-targets network and protein interactions network and analyzing the functions and pathways of targets. The main active ingredients of Lvjiao Buxue granules were obtained by TCMSP and literature excavation. Based on the DRAR-CPI, GeneCards and CoolGeN, the active components of Lvjiao Buxue granules were predicted and screened. Cytoscape software was used to construct the drug-active components-target network, and a protein database was constructed by using String database and Cytoscape software. The relation of the main active ingredients and targets were validated by Systems Dock Web Site. The GO and KEGG pathways involved in the targets were analyzed by DAVID databases. Using DisGeNET database to attribute the type of targets. The results showed that 49 active components and 89 targets of Lvjiao Buxue granules were involved. The network results showed that the composition of purine ribonucleosides, the regulation of cell death, especially the biological processes such as neutrophil and oxidative stress were mainly involved in the regulation of metabolic, cancer, tuberculosis, PI3K-Akt signaling and many other pathways to play its elevating leukocytes effect. This study reflects the characteristics of multi-components-multi-targets and multi-pathways of Lvjiao Buxue granules, which laid the foundation for further research into the mechanism of leukocyte elevation activity of Lvjiao Buxue granules.
The mechanism of detoxification of Chebulae Fructus against Aconiti kusnezoffii radix toxicity, which was known as Mongolian medical theory, was studied by establishing network of active components-targets-pathways of detoxification and enrichment analysis of targets and pathways based on network pharmacology. Firstly, the targets of active components collected from TCMSP and TCM Database@Taiwan were obtained through SwissTargetPrediction compared with disease targets from OMIM, TTD, DiGSeE. Then, the target enrichment analysis of GO functional annotations and KEGG pathways and protein function were analyzed by Metascape, furthermore, the action between main active ingredients and targets was assessed by SystemsDock Web Site. At last, the Cytoscape was used to construct the network of active components-targets-pathways. In conclusion, there were 15 components and 40 targets related to the cardiotoxicity caused by Aconiti kusnezoffii radix. Furthermore, Chebulae Fructus could regulate cardiac function to detoxify the toxicity by Aconiti kusnezoffii radix through the biological process of negative regulation of blood vessel diameter, regulation of ion transport circulatory system process, muscle contraction inorganic ion homeostasis and the pathways of neuroactive ligand-receptor interaction, calcium signaling pathway, adrenergic signaling in cardiomyocytes, etc.
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