Latest ArticlesNobiletin is a kind of polymethoxyflavonoid with many pharmacological effects, such as antiinflammatory and antioxidation activities. This study was carried out to investigate the inhibitory effects of nobiletin on P-glycoprotein (P-gp) in vitro and in vivo. The molecular mechanism for structure-inhibition relationships of nobiletin with P-gp was investigated. Nobiletin exhibited significant inhibition (IC50=2.21 μmol·L-1) on P-gp in MDR1-MDCKⅡ cells. In the cell toxicity test, the paraquat-treated cell viability was decreased with nobiletin by inhibiting P-gp activity. In the rats PK study, the AUC0-t of digoxin was increased 2.02 folds while the Cmax of digoxin was increased 3.29 folds, when nobiletin was used in the pretreatment of SD rats. Molecular docking analysis elucidated that the formation of Pi-Pi bonds with Phe974 was the key factor for P-gp inhibition. The research findings provide important guideline for prediction of potential interaction between nobiletin and P-gp.
The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy (mycophenolic acid + tacrolimus + prednisone). The Agena MassARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid (MPA) and its main metabolite mycophenolic acid glucuronide (MPAG) was detected by high performance liquid chromatography (HPLC). The correlation between IMPDH1 gene polymorphism (rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation (P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation (P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.
Two novel Mannich base derivatives of silybin, SLB-DEA and DHSLB-PIP, were designed and synthesized. All the structures of new Mannich base derivatives of silybin were characterized by 1H NMR and HR-MS. Their protective action against CCl4-induced liver injury in mice were investigated. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) were determined and the histopathological changes in liver tissues were examined. Pretreatment with a higher dosage of DHSLB-PIP (40 mg·kg-1) prevented CCl4-induced liver injury as indicated by the reduced levels of ALT, AST, LDH and TG. Meanwhile, liver histopathological improvement was observed in the model groups. The pharmacokinetics study in rats showed that the relative bioavailability of SLB-DEA and DHSLB-PIP were 172.5% and 259.8% compared with silybin. All the results suggest that SLB-DEA and DHSLB-PIP may protect liver against injury by CCl4 and the relative bioavailability was significantly increased, which is worth of further investigation for their druggability.
This study was designed to explore the intervention of muscle fatigue in rats with Astragali Radix using 1H NMR metabolomics methods. The fatigue model was induced in rats by forced swimming plus food restriction, and the effects of Astragali Radix (3, 6 and 12 g·kg-1) were investigated using the exhaustive time of rat swimming. After 3 weeks, the gastrocnemius was collected for 1H NMR detection, and the anti-fatigue effects of Astragali Radix were explored using multivariate statistical analysis. Astragali Radix significantly improved the exhaustive swimming time of rats. Compared with control group, the levels of isoleucine, leucine, creatine, phosphatidylcholine, trimethylamine oxide, taurine, guanidinoacetate, AMP, inosine, histidine, hypoxanthine, anserine in rat gastrocnemius of model group were increased. While the levels of lactate, acetone, choline, glycerophosphocholine, glycine were decreased. These 6, 11, 5 potential biomarkers could be reversely regulated by treatment with Astragali Radix (high dose, middle dose, low dose), respectively. Metabolomics analysis revealed that Astragali Radix has a certain anti-fatigue effects and the mechanism may be related to regulation of amino metabolism.
The hepatotoxicity of gefitinib is an important factor limiting its clinical application. In order to control the toxicity, we conducted this study to find the gene variation that can explain and predict the occurrence and severity of hepatotoxicity of gefitinib. Ninety patients with non-small cell lung cancer were included in the retrospective clinical study. Detailed hepatotoxicity induced by gefitinib and epidemiological characteristics were recorded. Twenty-six candidate single-nucleotide polymorphisms of molecular targets, metabolic enzymes, transporters and chemokines were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform. Various confounding factors, such as age, gender and smoking status, were included in the follow-up analysis and variability in the extent of hepatotoxicity was best explained by a multivariate logistic regression model incorporating. The severity of hepatotoxicity was associated with mitogen-activated protein kinase 1 rs13515 (OR=9.467, P=0.074). The research about pharmacogenomic of gefitinib identified the determinants of the drug-induced liver injury. These findings provide a basis to design clinical trials targeting a particular toxicity of gefitinib or similarly targeted agents to benefit patients on long-term gefitinib treatment.
The chemical constituents of Sabia limoniacea var. ardisioides were investigated using chromatographic methods, such as silica gel, Sephadex LH-20 and preparative HPLC. Eight compounds were isolated and their structures were elucidated by spectral data and physicochemical properties, which were identified as 5-methoxy-1, 2-methylenedioxyl oxoaporphine (1), fuseine (2), N-p-feruloyltyramine (3), N-trans-coumaroyl tyramin (4), quercetin (5), rutin (6), mutabiloside (7), and protocatechuic acid (8). Among those, compound 1 is a new compound, compounds 2-8 were isolated from this plant for the first time.
Interleukin-6 (IL-6)/janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) is a pivotal signaling pathway in the regulation of cell proliferation, survival, differentiation and T cell activation. Aberration of this pathway is involved in multiple autoimmunity diseases and cancers, therefore the pathway is considered as a hot target for drug development. In our study, we validated a cell-based model of IL-6/JAK/STAT3 and used it in screening of its inhibitors. HEK-Blue IL-6 cells of Invivogen Inc. were used to stably express IL-6 receptor and STAT3-induced secreted embryonic alkaline phosphatase (SEAP) report gene. After stimulation by IL-6, SEAP was secreted from cells and reacted with QUANTI-Blue. The product can be detected at 655 nm. The inhibitory effect of compounds on STAT3 signaling showed as IC50 was calculated by OD value. The results shown that IL-6 specifically activated the cells, which could be applied to screen the inhibitors for IL-6/JAK/STAT3 signaling pathway. The optimized screening conditions were described as below:50 000 cells/well, 1 ng·mL-1 IL-6 incubation for 20 h and reaction with QUANTI-Blue for 1 h. Based on this condition, we screened 14 natural products based on this cell model and arctigenin, cryptotanshinone and curcumin showed potential inhibitory activities on STAT3 signaling pathway with IC50 of 1.28, 2.96 and 6.61 μmol·L-1. Our study suggests that HEK-Blue IL-6 cells were suitable for screening inhibitors for the IL-6/JAK/STAT3 signaling pathway.
Shengmaiyin is widely used in the treatment of arrhythmia and has achieved a good effect. Due to the complexity of traditional Chinese medical formula, the pharmacological mechanism of Shengmaiyin in the treatment of arrhythmia is unclear. In this study, we used the internet-based Computation Platform (www.tcmip.cn) to explore the molecular mechanism. Shengmaiyin was found to treat the arrhythmia by modulating the pathway related to energy metabolism such as carbon metabolism, purine metabolism, carbohydrate metabolism, or by regulating the level of ATP. In this study, we find that the main active drug component in Shengmaiyin may be ginseng.
Mesoporous silica nanoparticles (MSNs) have been widely used as drug carriers in the diagnosis and treatment of diseases due to their specific characteristics, which include a large surface area, ordered mesoporous structures, easy surface modification and feasible sustained release action for encapsulated drugs. With the research development of MSNs, the biodegradability and removability of mesoporous silica nanomaterials have attracted considerable attention in the clinical application of the MSNs-based formulations. This paper was prepared to emphasize the preparation approaches of biodegradable mesoporous silica nanoparticles through the metal oxide doping method and the organic compound doping method. We discussed the biodegradable mechanism and process of such nanoparticles, and finally, provided an insightful and helpful review of the prospective application of the biodegradable mesoporous silica nanoparticles in medical field.
Neural stem cell is a cell type with the ability of self-renewing and the potential to differentiate into neurons, astrocytes or oligodendrocytes. Neurogenesis is beneficial for the recovery of many neurological diseases, such as stroke, Alzheimer's disease and so on. Neurogenesis capacity can maintain through the whole life, which includes the proliferation, migration and differentiation of neural stem cell, as well as the incorporation into the neuronal network of newborn neurons. The self-renewal and differentiation activities of neural stem cell are regulated by the microenvironment, which is defined as neural stem cell niche. Components of neural stem cell niche include cell-cell interactions, cytokines, extracellular matrix and vascular niche. Illustration of neural stem cell niche impact is far more significant for the treatment of certain nervous system diseases. This review summarizes the current understanding of the relationship between neural stem cell niche and the fate of neural stem cell.
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