As the common pathway of chronic renal diseases leading to end-stage renal failure, renal tubulointerstitial fibrosis is characterized by the deposition of extracellular matrix and scar hardening. Our study aimed to construct an in vitro cell culture platform to explore the impact of matrix stiffness on cell morphology and function of renal tubular epithelial cells. Photopolymerized polyacrylamide gels (PAA gel) with varying stiffnesses as model substrates was selected to simulate the matrix stiffness of normal and fibrotic renal tissues with elastic moduli ranging from 1 to 40 kPa. The human renal tubular epithelial cells (HK-2) were seeded on the surface of PAA gels. The impact of matrix stiffness on the morphology of HK-2 were investigated via immunofluorescence staining and confocal microscopy. The expression levels of glucose transporter 1 (GLUT1), glucose transporter 2 (GLUT2), glucose transporter 5 (GLUT5) were semi-quantitatively analyzed. With increasing matrix stiffness, both the levels of GLUT1 and GLUT5 in HK-2 cells were significantly decreased, whereas the expression level and the distribution pattern of GLUT2 in HK-2 remained unchanged with stiffness variation.

In this study, the change of intestinal microflora in rat fecal samples after amoxicillin administration was observed. In vitro incubation experiments combined with LC-MS/MS assay were used to test the role of intestinal flora in the metabolism of nifedipine. The effect of changes of intestinal flora was determined after amoxicillin administration on the metabolism of nifedipine. We found that the number and types of intestinal flora decreased after taking amoxicillin. After incubation for 12 h, the results showed that the remaining amounts of nifedipine in the N1 group (nifedipine) and N2 group (amoxicillin + nifedipine) were 0.057 6 and 0.064 8 μmol·L^-1, respectively, while the remaining amounts of nifedipine after 24 h of incubation were 0.039 6 and 0.050 4 μmol·L^-1, respectively. These results show that the intestinal flora is involved in the metabolism of nifedipine. After administration of amoxicillin, the metabolism of nifedipine was slowed down, the AUC_0-t was increased by 39.10%, t_max was advanced by 0.45 h, and the CL was reduced 34.71%. The data suggest that the combination may enhance the therapeutic effect of nifedipine. Therefore, drug-drug interactions mediated by gut microbiota cannot be ignored when combined with antibiotics and nifedipine, one of the important factors affecting drug efficacy.

Depression is currently the most popular disease in the world with a high suicide rate. Selective 5-HT reuptake inhibitors have been used as first-line drugs in clinics, but the therapeutic effect is greatly limited. The pathogenesis of depression is complicated, meanwhile the cholinergic hypothesis has received more and more attention. A large number of clinical and preclinical studies have shown that antagonists and partial agonists acting on nicotinic acetylcholine receptors have a significant effect on antidepressant therapy, which can improve the hippocampus recognizes, influence rewards and anxiety systems controlled by the ventral midbrain and ventral tegmental area, and regulate the amygdala pressure system, thereby improving mood and relieving depression. At present, the relationship between the cholinergic system and depression is still undergoing a lot of research. In this article, the relationship between α4β2 nicotinic acetylcholine receptor (nAChRs) and depression is reviewed to provide a reference for study of new anti-depression drugs.

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.

2, 3:7, 8-Bis(methylenedioxy)benzo[c]phenanthridine was synthesized in a strategy of converging synthesis with 6-bromo-2, 3-dihydroxybenzaldehyde, 5-nitronaphthalene-2, 3-diol, and dibromomethane, respectively, as starting materials. The reaction process included dioxy-de-dibromo nucleophilic substitution under alkaline condition, reduction reaction, Schiff base-forming reaction, and an arene radical cyclization step under the presence of Bu₃SnH and AIBN as radical initiator, among others. The 2, 3:7, 8-bis(methylenedioxy)benzo[c] phenanthridine as intermediate was reacted with NaBH₄ and different aliphatic acids as alkylation agent to afford 2, 3:7, 8-bis(methylenedioxy)-5, 6-dihydro-N⁵-alkylbenzo[c]phenanthridines. These dihydro-type products were aromatized using DDQ as oxidant under alkaline condition, and then, salinized using HCl as source of equilibrium anion to yield the series of target alkyl-de-sanguinarine-N⁵-methyl derivatives. All the synthesized alkyl-de-sanguinarine-N⁵-methyl derivatives exhibited significantly improved in vitro growth inhibitory activities against cancer cell lines as compared with sanguinarine and the positive control. In pharmacological experiments targeting five cancer cell lines, the target compounds showed activities five-fold active than that of sanguinarine. The findings of this study indicated that the structure modification strategy of substituting n-alkyls for the N⁵-methyl of natural sanguinarine can be used to improve the growth inhibitory activities against cancer cell lines through increasing liposolubility and steric hindrance to protect the active 5, 6-imine structure.

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.

Autoimmune 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.

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.