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.

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.

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 4^th 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 7^th day. Mental status was poor and body weight decreased significantly in model group since the 4^th 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.

Atherosclerosis (AS) is a complex metabolic syndrome that seriously harms human health, and its occurrence and development are directly related to the metabolic disturbances of free fatty acids (FFA). In this study, macrophage-derived foam cells were established as the model of early AS. Therefore, the metabolic disturbances of FFA in ox-LDL induced foamy macrophages were analyzed using target metabolomics. Then the effect of hydroxysafflor yellow A (HSYA) on regulating FFA was also explored. The quantitative analysis of 27 fatty acids was obtained within 20 min based on dynamic MRM mode. Thirteen metabolic biomarkers of macrophage-derived foam cells were identified using multivariate statistical analysis. It was found that upregulation of total SFA and downregulation of C12:0, C14:0, C18:1, total MUFA were the typical metabolic features in macrophage-derived foam cells. Furthermore, HSYA displayed obvious repairing effect on C12:0, C14:0 and C18:1, which were involved in de novo fatty acid biosynthesis pathway. Oleoyl-(acyl-carrier-protein) hydrolase (OLAH), as the key enzyme in de novo fatty acid biosynthesis pathway, may be a drug target of HSYA.

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.

Taking cabozantinib as leading compound, 13 novel small molecular c-Met inhibitors were designed and synthesized based on the obtained structure-activity relationships (SARs) of c-Met inhibitors. The structures of compounds were confirmed by ¹H NMR, ¹³C NMR and HR-MS. In vitro anti-tumor activity was evaluated by MTT method, and the mechanism was preliminarily disclosed by real-time dynamic living cell imaging and flow cytometry analysis. The results indicated that most of compounds showed good inhibition activity against human non-small-cell carcinoma cell A549 and human colorectal cancer cell HT-29 which was superior to cabozantinb. Compounds showed excellent cytotoxity and anti-proliferative activity against HT-29, and promoted cell apoptosis.

A rapid identification of the constituents in Gualoupi injection was developed by HILIC/Orbitrap Fusion Lumos HRMS. ACQUITY XBridge Amide column was used to isolate the constituents with large polarity. ESI with positive ion mode was employed and "Top Speed" DDA was applied in the MS² scan. Compound identification was carried out by using Compound Discoverer software through comparing the precursor and product ions information with those in ChemSpider and mzCloud database. As a result, 48 compounds was identified, including alkaloids, amino acid, nucleosides, nucleobases, etc., among which 25 was unambiguously identified by comparing the retention time and mass spectra information with those of reference standards. In general, the main constituents from Gualoupi injection were explained in this study. Additionally, full-scan mass spectra of 21 batches of the injection were collected by the established method. Subsequently, principal component analysis (PCA) with the peak area as the observation ID was employed to analyze the discrimination of different bathes of samples. The results indicated that the batch-to-batch difference was generally from the crude drug, and the preparation process of this injection was relatively stable. In conclusion, a rapid and effective method for the identification of compounds in Gualoupi injection was established by using UHPLC-Orbitrap Fusion Lumos HRMS and the inter-bath stability was also investigated, which may make a great contribution to the study of the bioactive ingredients in Gualoupi injection and also provide vital evidence for the standard promotion.

On base of traditional physiological studies, building a comprehensive evaluation system for the efficacy of Liuwei Dihuang Wan (LW) for regulating the growth and development of rats by indicators that the overall metabolic profile and biomarkers of urinary metabonomics. Sixty-seven day-old Sprague-Dawley rats were randomly divided into four groups that are the control group and low-dose, medium-dose, and high-dose groups of LW. At the age of 28 days, different doses of LW extracts were continuously administered for 16 days. On the basis of behavior, body weight, organ index and femur length, a UPLC-HDMS technique was used to establish urine metabolomics method to characterize the profile of urine metabolism before and after intervention of LW, analysis and identificate related to drug effects of differential metabolism markers, and study the effect of LW on the growth and development of rats. LW could improve the overall behavioral ability of rats, promote weight gain and the growth of organs and bones, and 36 differential metabolites and 13 target metabolic pathways of urine under the intervention of LW were identified, and 8 metabolic markers were regarded as a key marker that LW effect the growth and development of rats. LW has a significant regulatory effect on the urine metabolic network during the growth and development of rats. This study interpreted the scientific implications of the effect of "Nourishing Kidney Yin" on the growth and development of rats.

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.

Oral formulations of nanoemulsions (NE) were systematically designed, and then their effects on oral absorption of raloxifene (RAL), including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient[P_(O/W)] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSⅡ based on the solubility and P_(O/W). The best formulation of RAL-NE was composed of linoleic acid (LOA):isopropyl palmitate (IPP):cremophor RH40 (RH40):alcohol as 1.67:3.33:3:2. Drug loading in pre-nanoemulsion was 15 mg·g^-1 andentrapment efficiency of RAL in NE was (79.4 ±0.4)%. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations (P < 0.05). This paper provides references for oral NE research and development.

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.

S-adenosylmethionine synthetase, a key enzyme in plant metabolism, plays an essential role in the plant defence system. In present study, a full length cDNA sequence of AsSAMS1 gene was cloned by RACE and reverse transcription PCR from Aquilaria sinensis calli. Meanwhile, the bioinformatics, prokaryotic expression, tissue-specific expression analysis, and expression analysis under different abiotic stresses and hormone treatments were performed. The open reading frame (ORF) of AsSAMS1 gene was 1 183 bp, encoding a protein of 393 amino acids with a calculated molecular mass (MW) of 43.13 kDa. Bioinformatic analysis indicated that AsSAMS1 contained 3 SAMS characteristic sequences. The phylogenetic analysis indicated that AsSAMS1 protein had the highest level of homology with SAMS protein from Glycine soja. The recombinant AsSAMS1 protein was successfully expressed in Escherichia coli BL21 (DE3) cells using the prokaryotic expression vector pET28a-AsSAMS1 and the recombinant AsSAMS1 was purified by Ni²⁺ affinity chromatography. Expression analysis results in different tissues indicated that AsSAMS1 was primarily observed in stems, and then stem tips and leaves, following by roots. The transcript level of AsSAMS1 and the content of S-adenosylmethionine (SAM) were induced by various abiotic stresses including salt, drought, cold, and heavy metal stress. Furthermore, AsSAMS1 expression level was enhanced upon methyl jasmonate (MeJA), salicylic acid (SA), gibberellin (GA3), and abscisic acid (ABA) treatment. These results provided valuable insights for further study on the role of SAMS in the mechanism of agarwood formation and plant resistance.