Latest ArticlesThe size and surface morphology of carrier lactose had influence on the aerosolization performance of dry powder inhalers. In this article, chlorpheniramine maleate was blended with two types of commercial carrier lactose, which were Lactohale 100® and Respitose SV003® (SV003), as formulation model. In vitro experiments were conducted using fast screening impactor at 30 L·min-1 and 60 L·min-1 respectively. Meanwhile, computational fluid dynamics (CFD) coupling with discrete element modelling (DEM) was applied to discuss the movements of those two carrier particles in Handihaler® at the flow rate mentioned above. The dispersion characteristics of two formulations and the dispersion mechanism of Handihaler® were analyzed by establishing the relationship between in vitro experiments and numerical simulation. The results of in vitro experiments and CFD-DEM demonstrated that the aerosolization performance of formulation with SV003 was better. The linear correlation (R2=0.940 1) between fine particle dose and total energy loss by carrier collision within the wall of device was found by comparing the in vitro experimental results with CFD-DEM results. It revealed that particle-wall collision in Handihaler® had direct impact on the dispersion results of formulation.
Five components in the impurity profile of tinidazole glucose injection were detected and identified by UPLC-Q Exactive quadrupole-electrostatic field orbitrap high resolution mass spectrometry, in combination with retention time references, organic reaction mechanisms and UV spectral analysis. They are 2-methyl-5-nitroimidazole (impurity 1), 5-hydroxymethylfurfural (impurity 2), 1-(2-(ethylsulfonyl)ethyl)-2-methyl-4-nitro-1H-Imidazole (impurity 5), 1-(2-(ethylthio)ethyl)-2-methyl-5-nitro-1H-imidazole (impurity 6) and 1, 4-di-N-oxo-2-methyl-5-nitro-1H-imidazole (impurity 8) respectively, of which impurities 6 and 8 are identified for the first time. These results and detection methods are useful for monitoring the manufacturing process and quality control of tinidazole and glucose injection solution.
Tenofovir disoproxil fumarate (TDF) is a nucleoside analogue that has been widely used for clinical treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. The aim of this study was to investigate whether TDF has anti-Zika virus (ZIKV) activity in vitro. The inhibitory effect of TDF on ZIKV was detected by plaque reduction assay. Then, the anti-ZIKV activity of TDF at RNA level and protein level was verified by real time quantitative PCR and Western blot. Finally, MTT assay was used to determine the cytotoxicity of TDF. Our results showed that TDF not only reduced the formation of plaque after ZIKV infection, but also inhibited the replication of ZIKV RNA or expression of ZIKV NS2B protein. The 50% effective concentration (EC50) of TDF in inhibition of ZIKV replication were 14.96-27.47 μmol·L-1, while that of ribavirin was 56.01 ±12.16 μmol·L-1, which served as the positive control. The cytotoxicity of TDF and ribavirin in Vero cells were very low, with their 50% cytotoxic concentration (CC50) values being greater than 500 μmol·L-1. The therapeutic index of TDF calculated by CC50/EC50 was greater than 18.20, which was significantly higher than that of ribavirin. The results suggest that TDF has good anti-ZIKV activity in vitro and is expected to become a candidate drug for anti-ZIKV therapy.
Medicinal materials in China differ in quality by different ecological types. Our research group found that there were two ecotypes of domestic Panax quinquefolium L. according to the characteristics of ginsenosides, inside versus outside Shanhaiguan. The genetic and ecological mechanisms of quality variation of Panax quinquefolium L. is unknown. Based on the genetic-chemical-ecological strategy, transcriptome and HPLC technology were used for comprehensive correlation analyses of transcriptomic data, ginsenoside content and environmental climate ecological factors. The transcriptomic results showed that key genes of ginsenoside biosynthesis, such as HMGR, AS and FPS, were significantly down-regulated in the inside Shanhaiguan ecotype. HPLC results showed that the quality of outside Shanhaiguan ecotype Panax quinquefolium L. was higher than that of the inside ecotype, with the content of ginsenosides in outside Panax quinquefolium L. was higher than that of inside ecotype except Rb2. Correlation analyses revealed that content of Panax quinquefolium L. ginsenoside is positively related to the expression levels of ginsenoside biosynthesis key genes (MK, HMGS, HMGR, and AS), and negatively related to the expression of glycosyl transferase (GT). The content of ginsenosides is negative related with climate factors, such as temperature, sunshine, and is positively related with moisture in both ecological environments. This study has provided a new mechanistic insight into the quality variations of two ecotypes for Panax quinquefolium L. and established a scientific basis for studying the ecological factors for the quality of traditional Chinese medicine.
Deformation or failure of organs is the final stage involving fibrosis, caused by fibrous scars composed of excess extracellular matrix proteins. Cellular senescence means a stable stagnation state with no proliferation, during which the senescent cells maintain biochemical metabolism but promote excessive expression of extracellular matrix proteins due to secreting inflammatory factors, which contribute to the development of various organ fibrosis including myocardial fibrosis, and pulmonary fibrosis. It has been shown that both the incidence of organ fibrosis and the number of senescent cells increase with age. This review mainly summarizes mechanisms of cellular senescence and its contribution to the process of various organ fibrosis. Current anti-fibrotic drug therapy focused on cellular senescence is discussed. Cellular senescence has profound implications in the pathogenesis of fibrotic diseases and provides a new target for new effective treatments.
The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (< 32℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H & E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.
Mengla virus (MLAV), isolated from the bats in China, was identified as a new genus of filovirus in 2019, i.e. Dianlovirus genus of Filoviridae family. Among filoviruses, Ebola virus (EBOV) and Marburg virus (MARV) are the most contagious viruses with mortality rates of 24%-90%. Phylogenetic analysis showed that MLAV was closely related to MARV among the members of filovirus family. MLAV enters into host cells via viral glycoprotein (GP). The recombinant virus study indicated that MLAV has a potential for bat-to-human cross-species transmission. In this study, a GP-mediated MLAV entry evaluating model was established, and by using this model, we investigated the susceptibility of MLAV to the human cell lines sourced from different tissues and the African green monkey kidney cell lines. Four compounds, chloroquine, tetrandrine, clomiphene, and toremifene, which were known as EBOV and MARV entry blockers, were tested for HIV/MLAV-GP infection. It was found that chloroquine effectively blocked the entry of MLAV with the half maximal effective concentration (EC50) of 1.56 μmol·L-1, resembling its anti-EBOV and -MARV activities. To the best of our acknowledge, there is no anti-MLAV drug reported by far, and the identification of chloroquine as an MLAV entry inhibitor may provide an insight for developing anti-filovirus agents.
Transforming growth factor-β (TGF-β) belongs to a group of biologically active cytokines that bind to its receptors to activate Smad signaling and non-Smad signaling pathways. The biological functions of TGF-β include promoting cell epithelial-mesenchymal transition, tissue fibrosis, angiogenesis and tumor immune evasion, as well as dual effects of cancer suppression and cancer promotion. Given the fact that the ligand-and receptors-mediated abnormal activation of TGF-β signaling pathways play an important role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis, more than a dozen small-molecule inhibitors have been developed to block the TGF-β signaling pathways, providing a novel method for controlling the development of these diseases. At present, pirfenidone, an inhibitor for TGF-β production, has been approved for treatment of idiopathic pulmonary fibrosis, while the inhibitors of TGFβRI/ALK5 for therapeutics of tumors or myelodysplastic syndromes, including LY2157299, EW-7197 and LY3200882, are in the phase Ⅰ to Ⅲ clinical trials, with additional ones inhibiting TGFβRs such as SB-431542, LY2109761, TP-0427736, and IN-1130 being in the preclinical phase. This paper reviews recent advances in research of small-molecule inhibitors targeting TGF-β and its receptors.
This study aimed to investigate apoptosis induction of ginsenoside compound K (ginsenoside CK) in human liver cancer SMMC-7721 cells and the involvement of TGF-β1/Smads signaling pathway. MTT assay was used to detect cell viability following ginsenoside CK treatment in SMMC-7721 cells. Annexin V-FITC/PI assay was used to detect apoptosis. After ginsenoside CK, or TGF-β1/Smads pathway activator TGFβ1 and inhibitor LY2109761 treatment, the TGF-β1/Smads pathway proteins and apoptosis proteins were detected by Western blot. The results showed that ginsenoside CK inhibited the proliferation of SMMC-7721 cells in a dose-and time-dependent manner. Annexin V-FITC/PI showed that ginsenoside CK induced apoptosis in SMMC-7721 cells. Meanwhile, ginsenoside CK inhibited the expression of Smad2/3, p-Smad2/3, Smad4, but promoted Smad7 expression, cleavage of caspase-3 and down-regulated Bcl-2/Bax. Compared with TGFβ1 treatment alone, levels of Smad2/3, p-Smad2/3, Smad4 and the ratio of Bcl-2/Bax were down-regulated, whereas Smad7 or cleaved caspase-3 was up-regulated in the ginsenoside CK+TGF-β1 group. In addition, Smad2/3, p-Smad2/3 and Smad4 expression were decreased in LY2109761 group. Compared with LY2109761 group, cleaved caspase-3 expression and Bcl-2/Bax have no significant change in ginsenoside CK+LY2109761 group. Taken together, our results showed that ginsenoside CK induced apoptosis in SMMC-7721 cells, and such induction is related to inhibiting TGF-β1/Smads signaling pathway.
The long-term use of antibiotics in clinical practice leads to bacterial variation and resistance. In addition, the excessive or improper use of antibiotics in medical and agricultural fields increases the occurrence of bacterial resistance. In 2017, the World Health Organization has for the first time released a list of 12 bacteria or bacterial families that pose the greatest threat to human health and for which new antibiotics are desperately needed, and three quarters of them are Gram-negative bacteria. Gram-negative bacteria has multi-layered cell wall that prevents many antibiotics from accessing their targets. Therefore, it is very difficult to develop drugs against Gram-negative bacteria, no new class of antibiotic has been approved for Gram-negative pathogens in over fifty years. Here, we summarized recent advances in the study of new antibacterial agents with different mechanisms of action against Gram-negative pathogens.
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