Latest ArticlesWith the in-depth study of related substances and the development of consistency evaluation of generic drugs, relative correction factors are gaining increasing attention. By analyzing the domestic and foreign literature on correction factors in recent years, this paper describes the correction factor component, the current measurement method and its application. The rules and key points of use of an impurity correction factor and its determination and application are described, and some problems in its determination and application are discussed, providing a reference and basis for the standardization of research on impurity correction factors in the future.
3D printing technology has the advantages of accurate spatial distribution, accurate drug release and personalized drug dosage, which can make up for the shortcomings of traditional pharmaceutical technology. In recent years drop-on powder (DoP) 3D printing technology has been widely used in pharmaceutical preparation. Compared with other types of 3D printing technology, it is more simple, flexible and easy to operate. In 2015, Aprecia Pharmaceuticals announced that the US Food and Drug Administration (FDA) approves the launch of its first instant tablet Spritam® (levetiracetam) made with DoP 3D printing. After the first 3D printed medicine was launched, people also saw the unique advantages and broad prospects of DoP 3D printing technology platform in pharmaceutical preparation. This review focuses on the technical principles and key factors of DoP 3D printing, its application in the preparation field and its future development challenges.
In recent years, non-viral gene vectors have attracted great attention for efficient gene delivery due to the advantages, including low toxicity, low immunogenicity and simple preparation. Polyethylenimine (PEI) is one of the typical non-viral gene carriers that have been widely utilized for gene delivery owing to its superior capabilities in gene compression and buffering capacity. This article discusses the processes of gene delivery and the barriers of PEI-based carrier during the gene delivery, such as low biocompatibility, cytotoxicity, lack of specific targeting and insufficient gene release, etc. Therefore, we summarize the multiple approaches for the modifications of PEI in terms of improved biocompatibility, degradability, specific targeting and buffering capacity. Furthermore, we also review on the recent impressive progresses of smart stimuli-responsive PEI carriers, including endogenous stimuli (pH, reactive oxygen species, glutathione, biomolecular, etc), exogenous stimuli (light, temperature, magnetic field, etc) and dual-responsive strategies, which might provide guidance for the development of more efficient and safer non-viral gene vectors.
The solubility/dissolution, hygroscopicity and mechanical properties of drug candidates have a profound effect on oral bioavailability, processability and stability. The physicochemical properties of crystalline drug are closely related to inner crystal structure. Crystal engineering technologies, as strategies of altering the crystal structure and tailoring physicochemical properties at molecular level, possess the potential of enhancing the pharmaceutical performance of product. The current article reviewed the modification of drug solubility/dissolution, hygroscopicity and mechanical properties by crystal engineering technologies through polymorphic selection, amorphization/co-amorphization, as well as co-crystallization, which provided a reference for the applications of pharmaceutical crystallography in improving physicochemical properties and druggability.
Salvia miltiorrhiza Bge. is one of the most important traditional Chinese medicinal plants and is used for a variety of diseases and disorders, including cardiovascular diseases, hepatocirrhosis, chronic renal failure, Alzheimer's disease, angina pectoris, myocardial ischemia, liver diseases, and diabetic nephropathy. In recent years, with the shortage of uncultivated resources and uneven product quality of cultivated germplasm, the biosynthesis and regulation of its main active ingredient has become a topic of interest. The use of a multi-omics approach with Salvia miltiorrhiza may provide genetic information as well as insights into the synthesis and regulation of the active ingredient at the molecular level. The paper presented a systematic review of the genomics, transcriptomics, proteomics and metabolomics associated with Salvia miltiorrhiza, summarized the advances in biosynthesis, regulation and related functional genes, and also put forward some scientific problems of Salvia miltiorrhiza that need to be further studied in the future.
To study the anti-tumor activities and the related mechanisms of dicumarol, the CCK-8 method was used to identify anti-tumor activities of dicumarol. HepG2 cells were used to explore the anti-tumor mechanisms by measuring several physiological and biochemical indexes. The results show that dicumarol can significantly inhibit the growth of HepG2, Hccc-9810 and MDA-MB-231 cell lines in a dose-dependent and time-dependent manner, with HepG2 cells showing the greatest sensitivity to dicumarol (with an IC50 value of 3.19±0.68 µmol·L-1 at 48 h). Dicumarol arrested the cell cycle at S phase and down-regulated the expression of anti-apoptotic protein Bcl-2 while promoting the expression of the pro-apoptotic proteins Bax and cleaved caspase-9. Dicumarol significantly decreased the levels of glutathione (GSH) and superoxide dismutase (SOD) in HepG2 cells, and increased the levels of malonaldehyde (MDA) and reactive oxygen species (ROS). Dicumarol also down-regulated the protein levels of NAD(P)H quinone oxidoreductase 1, 3-phosphoinositide-dependent protein kinase 1, and hypoxia inducible factor-1α under hypoxic conditions. The above results show that dicumarol can inhibit the proliferation of HepG2 cells and induce cycle arrest and apoptosis. Dicumarol may down-regulate the expression of HIF-1α by inhibiting the activity of NQO1 and PDK1, which leads to the accumulation of ROS, thereby generating oxidative stress and inducing apoptosis in HepG2 cells.
Zika virus (ZIKV) is an emerging mosquito-borne virus that is associated with severe congenital brain malformations in the fetus and Guillain-Barré syndrome in adults. However, there are currently no drugs or preventive vaccines approved for ZIKV infection. Here, ciclesonide has been found significantly against ZIKV activity by plaque and cytotoxicity assays in vitro, and its 50% effective concentration (EC50) to ZIKV SZ01 and MR766 are (0.40±0.22) and (1.59±1.08) μmol·L-1, respectively. Its 50% cytotoxic concentration (CC50) to Vero cells are (64.70±7.33) μmol·L-1; Virus yield reduction and Western blot assays showed that ciclesonide can inhibit replication of ZIKV. In addition, ciclesonide can also inhibit the replication of ZIKV in A549 cells; the results of time of drug addition analysis indicated that ciclesonide mainly acts on the ZIKV RNA synthesis stage. Ciclesonide can also inhibit the internalization of ZIKV. These results indicated that ciclesonide is a potential drug against ZIKV.
High expression of Bcl-2 is associated with the development of pancreatic cancer, and downregulation of Bcl-2 is an effective approach for the treatment of pancreatic malignancy. In the present study exosomes were isolated from the cultured medium of human embryonic kidney cells (HEK293) by ultracentrifugation and exosome-coated Bcl-2 siRNA (exosiBcl-2) was synthesized using electroporation. The results showed that the particle size of exosiBcl-2 was 67.3±9.7 nm and the morphology of exosomes displayed a concave ring structure as determined by transmission electron microscopy (TEM). Western blot analysis indicated that exosomal proteins including CD9, CD81, CD63 and TSG101 were highly expressed. Confocal microscopy revealed that exosiBcl-2 was widely distributed in Miapaca-2 cells, and the transfection efficiency of exosiBcl-2 in Miapaca-2 was 77.2% as determined by flow cytometry. Treatment with exosiBcl-2 at a concentration of 100 nmol·L-1 resulted in an inhibitory effect on the growth of Miapaca-2 cells with an inhibition rate of 63%. ExosiBcl-2 treatment can downregulate Bcl-2 and upregulate Bax protein. This study provides evidence that exosiBcl-2 is able to inhibit the growth of pancreatic cancer cells and the nanoparticles have potential to be developed as a novel anticancer agent.
The goal of the present study was to determine the effectiveness and safety of hemoperfusion (HP) in beagle dogs with chronic kidney disease (CKD). The experimental protocol was approved by the Institutional Animal Care and Use Committee of Tianjin Institute of Pharmaceutical Research New Drug Evaluation Research (IACUC2019071501). Twelve CKD model beagles were randomly divided into two groups: a low-frequency treatment group (n=6) and a high-frequency treatment group (n=6). The dogs in the high- and low-frequency groups received HP treatment every 3 days and once per week, respectively, for two treatments, with each session lasting 2 h. The test results showed that high-frequency HP treatment significantly decreased the accumulation of toxins in the CKD beagles. Hematology, coagulation function, electrolytes and liver function indicated that the HP treatment was safe. The body index effects were consistent between the low- and high-frequency treatment groups. Therefore, HP treatment once every 3 days was safe at the animal level. Multiple HP treatments every 3 days were more conducive than weekly treatments to the removal of uremic toxins with better prognosis and had no associated safety hazards.
To identify the composition of iridoids from Hedyotis diffusa Willd and explore the mechanism on its anti-renal fibrosis effect based on network pharmacology, LC-Q/TOF-MS (liquid chromatograpy-quadrupole/time of flight mass spectrometry) was used to analyze the iridoid ingredients and the related targets of renal fibrosis were obtained by DisGeNET database and MalaCards database. The potential targets were screened by SYBYL-X7.3 software. We then imported the identified ingredients and potential target genes into Cytoscape3.7.1 to construct the compound-target network and the protein-protein interaction (PPI) network. Finally, the gene ontology (GO) functional enrichment analysis and KEGG pathway enrichment analysis of the selected core genes were made to explore the mechanism of iridoids against renal fibrosis. There were 10 active iridoid compounds and 111 corresponding targets including dimethylarginine dimethylaminohydrolase 1 (DDAH1), heparanase (HPSE), human kirsten rat sarcoma viral oncogene (KRAS), moesin (MSN), etc. in compound-target network. The GO functional enrichment analysis obtained 211 GO entries. Twenty related signal pathways including Toll-like receptor signaling pathway, transforming growth factor-beta (TGF-β) signaling pathway, renal cell carcinoma signaling pathway, and the Janus kinase/signal transducer and activator of tran-ions (Jak-STAT) signaling pathway were selected by KEGG enrichment analysis. We preliminarily investigated the mechanism of the iridoid compounds on renal fibrosis to provide guide information for the subsequent experimental research and clinical application.
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