Latest ArticlesCardiotoxicity is one of the main causes of failure in new drug development or drug withdrawal from the market. However, current methods for evaluation of drug cardiotoxicity suffer the shortcomings such as low clinical relevance, low reproducibility and lack of high throughput screening capacity. Therefore, there is an urgent need for establishing more accurate and reliable methods for cardiotoxicity evaluation of drugs. As a new generation of drug cardiotoxicity evaluation, cardiac organs in culture retain the biological characteristics and functions of heart cells in the body, and can realistically and accurately respond to the effects of drugs. This article reviews recent progress of in vitro culture of cardiac organs and 3D-cell models, with focuses on application and development potential of cardiac organs for evaluation of cardiotoxicity of traditional Chinese medicine. The advantage and future prospective of such cell- and organ-based models for unique challenges in evaluation of cardiotoxicity of traditional Chinese medicine have been discussed.
Drug-induced cardiotoxicity is a serious concern in recent years, and acquired long QT syndrome (LQTS) is an important manifestation of cardiotoxicity. hERG gene encodes the α subunit of the rapidly activated delayed rectifier potassium channel (Ikr), which plays an important role in action potential phase 3 repolarization. Drug inhibition of Ikr/hERG channel leads to prolonged QT interval, accompanied by Tdp malignant arrhythmia, which can cause sudden death. We studied the effect of berberines on the hERG K+ channels after combination with rosuvastatin and glibenclamide, and evaluated the cardiac safety of these drugs in combination. Whole cell patch clamp technique was used to detect the effect of the combinations of these drugs on hERG current on HEK293 cells stably expressing hERG gene. The results showed that the inhibitory effects of berberine or dihydroberberberine combined with rosuvastatin on hERG current were higher than single drug (P < 0.05), but the combination had no effect on the kinetics of hERG channel. Berberine or dihydroberberberine combined with glibenclamide had higher inhibitory effects on hERG current than the application of single drug (P < 0.05) while the time constant of hERG channel inactivation was shortened after the combination (P < 0.05). In addition, the combination of berberine and glibenclamide inhibited hERG channel activation (P < 0.05). In conclusion, our results demonstrated that the combination of berberine with rosuvastatin or glibenclamide significantly inhibited hERG current and the inhibition effects were higher than the application alone. Therefore, when the two drugs that have inhibitory effects on the hERG channel are combined, the risk of inducing prolonged QT interval is significantly increased, and therefore reducing cardiac safety.
The aim of the present study was to investigate the effect of Sophoral flavones on proliferation of cardiac fibroblasts (CFb) induced by high glucose and its underlying mechanism. Cardiac fibroblasts were exposed to different concentration of D-glucose (15, 25 and 35 mmol·L-1) at different time point (24, 48 and 72 h) in order to determine cell proliferation, and the model group was established by culturing CFb with 25 mmol·L-1 D-glucose for 48 h. Sophoral flavones (12.5, 25 and 50 mg·L-1) were employed for intervention. The cell viability was measured by MTT assay, and the levels of transforming growth factor-β1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), collagen Ⅰ and collagen Ⅲ were measured by ELISA. In addition, flow cytometry was employed to detect the cell cycle; while the protein expression of prohibitin (PHB) was observed via immunocytochemistry and Western blot. This animal experiment had been approved by Jilin Medical University Experiment Animal Ethics Review Committee. The results showed that 25 mmol·L-1 glucose could promote the proliferation of CFb; and the contents of TGF-β1, MMP-2, collagen Ⅰ and collagen Ⅲ in the model group were higher than that of control (P < 0.05). The number of cells in S and G2 phase increased under high glucose condition. In the model group, PHB translocation occurred at 6 h and protein expression decreased at 48 h (P < 0.01). Compared with the model group, 12.5-50 mg·L-1 Sophoral flavones reduced the contents of TGF-β1, MMP-2, collagen Ⅰ and collagen Ⅲ, increased the number of G1 phase cells, and increased the expression of PHB protein at 48 h (P < 0.05), with no effect on the nuclear translocation of PHB. These results indicated that Sophoral flavones could prevent the proliferation of CFb induced by high glucose, the mechanism of which may be related to increasing the expression of PHB protein.
We evaluated the effects of Danggui-Chuanxiong (GX) herb pair with different proportions (1:0, 3:2, 1:1, 2:3, 0:1) and preparation methods (water extract W, alcohol extract A, and water-alcohol extracts WA) on vasoactive substances and endothelial cell adhesion molecules in the serum of acute blood stasis in rats. An acute blood stasis model was co-replicated by ice water bath and subcutaneous injection of epinephrine hydrochloride in rats. The expressions of vasoactive substances (arachidonic acid metabolites, coagulation-fibrin system index) and adhesion molecules in the serum were detected by enzyme linked immunosorbent assay method; the Spearman method was used to analyze the correlation of those detection indicators; the partial least squares-discriminant analysis and multi-attribute comprehensive index method were used to comprehensively evaluate the total effect of GX herb pair samples with different proportions and preparation methods on vasoactive substances and adhesion molecules. The experimental scheme was approved by the Animal Experimental Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine. The results showed that GX 1:1_WA had the strongest effect on the improvement of vasoactive substances and adhesion molecules in the serum of acute blood stasis in rats (the total effect value was 6.96). When extraction method was same, the overall effect of GX 1:1 had better effect than that of other proportions; when the proportion of GX was same, the total effects of GX_WA and GX_A were better than GX_W. The combination of Danggui and Chuanxiong can significantly improve the expressions of vasoactive substances and adhesion molecules in the serum of blood stasis in rats. But the action strength of GX herb pairs was different when the proportions and preparations of GX herb pair were different. These findings provide a basis for clinical rational application of GX herb pair, and lay the foundation for in-depth research on GX herb pair for treatment of blood stasis related diseases.
Long non-coding RNAs (LncRNAs), defined as transcripts which are hundreds of nucleotides with little or non-protein coding potential. Recently, LncRNAs have caught much more attentions, instead of considering as noises of genome transcripts, and indeed they have been found to play important roles associated with some biological processes, such as tumorigenesis, immunology dysfunction, metabolism adjustment, and so on. The incidence of chronic kidney disease (CKD) in different regions of the world is about 10% to 15%, with high growth rate and high unawareness, including the diabetic nephropathy, membranous nephropathy, etc. Previous publications also suggest that LncRNAs have a close relationship with the kidneys, and it may become new therapeutic targets or new biomarkers to diagnose diseases. In this review, we will summarize LncRNAs' functions with chronic kidney diseases, and discuss the prospects of the clinical applications of LncRNAs in the treatment of CKD treatment.
Provirus Integration in Maloney murine leukemia virus (PIM) represents a novel class of unique Ser/Thr kinase, which has been identified to be over-expressed in multiple hematological malignancies and some solid tumors, and the expression quantity correlates with malignant grade and poor prognosis in patients with cancer. PIM kinase plays important roles in regulation of cell proliferation and differentiation through the phosphorylation of its protein substrates, and it has become the emerging target for cancer treatment. A large number of highly active PIM kinase inhibitors have been reported by domestic and foreign research institutions, and the research progress will be summarized according to affiliations in this review.
Benzoxaborole is a series of compounds with five member ring and boron atom. Since the approval of crisaborole and tavaborole by FDA, benzoxaborole gained lots of research interests and become widely used in current drug discovery. Specially, benzoxaborole derivatives were found to exhibit anti-bacterial, anti-fungal, anti-protozoal, anti-tumor and anti-inflammatory activities. Here, we will review the properties of benzoxaborole, structure activity relationships as well as the recent progress in the biological activity of benzoxaborole derivatives.
Tumor, especially malignant tumor has become one of the major diseases, a serious threat to the health of people around the world. Modern clinical practice shows that the natural active products extracted from traditional Chinese medicine, marine medicine and other natural drugs, such as terpenes, alkaloids, polysaccharides, volatile oils and peptides, can effectively inhibit the growth of tumor cells. In this paper, the active components of natural antitumor products in recent years were summarized and their related mechanism was elucidated, so as to provide theoretical basis for the further development of natural antitumor drugs.
Chiral amino acid analysis is a sensitive, efficient and economical method for controlling racemic peptide impurities, especially for synthetic polypeptide drugs with complex composition of amino acids. Unexpected amino acid enantiomers in racemic peptides can be measured by chiral amino acid analysis coupled with mass spectrometry. The position of amino acid isomerization in the peptide segment can be accurately mapped by mass spectrometry, which lays a solid foundation for screening of racemic peptide impurities and rapid identification or quantification of trace racemic peptide impurities. Combination of the two techniques is vital for quality control of the synthetic polypeptide drugs and for research of polypeptide drugs based on chemical synthesis. The strategies of peptide hydrolysis have been summarized in this review. The latest chiral amino acid analysis based on mass spectrometry is briefly reviewed. Based on our knowledge, we have pointed to the direction of research and control of racemic peptide impurities in synthetic polypeptide drugs.
The in vivo fate is a crucial factor that governs the successful translation of nanoformulations. However, one of the current biggest challenges is with the real-time monitoring of the body of the nanoparticles themselves. Conventional radioactive or fluorescent probes give signals even after they are disassociated from the particle matrix, generating interference to bioimaging and leading to misjudgment of results. Environment-responsive fluorescent dyes are regarded as promising tools due to signal switching in response to the changes in the environment. Currently, there are three categories of dyes in bioimaging of nanoparticles based on Förster resonance energy transfer (FRET), aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ). They have similar characteristics that strong fluorescence is emitted when they are embedded in the matrix of nanocarriers, whereas the fluorescence quenches upon release from the matrix due to dissociation of nanocarriers. The fluorescence switching reflects the existing status of the nanocarriers and therefore helps to interpret the in vivo behaviors. FRET and AIE probes have been widely used in elucidating the interactions between nanoparticles and cell models. However, they show intrinsic defects in studying in vivo fate of nanoparticles. ACQ-based dyes are sensitive to water, a universal factor in the biological environment. Therefore, with the help of bioimaging equipment, the in vivo trafficking process of nanoparticles can be unraveled. This review article tends to provide an overview on the rationale, pros and cons and applications of the three categories of environment-responsive fluorescent dyes in the investigation of the in vivo fate of nanocarriers.
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