Latest ArticlesBreast cancer is the most common malignant tumor in women worldwide. In breast cancer tumor tissues, a variety of targets related to the occurrence and development of breast cancer have been observed, and many drugs have been used in clinical applications for these targets. However, most of these drugs are small molecule inhibitors. With the long-term use of these drugs, acquired drug resistance often occurs in breast cancer patients. To overcome the drug resistance, the development of more efficient drugs is highly desirable in the treatment of breast cancer. Proteolysis targeting chimera (PROTAC) technology is a new kind of targeted protein degradation technology, which has shown broad prospect of applications in the field of drug development. The use of PROTAC technology to target the degradation of relevant targets in breast cancer has become a feasible strategy for breast cancer treatment.
Ursodeoxycholic acid (UDCA) is an essential drug for the treatment of cholestatic liver diseases. As the most important representative of endogenous drugs, the metabolism and disposition of UDCA in human is characterized by both host-gut microbial co-metabolism and hepato-billilary-intestinal circulation. These distinct metabolic and pharmacokinetic features have brought great challenges into the bioequivalence (BE) evaluation of UDCA generic formulations. These challenges include not only biopharmaceutical problems derived from the unique physiochemical properties of amphiphilic molecules and the large single dose, but also the drug metabolism and pharmacokinetic problems associated with endogenous metabolism, long terminal half-life, high inter-and intra-individual variations, as well as accurate determination of UDCA and its metabolites. This review summarized academic and industrial literatures about the clinical pharmacokinetics and endogenous metabolism of UDCA. Current guidelines and technical challenges of UDCA BE studies were extensively discussed. Knowledge summarized in this review is expected to provide valuable reference for the development of UDCA generic formulations.
N-Acetylaspartate (NAA) is a highly abundant brain metabolite. Nowadays, as an important marker reflecting the function of nervous system, NAA is widely used in the results analysis of nuclear magnetic resonance spectroscopy (1H MRS). NAA is synthesized in mitochondria of neurons and metabolized in oligodendrocytes. Additionally, NAA may be converted to the dipeptide N-acetylaspartylglutamate (NAAG), and catabolized into NAA and glutamate in astrocytes. NAA is related to a variety of central nervous system diseases, including Canavan disease, multiple sclerosis, depression, schizophrenia and other mental diseases. Therefore, NAA may be a biomarker of these diseases, and its related enzymes may be used as therapeutic targets for drug screening. Here, we combined the current research on the molecular mechanisms of NAA to reveal the process of NAA generation, metabolism and transport in the brain, explain the possible physiological effects of NAA and discuss its relationship with central nervous system diseases, explore the prospect of NAA in disease prediction and diagnosis, as well as the targeted treatment that may become the breakthrough of refractory diseases.
In recent years, multi-modal combined anti-tumor has become an effective strategy for clinical tumor treatment. Photothermal therapy with its characteristics of minimally invasive, controllable, high efficiency, and strong specificity, can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment. The research shows that the combination of photothermal therapy and chemotherapy has better synergistic antitumor effect. However, chemotherapeutic drugs and photothermal agents may have different pharmacokinetic behaviors in vivo, so it is difficult to ensure their effective transmission in tumor site, and the free form is easy to be metabolized and degraded in vivo. How to deliver the two therapeutic modes of drugs/photothermal reagents to tumor tissues in a specific, efficient and synchronous manner to achieve the best combined antitumor effect is an important problem to be solved in the combined antitumor application. The development of nano-drug delivery technology provides a new idea for the application of tumor treatment. In this paper, combined with the latest research progress in this field, the anti-tumor mechanism of photothermal therapy combined with chemotherapy, the advantages of nano drug delivery, the types and characteristics of commonly used nano materials and the principle of drug delivery are reviewed in order to provide a reference for the further development of multi-mode combined treatment of tumor.
Animal derived traditional Chinese medicines (ATCMs) are an important part of traditional Chinese medicine (TCM). The lack of proper ideas and strategies made it not systematic and perfect enough on investigating bioactive components and quality evaluation of ATCMs, which restrict many aspects of ATCMs investigation including clinical applications, pharmaceutical technologies, and quality control. Therefore, based on our previous investigations of animal horn and animal derived gelatin TCMs, and the research progress at home and abroad, ideas and strategies for investigating the correlations between proteins/peptides and their bioactivities in animal horn and animal gelatin derived TCMs based on integrated "proteomics/peptidomics-modifications" methods was proposed. Firstly, proteomics and peptidomics analysis can be used to study proteins and peptides in ATCMs. Secondly, modification analysis can be used to reveal those chemical modifications on proteins and peptides of ATCMs. Thirdly, the correlations between components, modifications and traditional bioactivities can be systemic discussed. Based on the present study, hopefully, enough evidences and reference can be provided to resolve the issues in ATCMs investigations on modernization and bioactive material basis.
An ethanol extract of Chloranthus henryi (Chloranthaceae) was subjected to various chromatographic procedures including silica gel column chromatography, MCI column chromatography, Sephadex LH-20 column chromatography, and preparative HPLC. Five purified sesquiterpenes analyzed by spectroscopic analyses (MS, IR, NMR) and single crystal X-ray diffraction were elucidated as (1S, 6S, 8R)-8-ethoxychlomultin C (1a), (1R, 6R, 8S)-8-ethoxychlomultin C (1b), (+)-phaeocaulin D (2), atractylenolide Ⅰ (3), and 8-β-ethoxyasterolid (4). Compounds 1a and 1b were a new pair of sesquiterpene enantiomers and compounds 2-4 were isolated from this plant for the first time. Compounds 1a, 1b, 2 and 3 increased cell viability in H2O2-treated PC12 cells from (43.41±1.59)% to (61.71±7.56)%, (66.05±5.61)%, (74.34±3.32)% and (69.58±5.02)% at 10 μmol·L-1, respectively.
Drug transporters and metabolic enzymes are the key proteins in the disposition of drugs in the body. In recent years it has been found that there is a cooperative relationship between drug transporters and metabolizing enzymes. Functional changes in drug transporters or metabolizing enzyme can affect the ability to eliminate drugs. Therefore, it is important to clarify this cooperative relationship, which is directly related to the pharmacokinetics, pharmacodynamics and adverse effects of drugs. Intestine and liver are the main organs of drug metabolism. There are abundant drug transporters and metabolizing enzymes in the tissues. This paper reviews the influence of the cooperative relationship between drug transporters and metabolizing enzymes on drug disposition by intestine and liver.
This study was to determine the expression of the cell cycle inhibitor p21 in alveolar macrophages (AMs) and the role of p21 in activation of AMs in bleomycin (BLM) injury-induced lung fibrosis. The expression of CD206 in AMs was measured by immunofluorescence staining. Reverse transcription-polymerase chain reaction (RT-PCR) assay was used to detect the expression of macrophage activation markers. The coculture assay for macrophage and fibroblast was employed to explore the effect of macrophage on fibroblast activation. Immunofluorescence staining and western blotting assay were adopted to detect the expression of p21 in fibrotic tissues. AMs were treated with p21 knockdown or overexpression virus, RT-PCR and the co-culture system were used to explore the effect of p21 expression on macrophage activation. The Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College approved all of the protocols for this research. Our results showed that the expression of CD206 and macrophage activation markers was increased in AMs from fibrotic mice, indicating that AMs from fibrotic mice were associated with a profibrotic phenotype. Moreover, the expression of p21 was upregulated in AMs after BLM treatment. Depletion of p21 suppressed macrophage activation, while overexpression of p21 promoted the profibrotic phenotype of AMs from healthy mice. In summary, BLM injury causes the progressive accumulation of p21 in AMs, which induces the production of a number of profibrotic factors promoting the development of pulmonary fibrosis.
Recombinant adeno-associated virus (rAAV)-based vector has shown great promise for human gene therapy, due to its advantage in eliciting long-term transgene expression, absence of adverse effect, infection ability to both dividing and non-dividing cells, non-genomic integration, and low immunotoxity. To date, three AAV-based products have been authorized to enter European and American markets, and more than 200 rAAV-based candidates are in the process of clinic trails. Nevertheless, domestic industry is facing the challenge of manufacturing clinical grade rAAV vector, and regulatory agencies are lack of practical experience in assessing such products. Herein, this paper summarizes the latest research progress of rAAV-based gene therapy products, and discusses some quality assessment concerns in raw materials, manufacturing process and quality control, expecting to promote its clinical transformation and application.
In this study, physical fingerprint and multivariate statistical analysis was applied to characterize the quality consistency of different sources of carboxymethylcellulose sodium, and the visualization of R language was used to explore the intrinsic correlation on its performances, and we drew contour maps between independent variables and flowability of powder to find the design space. Through the physical fingerprint and multivariate statistical analysis, it was found that there were differences in the powder properties of carboxymethylcellulose sodium from different sources, and its moisture content, bulk density and tapped density have a great influence on the fluidity. The fillibility was positively correlated with flowability, both negatively correlated with compressibility by R intelligent visualization analysis, which was statistically significant (P < 0.01). When the angle of repose is 30°-40°, the appropriate design space was found as 5.092 2% < moisture content < 7.006 7%, 0.560 2 g·cm-3 < bulk density < 0.579 9 g·cm-3, and 0.646 3 g·cm-3 < tapped density < 0.816 5 g·cm-3. The results show that it is scientific and feasible to evaluate the quality consistency of pharmaceutical excipients by using the physical fingerprint, multivariate statistical analysis and visualization methods, which provides new ideas for the production and quality evaluation of excipients and the development of generic prescriptions.
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