Latest ArticlesPeptides have been extensively used in the fields of gene/drug delivery and disease targeting therapy. However, natural peptides are sensitive to protease digestion with short circulatory half-lives in vivo. Many studies on structural modifications of peptides have been reported to improve the delivery or therapeutic effect. In this review we focus on the recent literature on peptide stability in accordance with different structural modifications and summarize the methods and influential factors that are involved in the improvement of stability and half-life in vivo. This review will provide the scientific basis and theoretical references for further investigations and applications in vivo.
A new carbazole alkaloid was isolated from the aqueous extract of the stems of Clausena lansium (Lour.) Skeels by various chromatographic methods, including HPD-100, PRP-512A, silica gel, and reverse phase C18. Its structure was determined by spectroscopic and chemical methods, including UV, IR, HR-ESI-MS, 1D/2DNMR and ECD. Compound 1, named as Claulamine F, showed no antimicrobial activity on Staphylococcus aureus, Escherichia coli or Pseudomonas aeruginosa. In addition, compound 1 exhibited no cytotoxicity on five kinds of cancer cells through MTT methods.
The p21-activated kinase 1 (PAK1) is a member of the P21-activated protein kinase family that plays an important role in the proliferation and on cogenesis of pancreatic cancer. PAK1 is an important target for the treatment of pancreatic cancer. At present, akinase inhibitor targeting PAK1 is still in the preclinical research stage. Therefore, screening for new PAK1 kinase inhibitors is of great significance. In this study the natural compound celastrol was found to have a significant inhibitory effect on PAK1, with an IC50 value of 3.614 μmol·L-1. Molecular docking results showed that celastrol had good binding to PAK1. An MTT assay indicated that celastrol inhibited the proliferation of pancreatic cancer cells BxPC-3 and PANC-1. Mechanistic studies revealed that the inhibition of pancreatic cancer cells by celastrol was reversed by PAK1 siRNA. Celastrol inhibited PAK1 and the subsequent activation of downstream signaling pathways, thereby activating apoptosis signaling pathways and triggering apoptosis in pancreatic cancer cells. These findings suggested that celastrol induced apoptosis in pancreatic cancer cells by suppressing the PAK1 kinase signaling pathway and has potential value for the treatment of pancreatic cancer.
Notoginseng (Sanqi), the root of Panax notoginseng (Burk.) F. H. Chen (Araliaceae), is one of the most valuable traditional Chinese medicines (TCM). It has been widely used in China with a long history for treatment of haemorrhage, edema, and cardiovascular disorders. Steamed P. notoginseng has been considered to have stronger therapeutic functions than raw P. notoginseng in the treatment of tumors, cardiovascular diseases, etc. Saponins are the principal chemical and pharmacological constituents in P. notoginseng. Thus, it is of great importance to determine the constituent saponins and determine any differences between fresh P. notoginseng and steamed P. notoginseng. We used a rapid and direct analytical method based on liquid extraction surface analysis combined with mass spectrometry (LESA-MS) to identify saponins in the xylem, phloem and cambium of fresh and steamed P. notoginseng root slices. The results revealed that ginsenosides Rg1, Rb1, Re, Rd, notoginsenoside R1 and their malonyl group versions were most abundant in fresh root slices, while in steamed slices ginsenosides Rg5, Rk1 and other minor polar components could be detected, and the relative content of large polar components was lower. The described method is fast, robust and sensitive and the process does not need traditional and cumbersome pretreatment such as crushing, extraction and separation. It is the first non-destructive study on the differences in saponins between fresh and steamed P. notoginseng root slices.
Cionbufagin has anti-inflammatory and analgesic effects. It is of great value in the treatment of bone cancer pain, but its mechanism is still unclear. To generate a bone metastasis model of breast cancer, 4×105 Walker-256 cells were inoculated into the left hind limb of SD rats. The experimental protocol was approved by the Medical Laboratory Animal Ethics Committee of Medical College of China Three Gorges University. Rats were randomly divided into sham, model, cionbufagin, morphine, saline, minocycline, microglia inhibitor (RS102895) and co-treatment with cionbufagin and minocycline group. The cionbufagin (5 mL·kg-1, i.p.), morphine (8 mg·kg-1, i.p.) and co-treatment groups (included cionbufagin 5 mL·kg-1, i.p.) received continuous administration from day 9 to day 21. The saline, minocycline (2.5 μg·μL-1, 20 μL), RS102895 (1.5 μg·μL-1, 20 μL) and co-treatment groups (included minocycline 2.5 μg·μL-1, 20 μL) received continuous administration by intrathecal cannulation from day 12 to day 21. Bone destruction of the left hind limb of rats was detected by hematoxylin-eosin staining (H&E). The pain threshold before treatment and at day 2, 5, 7, 9, 12, 14, 17 and 20 was measured by behavioral indexes. Activation and expression of a microglia marker (Iba-1) was determined by immunofluorescence and Western blot. The level of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in rat spinal cord was measured by enzyme-linked immunosorbent assay (ELISA). H&E results showed that cionbufagin effectively inhibited the destruction of bone marrow in rats with bone cancer pain; cionbufagin treatment significantly increased the mechanical and thermal pain threshold. Immunofluorescence showed that cionbufagin effectively inhibited the activation of microglia in the spinal dorsal horn. Western blot analysis confirmed that the activation of microglia in the spinal dorsal horn was inhibited by cionbufagin treatment. It was also found that the CCL2/CCR2 pathway may be involved in the analgesic effect of cionbufagin. These results suggest that cionbufagin can effectively alleviate bone cancer pain, possibly by inhibiting the release of inflammatory factors and the activation of spinal microglia cells through the CCL2/CCR2 pathway.
Nonalcoholic fatty liver disease (NAFLD) is a genetic and environmental factor-associated metabolic disease that can lead to fibrosis, cirrhosis and hepatocellular carcinoma. In recent decades the prevalence of NAFLD has increased, but effective pharmacotherapy is limited. Treatment regimens in traditional Chinese medicine (TCM) have made significant contributions to the control of NAFLD, but underlying mechanisms are far less elucidated. Increasing evidence suggests that gut microbiota play a crucial role in the pathogenesis and development of diseases including NAFLD. The outcomes of such research open a new approach in identifying the molecular mechanisms of TCM. Here we review the evidence that gut microbiota might be a target in the treatment NAFLD using TCM.
The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of a series of cytokines such as pro-inflammatory factors, chemokines and proteases, and is a key feature of senescent cells. SASP is a double-edged sword that can resist a harmful environment in normal cells, but with the decline of body function, the massive secretion of cytokines, chemokines and proteases accelerates aging while inducing inflammation, leading to the development of various aging-related diseases. This article reviews the composition and physiological functions of SASP, the changes in SASP during aging, the regulatory pathways associated with SASP, and the anti-aging drugs that regulate SASP. This article aims to present a more comprehensive understanding of SASP and lay the foundation for SASP-based anti-aging research and the discovery of new targets for anti-SASP drugs.
The coagulation Ⅷ factor (FⅧ) contains eight pairs of disulfide bonds, which are involved in maintaining its structure and function. It has been demonstrated that the disulfide bond between Cys1899/Cys1903 of the A3 domain in the light chain impedes secretion. In our previous work, an engineered inter-chain disulfide in the B domain-deleted FⅧ (BDD-FⅧ) promoted heterodimer assembly and secretion of separately expressed heavy and light chains. In this study, we constructed two BDD-FⅧ variants, one of which contains an engineered inter-chain disulfide bond (F8C) between Met662 > Cys and Asp1828 > Cys mutations and another contains an endogenous A3 domain with a disrupted disulfide bond from F8C (F8CG) by replacement of Cys1899 and Cys1903 with Gly in F8C. We explored their function and secretion. By transducing F8C and F8CG into HEK293 and COS-7 cells, the formation of disulfide bonds and the secretion and coagulation activity of the two variants in the culture media and their binding affinity for von Willebrand factor (vWF) could be observed. The results show that variants F8C and F8CG are mainly the disulfide bonded heavy and light chain dimer, while the wild type BDD-FⅧ (F8) is dominated by the easily dissociated heavy and light chain dimer. The secretion and activity of F8C was significantly higher than that of F8, while the secretion and activity of F8CG was significantly higher than that of F8C. The vWF binding of the two variants is similar to F8. This indicates that the BDD-FⅧ variant F8CG may be attractive molecule for protein replacement and as a transgene in gene-therapy strategies. These findings are encouraging for future studies targeting disulfide bond elimination for further enhancement of FⅧ secretion.
Melanoma is a malignant tumor with a high degree of malignancy. The incidence of melanoma keeps increasing annually. In this study, a melanoma targeted hyaluronic acid (HA) nanogel was synthesized via crosslinking of thiolated HA with terminally functionalized F127-TPGS mixed micelles. Its stability in vitro was evaluated by the average particle size, and the cytotoxicity of the nanogel was investigated by in vitro cell based assays. Next, cell uptake studies were performed to quantitatively and qualitatively investigate the uptake of the nanogels in B16F10 cells. A small sized nanogel with a diameter of 30 nm was synthesized, which was proven to be minimally cytotoxic against both 3T3 or B16F10 cells. Compared with 3T3 cells with low levels of CD44, B16F10 cells with high levels of CD44 showed significantly higher cell uptake efficiency (P < 0.05).
Physiologically based pharmacokinetic (PBPK) modeling is an important tool to predict pharmacokinetic or pharmacodynamic profiles in special populations, especially in children and infants where designing and conducting clinical studies is difficult. The application of PBPK modeling can effectively promote the development of pediatric drugs and their clinical use. At present, PBPK modeling of pediatric populations is mainly applied in clinical trial design, drug-drug interaction (DDI) risk assessment, and dose selection in children. This review discusses the advantages of PBPK modeling in pediatric drug research and summarizes how to extrapolate a PBPK model from adults to children. The theoretical basis for pediatric PBPK models, the modelling process and important physiological parameters during the modeling process are introduced. Some successful applications of PBPK modeling in pediatric drug research and development are also presented. This review also analyzes the current limitations and future directions of pediatric PBPK modeling.
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