This work investigates the effects of Guilingji (GLJ) on D-galactose-induced aging and changes in serum metabolites by UHPLC-Q exactive orbitrap-MS in rats. The rat model of aging by subcutaneous injection of D-galactose (300 mg·kg^-1) was used to analyze the effect of different concentrations of GLJ (37.5, 75, 150 mg·kg^-1) on an open field test in aging rats. Rat serum was collected after 8 weeks and subjected to LC-MS to analyze the anti-aging effect of GLJ. Animal experimentation was approved according to the Committee on the Ethics of Animal Experiments of Shanxi University (SXULL2014032). GLJ significantly improved the autonomous activity of rats. Compared with the control group, 23 metabolites in the treated group changed significantly, involving three main pathways. The group that was given GLJ had altered regulation of 4 serum metabolites in two pathways. Our results indicate that GLJ can delay aging behavior in rats; the mechanism of this anti-ageing effect remains to be determined.

To detect the inhibitory effect of Astragalus protein on the proliferation of hepatocellular carcinoma cell line HepG2, transcriptomics was used to explore the anti-tumor mechanism of Astragalus protein. The dried roots of Astragalus was precipitated by ammonium sulfate to obtain Huang Qi protein (HQP) with different molecular weights. The effect of HQP on HepG2 and its toxic effect were detected by hemocytometry. Cell necrosis was detected by flow cytometry and Hoechst/propidium iodide (PI) double staining. The necrotic marker protein receptor interacting serine/threonine kinase 1 (RIP1) was determined by Western blot. Transcriptome sequencing was performed on the control group and dosing group RNA, and differential expression genes were analyzed for RNA-seq results. qRT-PCR was used to verified the relative mRNA expression levels of candidate genes. The results showed that the inhibition of HepG2 proliferation was more obvious with the increase of HQP concentration. When the concentration of HQP was 100 μg·mL^-1, the necrosis rate increased to 18.78%, and the number of red necrotic cells stained with PI was observed under the microscope. The Western blot results showed an increase in RIP1 protein levels. The results of RNA-seq analysis showed that 26 000 related genes were regulated by HQP, and 979 genes were more regulated. KEGG analysis found that some differentially expressed genes were associated with p53 signaling pathway, and qRT-PCR further verified that the sequencing results were reliable. HQP may cause programmed necrosis of HepG2 cells and may be involved in the p53 signaling pathway.

To study the mechanism of Huangqin decoction (HQT) in the treatment of ulcerative colitis (UC) by using network pharmacology, chemical components and targets related to the four herbs of Chinese meteria medical in HQT were searched through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) to construct the interaction network diagram of the target point of the compounds. The UC-related targets were screened through OMIM, TTD, and GeneCard databases. The compound-target network was constructed using Cytoseape_v3.7.1 software; based on the STRING database, a target interaction network for HQT for UC was constructed, and the core target of HQT for UC was selected based on topological parameters. GO (gene ontology) biological process enrichment analysis and KEGG (KEGG pathway analysis) pathway annotation analysis were performed on the disease and drug intersection targets using the R package clusterprofile version 3.12.0 in Bioconductor. The HQT compound-UC target network contains 128 compounds and corresponding targets 141. The core targets are AKTI, IL6, PTGS2, IL10, IL1β and so on. GO functional enrichment analysis yielded 151 GO terms, and KEGG pathway enrichment screening resulted in 33 associations with UC, mainly involving PI3K-AKT signaling pathway, NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway and so on. The synergetic effect of HQT with multi-components and multi-pathway was confirmed by network pharmacology, and the main possible mechanism of HQT in treating UC was predicted, which lay a foundation for the identification of effective components, the mechanism of action, and clinical application.

Recently, the hepatotoxicity issue regarding to Psoraleae Fructus (PF) has attracted remarkable concerns, which highlights the urgent need to explore the toxicity attenuation method for PF. In this study, we proposed an alcohol soaking and water rinsing method for pre-processing PF based on the record in the classics - "Lei Gong Pao Zhi Lun", aiming to attenuate the potential hepatotoxicity of PF. The optimal pre-processing methods and parameters were investigated by U*12(10⁸) uniform design coupled with 3D-cultured human-derived liver organoids model and high-content imaging. The results showed that there were significant variations among the hepatotoxicity intensities of different pre-processed PF products. Four factors, including the concentration of alcohol, the ratio of material and alcohol in alcohol soaking, the time of alcohol soaking and the times of water rinsing, were found as independent significant factors (all P < 0.01). The optimal pre-process parameters were further predicted and verified as follows:the alcohol concentration is 80%, the times of alcohol soaking is 3, the ratio of alcohol and material of alcohol soaking is 3, the time for alcohol soaking is 30 h, the ratio of water and material of water rinsing is 2, the times of water rinsing is 3, the time water rinsing is 12 h and the time of steaming is 5 h. This research demonstrated that the alcohol soaking and water rinsing method can effectively reduce the potential hepatotoxicity of PF. This method provides a reference for reducing the risk of PF liver injury from the perspective of Chinese medicinal materials pre-processing.

Based on the structure of inhibitors XL765 and WR23, the quinoxaline scaffold was selected as an attractive structure for drug design. In this protocol, the 2-position of quinoxaline was modified with a substituted phenoxy fragment. Meanwhile, the linking chain at the 3-position was changed to a sulfonyl hydrazine or was removed. A series of substituent groups were added at the 6-position of the quinoxaline scaffold. Twenty-two quinoline derivatives were designed and synthesized, and their structures were confirmed by ¹H NMR, ¹³C NMR, and ESI-MS. All compounds were screened for anti-tumor activity in vitro in A549, MCF-7, HCT-116 and HepG2 cancer cells. The results showed that P6b was effective, P6e and P6f had better activity against HCT116 (IC₅₀=3.24, 4.78 and 4.50 μmol·L^-1), and P6d had strong inhibitory effect on MCF-7 (IC₅₀=0.228 7 μmol·L^-1).

The resistance and dose limitation of tumors is a serious obstacle to cytotoxic drug therapy in the field of medical oncology. Nitric oxide (NO) is a powerful adjuvant for tumor hypersensitivity for traditional chemotherapy and radiation therapy. The concentration of NO plays an important role in affecting its anti-tumor effect. This review summarizes the mechanism of concentration-dependent effects of NO on tumor cells and the mechanism of chemotherapy sensitization. It provides evidence for rational use of NO to exert anti-tumor effects, and overcoming multidrug resistance and anti-tumor drug development.

Peptides 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.

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.

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.

Cardiovascular diseases (CVDs) and malignant tumors are the main causes of death worldwide. The etiology study of CVDs and malignant tumors has found a series of widely recognized risk factors. Medical practice and medical theory usually focus on one of the diseases, but more and more evidence reveals that malignant tumors usually involve the cardiovascular system, thus leading to thromboembolism, heart failure, etc. Anti-cancer treatment proves to induce CVDs, while CVDs seem to increase the risk of malignant tumors. This situation requires researchers to conduct further combined crossover study on both CVDs and malignant tumors. In this review, we discuss the potential common risk factors of cardiovascular diseases and malignant tumors, the pathological and physical mechanism of the two kinds of diseases, the cardiac toxicity induced by tumor therapy and the impact of cardiovascular drugs on cancer from the perspective of cardio-oncology, and in the endput forward the prospect of prevention and treatment.