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.

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.

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.

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.

Coronaviruses (CoVs) are associated with some mammalian infectious diseases, which have caused several outbreaks of respiratory system infectious diseases in recent years. There is no effective vaccine or approved drug treatment against coronaviruses, and the development of anti-coronavirus agents is an urgent priority. Phenothiazines are a class of antipsychotic drugs, which were found that they have some other biological activities, like promising antibacterial, antifungal, anticancer, antiviral, etc. They can be used for drug repurposing. This review summarizes current researches on the potential anti-coronavirus activity of phenothiazine, discusses the mechanisms and some research difficulties, and provides a foundation for developing anti-coronavirus drugs which use phenothiazine as the lead compound.

Based on Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment (7^th edition), the metabolism and pharmacokinetics of drugs used in clinical treatment of COVID-19 were reviewed. The antiviral drugs include remdesivir, chloroquine/hydroxychloroquine, lopinavir/ritonavir, favipiravir, arbidol, baicalin, baicalein and forsythin. Among them, the metabolism and pharmacokinetics of arbidol, baicalin and forsythin are the research results of the author's laboratory. This article aims to provide reference for the efficacy evaluation and rational drug use of COVID-19.

Resveratrol possesses a wide range of biological activities, such as anti-cancer, anti-oxidation, induction of apoptosis, etc., but its poor drug properties, rapid metabolism, low target selectivity and bioavailability limit its application value. Studies have shown that modification of the structure of natural compounds can improve their pharmacological activities. To improve the bioavailability of resveratrol, many researchers have undertaken the synthesis and activity evaluation of resveratrol derivatives and analogues. They have modified the phenolic hydroxyl groups, double bonds and benzene ring of resveratrol so as to further understand the interactions among functional groups and its structure-activity relationship. In this paper, we review the chemical structures, synthetic methods and mechanisms of biological activity of resveratrol monomer derivatives as well as their related therapeutic applications, especially in the anticancer area over the last decade. This will provide some reference value for the further research and development of resveratrol-related drugs.

Photodynamic therapy (PDT) has attracted wide attention due to its unique advantages such as minimal invasiveness, high efficiency and high selectivity, and its ability to induce anti-tumor immune response. However, the treatment process is heavily dependent on the oxygen content of the treatment site, and the widespread oxygen deficiency in malignant tumors severely limits its efficacy. In addition, PDT-mediated oxygen depletion exacerbates tumor hypoxia, which further reduces its therapeutic effect. In recent years, many researches have been devoted to overcoming this problem. This paper summarized various strategies based on tumor hypoxic PDT in recent years, discussing the advantages and disadvantages of these strategies, and analyzing the main challenges and future directions of PDT in the treatment of tumors, so as to provide references for the in-depth study of photodynamic therapy of tumors.

Xenograft mice are preclinical animal models of tumors and are widely utilized in anti-tumor research. PK/PD modeling of anti-tumor agents is an approach that can capture the time profile of the "dose-plasma concentration-biomarker level-tumor volume" process based on experimental data from xenograft mice using a non-linear mixed-effect model. PK/PD modeling can help optimize the dosing regimen for anti-tumor therapy, evaluate any synergistic effect and help identify an optimal schedule for combination therapy, as well as providing a preliminary estimate of a drug's efficacy and anti-tumor potency in the human body. PK/PD modeling can also help by quantitatively explaining the mechanism of the tumor-inhibitory effect as indicated by changes in biomarker levels after a drug acts on its target. This article provides a systematic summary of the background, application range, and limitations of the mainstream anti-tumor agent PK/PD models. Recent advances in model structure development are reviewed in detail. Finally, we discuss promising applications of PK/PD models in anti-tumor medicine development from the perspective of a drug's mechanism of action, optimization of combination therapy schedules, and their clinical translation.