C17 is a small molecule containing 2, 4-diaminoquinazoline and aryl piperazine. Docking was used to compare the affinity of C17 for five dopamine receptor (DR) subtypes. Pancreatic cancer SW1990 and PANC-1 cell lines were used in in vitro and in vivo studies. The effect of C17 on the expression level of D1DR was investigated by immunofluorescence. A cytotoxicity assay, clone formation assay and flow cytometry were used to investigate the ability of C17 to inhibit on cell survival, clone formation, and to suppress cancer stem-like cells (CSCs). The ability to suppress tumorigenesis was investigated by inoculating nude mice with SW1990 cells pre-treated with different concentrations of C17. Finally, the anti-tumor efficacy and safety of C17 and its combination with the multitarget tyrosine kinase inhibitor sunitinib (SUN) were evaluated in SW1990 xenograft mice. Our results demonstrate that C17 is most likely to bind to D1DR among the five DR subtypes. D1DR expression was increased in C17-treated cells, which could be reversed by SCH23390, a D1DR-specific antagonist. The IC₅₀ values of C17 on the survival of SW1990 and PANC-1 cells were 12.56 and 10.56 μmol·L^-1, respectively. C17 could suppress clone formation ability, CSC frequency and in vivo tumorigenesis in a dose-dependent manner. In the SW1990 xenograft model, 50 mg·kg^-1 of C17 could weakly inhibit the tumor growth, and the tumor volume with 50 mg·kg^-1 of C17 in combination with 10 mg·kg^-1 of SUN group was smaller than that in SUN 10 mg·kg^-1, SUN 20 mg·kg^-1 group and gemcitabine (GEM) group. In addition, body weight, blood test, and organ index results showed good safety with all dosing regimens. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University. C17 may be a promising candidate for the treatment of pancreatic cancer.

Liver fibrosis is a critical pathological structural basis of a variety of chronic liver diseases such as alcoholic liver disease, viral hepatitis and nodular cirrhosis, while liver regeneration is the key mechanism for protecting liver against multiple injuries, promoting inflammation resolution and reversing liver fibrosis. When fibrosis occurs after liver injuries, the alternation of liver regeneration status in fibrosis usually plays an essential role in the outcome of diverse liver diseases. In this review, the differences between "homeostatic regeneration", "normal regeneration" and "aberrant regeneration" were identified in terms of the occurrence conditions, the basic state of the liver, the effects on liver repair, the types of cells involved and the pathogenesis. Emphatically, we not only summarize the differences of mechanisms between "aberrant regeneration" and "normal regeneration" in the pathogenesis of liver fibrosis, but also elucidate the features of "aberrant regeneration" in various liver fibrosis models, as well as the therapeutic strategies for the treatment of liver fibrosis based on "aberrant regeneration", expecting to provide evidence and clues for considering the risks and proposing possible solutions in clinical treatment of liver fibrosis.

The aim of this research is to investigate the effects of resveratrol on the inflammatory factors, oxidative stress indexes and the related genes of nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in RAW264.7 macrophages induced by monosodium urate (MSU) and to provide a theoretical basis for the treatment of acute gouty arthritis (AGA). Different concentrations of resveratrol were used to treat RAW264.7 cells for 5 hours, then MSU was added to stimulate them for 24 hours. The proliferation of RAW264.7 cells were detected by CCK-8 method. The level of tumor necrosis factor α secreted by cells were detected by ELISA method. The content of reaction oxygen species (ROS) in cells were detected by 2', 7'-dichlorodi-hydrofluorescein diacetate (DCFH-DA) probe method. The contents of superoxide dismutase (SOD) and malonaldehyde (MDA) in cells were detected by the kits. The expression of Nrf2, Kelch like ECH related protein 1 (Keap1), NAD(P)H quinone oxidoreductase 1 (NQO1), HO-1 mRNA were detected by real time PCR method. The results showed that resveratrol could inhibit the proliferation of RAW264.7 cells, significantly inhibit the TNF-α level of RAW264.7 cells induced by MSU, significantly inhibit the expression of ROS and MDA, and increase the expression of SOD in RAW264.7 cells induced by MSU. Resveratrol could reduce the expression of Keap1 mRNA in RAW264.7 cells induced by MSU, and increase the expression of Nrf2, NQO1, HO-1 mRNA. It is suggested that resveratrol can inhibit the inflammatory response of RAW264.7 macrophages induced by MSU, and improve the antioxidant capacity of macrophages by regulating Nrf2/HO-1 signal pathway.

This study was designed to investigate the effect and mechanism of astragaloside IV (ASIV) on mitochondrial morphology and function of rat cardiomyocytes under hypoxia/reoxygenation injury. H9c2 cells were divided into control group, hypoxia/reoxygenation (H/R) group, and H/R + ASIV group. Cell viability and lactate dehydrogenase (LDH) leakage were measured by cell counting kit-8 (CCK-8) and LDH assay kit, respectively. Oxidative stress levels, such as superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA), were analyzed by commercial kits. Intracellular and mitochondrial reactive oxygen species (ROS) levels were detected by dihydroethidium (DHE) and MitoSOX. Changes of the mitochondrial membrane potential were detected using the fluorescent probe JC-1. Opening of mitochondrial permeability transition pore was examined via calcein acetoxymethyl ester (calcein-AM). Apoptosis was assessed using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay kit. To detect protein expression of dynamin-related protein 1 (Drp1), mitofusin1 (Mfn1), Mfn2, Bax, B-cell lymphoma-2 (Bcl-2), and cleaved cysteine-aspartic protease (caspase)-3, Western blot analysis was carried out. Compared with the control group, ASIV (100 μmol·L^-1) significantly improved H/R induced cell injury, LDH leakage, decrease of SOD activity, and GSH content, increase of MDA content and ROS content, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, ROS production activation, mitochondrial fission/fusion imbalance, and cell apoptosis. In addition, the effect of ASIV against H/R injury was also verified on primary rat cardiomyocytes. The animal welfare and experimental process follow the rules of Animal Ethics Committee of Zhejiang Chinese Medical University. In conclusion, ASIV may play a protective role in mitochondria by regulating morphological dynamic stability and mitochondrial function, inhibiting excessive synthesis of ROS, improving the internal environment of oxidative stress, reducing cell apoptosis, and thereby protecting against cardiomyocytes' hypoxia/reoxygenation injury.

To establish a method for the determination of polymer impurities in cefixime raw materials and preparations, a cefixime degradation solution containing polymer impurities was prepared by forced polymerization. Polymer impurities in the degradation solution were separated and identified by high performance gel chromatography and the column switching-LC-MSⁿ method. A new RP-HPLC method for cefixime polymer was established and validated with a Phenomenex Gemini-C18 column using a mobile phase gradient elution of 0.5% formic acid-water solution and 0.5% formic acid-acetonitrile solution. The results showed that when using this high performance gel chromatography method some small molecular weight impurities were co-eluted with the polymers, resulting in a poor specificity and poor quantitative accuracy. But when using the RP-HPLC method, three polymer impurities were detected with good specificity, sensitivity and robustness, including two cefixime dimers, and dehydrate dimer. Therefore, the described RP-HPLC method is suitable for the quality control of polymer impurities in cefixime, and cefixime degradation solution can be used as suitable solution for analysis of cefixime polymers.

K-values of 56 batches of 7 types of povidone were measured by microfluidic rheometry and with a Ubbelohde capillary viscometer. The K-values of the two methods were tested by SPSS software and the results showed that there was no significant difference between the two methods (P > 0.05). Taking K-values measured with the Ubbelohde capillary viscometer (K_u) as the abscissa and K-values measured by microfluidic rheometry (K_m) as the ordinate a linear equation was calculated:K_m=0.893 9K_u + 4.617 6, R²=0.986 2, with good linearity, indicating that the microfluidic rheometer method can replace the Ubbelohde capillary viscometer in determining K-values of povidone. The microfluidic rheometer method has the benefits of less sample consumption, faster determination, and is more accurate, and it can be used with high-throughput automatic acquisition, which provides a more convenient method for the determination of K-values of different types of povidone. The weight-average molecular weights (M_w) of each type of povidone were measured by gel permeation chromatography-multi angle laser light scattering (GPC-MALLS), and the relationship between M_w and K_m was lgM_w=-0.000 4 K_m² + 0.072 7 K_m + 2.791, R² =0.990 1. The fitting relationship was good, and M_w could be calculated by K_m by the equation.

Epithelial cell adhesion molecule (EpCAM) is a popular target for cancer therapy. In this research, 3 nanobodies with high specificity and endocytosis activity against EpCAM were developed, which provides a basis for the study of immunotoxin based on EpCAM. In our preliminary experiments, we have immunized a camel with EpCAM-Fc antigen and constructed a high-quality phage display library. Seventeen nanobodies with different complementarity determining region (CDR) 3 sequences have been screened after 3 rounds of biopanning by phage display technology. The animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Fudan University School of Pharmacy. After purification, 7 nanobodies showed high cell binding activity by fluorescent activated cell sorting (FACS) identification. Furthermore, 3 nanobodies presented high endocytosis activity based on FACS and laser confocal microscopy, which also showed high affinity to EpCAM measured by ForteBio. According to this study, we aimed to provide a novel alternative approach to the EpCAM-targeted therapy and to provide guidance for the study of nanobody based immunotoxins for other targets.

Drug-drug complexes play important roles in improving the physicochemical properties of drugs including the solubility, dissolution rate and stability of the active pharmaceutical ingredients (APIs). In this paper, the design, synthesis, characterization, changes in physicochemical and pharmacologic properties, structural polymorphisms and the research and development pipelines of a variety of drug-drug cocrystals/salts synthesized based on the crystal engineering design are reviewed. This may provide theoretical support for the development of the new solid-state combinational drugs.

Dithiocarbamates and their derivatives with unique molecular structures possess diverse biological activities, which have become the research focus in the chemical and pharmaceutical fields in recent years. Here, we will review the structures, synthesis as well as biological activities of dithiocarbamates and their derivatives in anti-oxidation, anti-virus, anti-bacterial, anti-tumor and anti-Alzheimer's disease, and make a prospect for their development in the future.

Parkinson's disease (PD) is the second most common neurodegenerative disease of the central nervous system. It is currently believed that PD is related to factors such as age, gender, family inheritance, gene mutation and environment. The pathogenesis of PD is complex and is related to dysfunction and loss of dopaminergic neurons, involving accumulation of α-synuclein, neuroinflammation, oxidative stress, mitochondrial dysfunction and excessive accumulation of neuromelanin. In many ways, various factors act both independently and through cross-promotion, resulting in an ongoing pattern of brain tissue damage and progressing PD pathology. This article reviews the recent research on the pathogenic factors and pathogenesis of PD and explores new ideas and potential targets for PD treatment and drug development.