Xanthine oxidase (XO) is a key enzyme in the synthesis of uric acid. Therefore, XO inhibitors play an important role in the antihyperuricemic therapy. Based on the template structures of febuxostat and topiroxostat, 18 amide derivatives were designed and synthesized. Among them, six showed apparent inhibitory activity against XO under the concentration of 10 μmol·L^-1. Molecular docking revealed the possible interaction mode of this compound class, which may provide a clue for further molecular design.

Studies have shown that acetylcholinesterase inhibitors donepezil and galantamine have effects of reducing neuronal damage caused by glucose deprivation and reducing the cerebral infarction volume of cerebral ischemic animals, but their effects may not be entirely dependent on its inhibition of cholinesterase activity. In order to study the effects of donepezil and galantamine on neuronal injury of cerebral ischemia, the rat neuron-astrocyte co-culture model was successfully established in this study. In this model, we studied the effects of donepezil and galantamine on neuron apoptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and investigated the mechanism. The results showed that donepezil and galantamine significantly reduced the neuron apoptosis, and promoted the synthesis and secretion of BDNF and NGF in astrocytes in the co-culture system. Donepezil and galantamine activated the PI3K/Akt pathway and ERK pathway, and promoted the phosphorylation of the nuclear transcription factor CREB. These results suggest that donepezil and galantamine exhibit protective effects on neuronal damage induced by OGD/R. The mechanism may be related to activation of PI3K/Akt pathway and ERK pathway in astrocytes and promote phosphorylation of CREB, which lead to the synthesis and secretion of BDNF and NGF from astrocytes.

Cathepsin K (CTSK) is considered a critical pharmaceutical target in the treatment of osteoporosis. CTSK exerts proteolytic activities against regulatory proteins besides its collagenase function, which may account for some of the adverse reactions when blocked by active site-directed inhibitors. Exosite inhibitors that can discriminate between the therapeutic collagenase and other biological activities of CTSK specifically inhibit the collagenase activity of CTSK without interfering with the other proteolytic activities of the protease. Active recombinant CTSK was expressed in Pichia pastoris, and purified by n-butyl sepharose and SP sepharose column chromatography. Herba Ecliptae is a common traditional Chinese medicine in the treatment of bone diseases. Collagenase assay and benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin (Z-FR-MCA) substrate assay based on CTSK are applied to verify the exosite inhibitors. n-Butanol extract of Herba Ecliptae are the most active fraction and eclalbasaponin Ⅸ isolated from n-butanol fraction is the potential exosite inhibitor of CTSK.

This study aims to prepare lipid bilayer-coated calcium phosphate core-shell nanoparticles (LCAPNs), which can dissolve in an acidic environment to improve the tumor cell toxicity of antitumor drug. Paclitaxel (PTX) loaded lipid coated calcium phosphate nanoparticles (PTX-LCAPNs) were prepared by thin-film dispersion method. The morphology, particle size and in vitro release behavior were characterized. Meanwhile, the intracellular uptake, intracellular dissolution, cell toxicity of PTX-LCAPNs and intracellular accumulation of PTX were evaluated in human HCC cell line (Huh-7). The results suggested that the mean diameter of the spherical LCAPNs was 124.73±6.41 nm. The PTX-LCAPNs demonstrated little drug leakage in simulated normal physiological conditions, while a rapid release was observed in simulated intracellular condition in vitro. Moreover, the PTX-LCAPNs achieved 1.7 fold improvement in the intracellular PTX concentration leading to 5-fold reduction in half maximal inhibitory concentration (IC₅₀) values of PTX compared with calcium phosphate nanoparticles loaded with PTX (PTX-CAPNs), demonstrating a stronger cancer cell lethality.

Over the past four decades, monoclonal antibodies (MAbs) have evolved from bioscience research tools to powerful biopharmaceutical MAbs products for multiple diseases treatment. More than 50 therapeutic MAbs have been approved by FDA, widely used in cancer, autoimmune diseases and other diseases in current market. This article reviews the current progress of MAbs development technology, key molecules for cancer-targeted therapy and immunotherapy, and emphasizes the importance of MAbs for disease diagnosis and treatment.

A method of ultra flow liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was developed to elucidate the impurity of linezolid tablets. Linezolid was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal. The structure identification of the degradation products and the fragmentation patterns for the related impurities were analyzed. A total of four degradation impurities were characterized, impurity 1 is (S)-1-amino-3-((3-fluoro-4-morpholinophenyl)amino)propan-2-ol, impurity 2 is (S)-4-(4-(5-(acetamidomethyl)-2-oxo-oxazolidin-3-yl)-2-fluorophenyl)morpholine 4-oxide, impurity 3 is (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one, impurity 4 is (R)-N-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)acetamide. Acid degradation induced impurity 3 and impurity 4, base degradation induced impurity 1 and impurity 4, oxidation degradation induced impurity 2, hydrolysis degradation induced impurity 4. The study also determined calibration factor using impurity references, and the calibration factors were found to be 1.3, 1.4, 0.9 and 1.1, respectively. The toxicity of the degradation impurities was predicted by web-based prediction system. The results from this study provide an important reference in quality control and evaluation of linezolid.

The purpose of this study was to develop a screening method to determine the activity and selectivity of SGLT2 inhibitor. Human SGLT1/SGLT2 cDNA was inserted into the pMSCVpuro mammalian expression vector and the plasmid was transfected into HEK293 cells. Stably transfected clones were selected in puromycin containing medium. To evaluate the expression of human SGLT1 and SGLT2 in stable transfected cells, RT-PCR, Western blot and immunofluorescence analysis were performed. 1-[N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl)amino]-1-deoxy-D-glucose (1-NBDG) was used as a substrate in the uptake assay to evaluate the Na⁺ dependent glucose transport activities of SGLT1/2. The inhibitory activity and selectivity of dapagliflozin/phloridzin were also determined, respectively. The hypoglycemic efficacy of dapagliflozin was evaluated in mice with normal blood glucose and mice with alloxan-induced T1DM. The result showed that SGLT1 was overexpressed in pMSCVpuro-SGLT1 transfected HEK293 cells. SGLT2 protein was overexpressed in pMSCVpuro-SGLT2 transfected HEK293 cells and located in both cytoplasm and membrane. The Na⁺ dependent 1-NBDG uptake was significantly increased in pMSCVpuro-SGLT1/SGLT2 transfected cells compared to that in pMSCVpuro-null transfected cells. The selectivity of dapagliflozin, whose half maximal inhibitory concentration (IC₅₀) for SGLT2 (2.24×10^-10 mol·L^-1) was far lower than that for SGLT1 (6.20×10^-7 mol·L^-1), was better than that of phloridzin. The oral glucose tolerance was elevated after a single dose of dapagliflozin in normal mice. In T1DM mice, compared with model group, no-fasting glucose level was decreased at 1 h after administration and maintained at a lower level for 24 h in a dose-dependent manner. A 20-day administration with dapagliflozin dose-dependently improved the hyperglycemia status. Taken together, a system to evaluate the activity and selectivity of SGLT2 inhibitors was established using 1-NBDG in vitro and the hypoglycemic efficacy in vivo in this study. The advantages of this system include non-radioactivity, high efficiency, and good stability which may provide a technique platform for development of novel SGLT2 inhibitors.

This study was designed to establish an ultra-liquid chromatography-mass spectrometry method for the reliable identification the multiple chemical components in Huangqi Jianzhong Tang (HQJZ). The ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap mass spectrometry method was applied to identify the chemical constituents in the HQJZ rapidly. A total of 71 compounds including two major categories of saponins and flavonoids were identified or tentatively deduced on the basis of their retention behaviors, fragments of multistage mass spectrometry or by comparing with reference substances and literatures. Among them, 20 compounds were from Astragali Radix, 14 were from Paeoniae Radix Alba, 37 were from Glycyrrhizae Radix et Rhizoma Praeparata cum Melle, 3 were from Rhizoma Zingiberis Recens, 2 were from Cinnamomi Ramulus and Jujubae Fructus, respectively. The LC-MS method was used to qualitatively analyze the chemical constituents of HQJZ, which provides a scientific basis for the quality control of HQJZ.

The radiation is regarded as the fourth biggest pollution following the water, air and noise pollution, which generates a broad impact on human physiology and healthy. The radiation mainly comes from medical rays, industrial rays, nuclear wastes and atmospheric ultraviolet rays. The universality makes people pay more and more attention to the damage effect and mechanism of radiation. The radiation is divided into ionizing and non-ionizing radiation. It is a good idea to study the effect of ionizing and non-ionizing radiation on drug's metabolism, which may give a guidance to clinical medication to avoid adverse reactions and to support personalized medicine. This article reviews the effect of ionizing radiation (γ-rays, X-rays, uranium and cesium) and non-ionizing radiation (ultraviolet rays) on drug metabolism, their impact on metabolic characteristics of some drugs and the impact on expression of enzymes and transporters in drug metabolism, which is conducted with a focus on clinical significance.

Cryptococcal meningitis, caused by fungus Cryptococcus neoformans, is responsible for over a million infections and 600 000 deaths annually. Largely due to the limited treatment options and the intrinsic drawbacks coupled with drug resistance to current therapies, it is urgent to discover novel antifungal agents against cryptococcosis. An ideal antifungal drug should at least satisfy the following criteria: fungicidal, fungus-specific, permeable for the host barriers such as cell membranes of phagocytes and the blood-CNS barrier. Both discovery of candidates with novel mode of action and repurposing existing molecules with potent anti-cryptococcal activity are effective ways in discovery of new anti-cryptococcal agents. Here, we summarized recent advances in the study of anti-fungal activities, mechanisms of action, and clinical developments of new anti-cryptococcal drugs.