Hypoxia is one of the most significant characteristics of solid tumors. Hypoxia microenvironment can lead to the overexpression of hypoxia inducible factor-1α (HIF-1α). As the most critical transcription factor in the hypoxia response, HIF-1α activates downstream gene expression resulting in abnormal tumor cell proliferation, tumor angiogenesis, unusual energy metabolism, increased drug resistance, invasion, and metastasis. Down-regulation of HIF-1α expression is considered as a promising approach for the treatment of solid tumors, whereas the clinical efficacy of most existing HIF-1α inhibitors is restricted in low efficacy and high toxicity. Therefore, it is particularly important to develop powerful and safe novel drugs against the overexpression of HIF-1α. In recent years, numbers of studies have proved that a variety of chemical components of traditional Chinese medicine can directly or indirectly inhibit the activation of HIF-1α, which has a broad prospect in the fight against hypoxia-induced tumor progression. In this review, we summarized various anti-tumor active components of traditional Chinese medicines responsible for inhibiting the expression of HIF-1α in last ten years and analyzed the corresponding mechanism, with a view to further research as a reference.

As one of the most critical post-translational modifications, glycosylation of therapeutic proteins has a profound impact on their safety, efficacy and consistent. However, glycosylation is not a template-driven process, therefore variability in the glycosylation pattern of a protein can arise. This makes challenges of glycan analysis and control. Here, we review the overall control strategy, basic requirements for standardized protocols and the novel technologies of glycosylation analysis to accelerate the development of therapeutic glycoproteins.

We provide a new preclinical pharmacodynamic evaluation method of cerebral thrombolytics using beagle dogs with acute thrombotic cerebrovascular occlusion. An intracranial large vessel occlusion animal model was generated by pushing an autologous thrombus to the left carotid artery under X-ray angiography. The experiments were approved by the Animal Care and Welfare Committee Institute of Materia Medica, China Academy of Medical Sciences (CAMS), Peking Union Medical College. According to the degrees of cerebral blood flow reperfusion, the new method has 0, Ⅰ, Ⅱ (Ⅱa and Ⅱb), Ⅲ levels. Respectively, 0 level represents no blood flow through the area of vascular occlusion; Ⅰ level has low perfusion; Ⅱa level is less than half the infusion; Ⅱb level is more than half perfusion; Ⅲ level is completely recanalization perfusion. Alteplase was used as a positive drug to verify the accuracy of the method. Our results suggest that 100% of dogs reached the level of grade I and below in the model group, while 83% reached the level of grade IIa and above in the alteplase group. Results of a rank sum test showed that alteplase significantly improved the reperfusion of occluded cerebral vessels. We propose a method to evaluate the efficacy of thrombolytic drugs on dogs with middle cerebral artery occlusion.

Transient receptor potential vanilloid ion channel subtypes 2 (TRPV2) is a calcium permeable nonselective cation channel. TRPV2 is expressed in nerves, blood vessels, spleen, and other organs, and participates in the regulation of a variety of important physiological functions, such as nociception, neural development, and immune response. Here we reviewed the research progress on the structure, modulators, and physiological functions of TRPV2 channel to provide references for future research.

The activity and expression of drug metabolizing enzymes and transporters changes significantly under high altitude hypoxia. The gut microbiota is an important factor affecting the metabolism of drugs through direct and indirect actions, changing the bioavailability, biological activity or toxicity of drugs and affecting the efficacy and safety of drugs. High altitude hypoxia significantly changes the structure and diversity of the gut microbiota, which may play a role in drug metabolism. This article reviews the effects of high-altitude hypoxia on the gut microbiota and the effects these changes on drug metabolism.

To explore the preventive effects and potential mechanism of mulberry leaf water extract (MLWE) on type 2 diabetes mellitus (T2DM), this study observed the influence of MLWE on the metabolism of arachidonic acid (AA). T2DM mice were induced by high fat and high sucrose (HFHS) diet and intra-peritoneal injection of streptozotocin. The mice were randomly divided into a normal control group treated with drug-free solution (NC group), a normal control group treated with MLWE (NCML group), a diabetes mellitus (DM) group treated with drug-free solution (HFHS group), and a DM group treated with MLWE (HSML group); mice were maintained on this protocol for 10 weeks. Animal experimentation was approved by the Committee on the Ethics of Animal Experiments of Xuzhou Medical University. Mice livers and plasma were collected at the end of experiment. Fasting blood glucose (FBG) and fasting blood insulin (FBI) were detected by kits. The mRNA and protein expression levels of relative metabolic enzymes related to AA in mice livers were respectively detected by quantitative real time PCR (qPCR) and Western blot. The contents of AA and its relative metabolites in mice plasma were determined by liquid phase chromatography coupled with tandem mass spectrometry. The results showed that there was no significant variation for the relative expression of metabolic enzymes, contents of FBG, FBI, AA, and its relative metabolites between NCML group and NC group. Compared with NC group, the relative expression of fatty acid synthase (Fasn), phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and lipoxygenase-5 (LOX-5), and the levels of FBG, FBI, AA, and its relative metabolites in DM group were obviously increased, while that of carnitine palmitoyltransferase 1A (CPT1A) and cytochrome P450 family 4A (CYP4A) were significantly decreased. After intervention with MLWE, those changes could be improved, indicating that MLWE could prevent T2DM by acting on AA metabolism.

We established in vitro evaluation methods of the nebulization characteristics of budesonide suspension for inhalation and analyzed the influence factors. The delivery rate and total drug substance delivered (TDD) of two manufacturers were determined by using the breath simulator with different nebulizers. The aerodynamic particle size distribution was investigated by next generation impactor (NGI) and HPLC as well. The fine particle dose (FPD), the mass median aerodynamic diameter (MMAD), the delivery rate and TDD results of the same sample with different nebulizers were significantly different (P < 0.01), mainly due to the different design parameters of the nebulizers. The FPD of two samples were significantly different (P < 0.01) by the same nebulizers, probably due to differences in physical and chemical properties differences such as suspension particle size. The analysis method of nebulization characteristics provided in this paper can be used to select the nebulization device with appropriate delivery dose and aerodynamic particle size distribution (APSD) for different inhalation liquid preparations in clinical practice, and can also be used as the guidance for the selection of nebulization device and analysis method in the research and development of generic inhalation liquid preparations and quality consistency evaluation.

The objective of the study was to investigate the effects of nebulizers and add-on spacers on nebulization performances of Re-Du-Ning injection. Chlorogenic acid and geniposide were taken as the chemical markers of the injection. In vitro nebulization performances including real-time particle size distribution, aerodynamic particle size distribution (APSD), respirable drug delivery rate (RDDR) and percentage of respirable delivered dose (RDD%), residual rate and nebulization time were determined after nebulization of Re-Du-Ning injection via jet or mesh nebulizers. The delivery efficiency was the ratio of delivery dose to the drug content of the injection. The aerosol delivery efficiency of Re-Du-Ning injection for the jet nebulizer was about 30% of the nominal dose whereas those for mesh nebulizers varied from 24% to 35% in adult breathing pattern. Upon the inclusion of spacers, the delivery efficiencies of mesh nebulizers increased to 37%-68% whereas the presence of a spacer decreased the delivery efficiency of the jet nebulizer. When the aerosols of mesh nebulizer exhibited comparative fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) to those of the jet nebulizer, the RDD% of the former nebulizer with a spacer was more than two folds of the latter. These results indicated that the addition of spacer was demonstrated to significantly improve the delivery efficiency of Re-Du-Ning injection by mesh nebulizers.

In recent years, the research on myocardial ischemia disease is increasingly in-depth, and there are more and more drugs related to the anti-myocardial ischemia, among which natural medicines play an important role. In order to deal with myocardial ischemia diseases caused by a variety of pathogenic causes, the research on natural medicines is more and more deep. At present, natural medicines containing saponins, flavonoids, alkaloids and other compounds are the research objects. At the same time, great progress has been made in the research on the clinical application of natural drugs against myocardial ischemia. This article reviews the research progress of natural medicines against myocardial ischemia at home and abroad in the past ten years.

Blocking the binding of programmed death 1 (PD-1) on the T cells and programmed death ligand 1 (PD-L1) on the tumor cells has become a hotspot in the field of tumor immunotherapy. Small-molecule checkpoint inhibitor targeting PD-1/PD-L1 axis is the new direction of tumor immunotherapy. In the present study, we investigated the anti-tumor role of hyperoside by regulating the PD-L1 level in non-small cell lung cancer (NSCLC). Changes of total PD-L1 and membrane PD-L1 levels were determined by Western blot, flow cytometry, and PD-1/PD-L1 interaction assays. The expression of mRNA level of PD-L1 was detected by real-time PCR. The cytotoxicity of activated human T cells toward co-cultured tumor cells was measured by cell impedance assay and crystal violet experiment. The antitumor effect of hyperoside in vivo was examined by C57BL/6 mice bearing Lewis xenograft tumor. Western blot and flow cytometry assay showed that hyperoside significantly downregulated the abundance of PD-L1 in H1975 and HCC827 cells in dose- and time-dependent manner. PD-1/PD-L1 binding assay revealed that hyperoside reduced the binding of tumor cells to recombinant PD-1 protein. In addition, hyperoside decreased the abundance of c-Myc, a key transcriptional regulator of PD-L1, in H1975 and HCC827 cells. Cell impedance and crystal violet staining indicated that hyperoside enhanced the killing activity of co-cultured T cells toward tumor cells. Animal experiments (all animal experiments were conducted in accordance with the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences) revealed that hyperoside treatment displayed significant suppression in the growth of Lewis tumor xenografts in C57BL/6 mice with an inhibition rate of 48.3% at 25 mg·kg^-1. Our results demonstrate that hyperoside exerts its anti-NSCLC activity by reducing the PD-L1 level. Our study provides an important material basis and scientific basis for developing hyperoside into a new small molecule drug for tumor immunotherapy.