Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota.

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have been few studies on the pharmacokinetics of febuxostat in HN animal models or in patients. In this study, a high-purine diet-induced HN rat model was established. The pharmacokinetics of febuxostat in HN rats was evaluated using LC-MS/MS. Astragaloside IV (AST) was used to correct the abnormal pharmacokinetics of febuxostat. Gut microbiota diversity analysis was used to evaluate the effect of AST on gut microbiota. The results showed that the delayed elimination of febuxostat caused drug accumulation after multiple administrations. Oral but not i. p. AST improved the pharmacokinetics of febuxostat in HN rats. The mechanistic study showed that AST could regulate urea metabolism in faeces and attenuate urea-ammonia liver-intestine circulation. Urease-related genera, including Eubacterium, Parabacteroides, Ruminococcus, and Clostridia, decreased after AST prevention. In addition, the decrease in pathogenic genera and increase in short-chain fatty acids (SCFA) producing genera also contribute to renal function recovery. In summary, AST improved the pharmacokinetics of febuxostat in HN rats by comprehensive regulation of the gut microbiota, including urea metabolism, anti-calcification, and short-chain fatty acid generation. These results imply that febuxostat might accumulate in HN patients, and AST could reverse the accumulation through gut microbiota regulation.

Circular RNA hsa_circ_0000730 restrains cell proliferation, migration, and invasion in cervical cancer through miR-942-5p/PTEN axis.

Circular RNAs (circRNAs) play prominent roles in regulating the progression of cancers. This study is aimed to decipher the role of hsa_circ_0000730 in cervical cancer (CC).The differentially expressed circRNAs of CC were screened out from the Gene Expression Omnibus database. qRT-PCR was used to detect circ_0000730 expression in CC tissues and cell lines, and the Kaplan-Meier curve was adopted to figure out the relationship between circ_000730 expression and the overall survival time of CC patients. BrdU assay and Tanswell assay were utilized to examine the proliferation, migration, and invasion of CC cells. Western blot was adopted to detect PTEN protein expression. Bioinformatics analysis and dual-luciferase reporter assay were used to examine the target relationship between miR-942-5p and circ_0000730 or PTEN, respectively.Circ_0000730 was among the differentially expressed circRNAs in CC. Circ_0000730 was significantly down-regulated in the cancer tissues of 50 CC patients and CC cell lines. Additionally, underexpression of circ_0000730 was associated with the shorter survival time of CC patients. Gain- and loss-of-function assays highlighted that circ_0000730 significantly inhibited the proliferation, migration, and invasion of CC cells. Mechanistically, miR-942-5p was identified as a downstream target of circ_0000730, and circ_0000730 could positively regulate PTEN expression via repressing miR-942-5p in CC cells.Circ_0000730 inhibits the proliferation, migration, and invasion of CC cells via regulating miR-942-5p/PTEN axis. Circ_0000730 probably acts as a tumor suppressor in CC, and it may be a candidate target for the treatment of CC.

Two birds with one stone: a NIR fluorescent probe for mitochondrial protein imaging and its application in photodynamic therapy.

Mitochondrial proteins, most of which are encoded in the nucleus and the rest of which are regulated by the mitochondrial genome, play pivotal roles in essential cellular functions. However, fluorescent probes that can be used for monitoring mitochondrial proteins have not yet been widely developed, thereby severely limiting the exploration of the functions of proteins in mitochondria. Towards this end, here we propose a near-infrared (NIR) fluorescence probe MPP to effectively illuminate the dynamic changes in mitochondrial proteins in live cells under oxidative stress, with excellent temporal and spatial resolution. Of particular importance, MPP extends the study of the pharmacology involved in apoptosis induced by anti-cancer drugs (hydroxycamptothecin (HCPT), epirubicin (Epi) and cyclophosphamide (CPA)) for the first time. Furthermore, employing a protein-activatable strategy, this probe could serve as an excellent phototherapeutic agent in photodynamic therapy (PDT). Finally, in vivo experiments suggest that this versatile probe can be used to image tumors in HeLa tumor-bearing mice for 24 h, which demonstrates that our probe could play a dual role as a robust phototherapeutic and imaging agent.

Pharmacophore-inspired discovery of FLT3 inhibitor from kimchi.

Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3'-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.

Electrochemical preparation and properties of a Mg-Li-Y alloy via co-reduction of Mg(ii) and Y(iii) in chloride melts.

Mg-Li based alloys have been widely used in various fields. However, the widespread use of Mg-Li based alloys were restricted by their poor properties. The addition of rare earth element in Mg-Li can significantly improve the properties of alloys. In the present work, different electrochemical methods were used to investigate the electrochemical behavior of Y(iii) on the W electrode in LiCl-KCl melts and LiCl-KCl-MgCl2 melts. In LiCl-KCl melts, typical cyclic voltammetry was used to study the electrochemical mechanism and thermodynamic parameters for the reduction of Y(iii) to metallic Y. In LiCl-KCl-MgCl2 melts, the formation mechanism of Mg-Y intermetallic compounds was investigated, and the results showed that only one kind of Mg-Y intermetallic compound was formed under our experimental conditions. Mg-Li-Y alloys were prepared via galvanostatic electrolysis, and XRD and SEM equipped with EDS analysis were used to analyze the samples. Because of the restrictions of EDS analysis, ICP-AES was used to analyze the Li content in Mg-Li-Y alloys. The microhardness and Young's modulus of the Mg-Li-Y alloys were then evaluated.

DNA nanopore functionalized with aptamer and cell-penetrating peptide for tumor cell recognition.

In the present work, DNA nanopore was composed of a bundle of six DNA duplexes folded from six DNA strands and functionalized with Ramos cell aptamer and cell-penetrating peptide (CPP). Herein, we present a unique dually conjugated molecule with an aptamer and cell-penetrating peptide for targeting and recognition of Ramos cells. The aptamer sequence was specific bound to Ramos cell, at the meanwhile the nanopore assembly was taken onto the surface of cell membrane and then got into the cells with the help of CPP. Specific targeting and increased intracellular uptake of nanostructures by Ramos cells were aimed. The intracellular uptake of the structure was determined using confocal microscopy. This study is the first to describe the recognition of tumor cells with functional DNA nanopores, establishing the foundation for the tumor cell detection with low cytotoxic agents. Graphical abstract DNA nanopore was composed of a bundle of six DNA duplexes folded from six DNA strands and functionalized with Ramos cell aptamer and cell-penetrating peptide. The dually conjugated molecule was found to show both improved cellular uptake and effective Ramos cell targeting.

Targeted therapy for gastric cancer: Current status and future directions (Review).

According to the 2012 statistics of the International Agency for Research on Cancer (IARC), gastric cancer is the fifth most common malignancy, and the third leading cause of cancer-related deaths worldwide. Conventional chemotherapy and radiation have shown limited efficacy for advanced gastric cancer, showing an overall survival (OS) rate of ~10 months. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is the first approved molecularly targeted agent for HER2-overexpressing gastric cancer, which was found to prolong the OS and the progression-free survival (PFS) of patients. However, HER2 overexpression is present only in a minority of patients with gastric cancer. Hence, other targeted agents are urgently needed. Ramucirumab, a novel human IgG1 monoclonal antibody that selectively targets the extracellular domain of VEGF receptor 2 (VEGFR2), is regarded as a new standard second-line treatment for patients with advanced gastric cancer. The combination of two or more targeted agents directed against two different molecular targets may improve the survival of patients with advanced gastric cancer. Although great efforts have been made, the effect of targeted therapy for gastric cancer is limited. One key reason is that participants in clinical trials for new targeted agents were not selected by detection of the targeted molecule. Here, we review clinical trials related to molecular targets such as anti-epidermal growth factor receptor signaling including anti-HER2 and anti-EGFR1, anti-VEGF signaling, anti-mammalian target of rapamycin (mTOR), tyrosine kinase inhibitors (TKIs) and anti-MET.

A Quinoline-Based Ratiometric and Reversible Fluorescent Probe for Cadmium Imaging in Living Cells.

We report a novel ratiometric and reversible fluorescent probe for Cd(2+) detection utilizing a 6-(dimethylamino)quinaldine derivative as the fluorophore and a 2-hydrazinopyridine derivative as Cd(2+) chelator. This ratiometric fluorescent probe possesses favorable photophysical properties. It shows a large (55 nm) red-shift from 515 nm to 570 nm in the emission spectrum. Moreover, this probe also exhibits an excellent linear relationship of fluorescence intensity ratio (F570/F515) (R(2)=0.989) vs. Cd(2+) concentration in the range of 0-10 µM at physiological pH, which can serve as a "quantitative detecting" probe for Cd(2+). Utilizing this sensitive and selective probe, we have successfully detected Cd(2+) in living cells.

[The effect of eukaryotic expression plasmid ARHI on gastric cancer].

OBJECTIVE: To study the effect of expressed aplasia ras homolog member I (ARHI) on the malignant biological behaviors of gastric cancer including the proliferation, migration and invasion of the cell. METHODS: The eukaryotic expression plasmid of ARHI was constructed and transfected into MKN-28 cell with lipofectamine 2000 as pEGFP-ARHI group, transfected with pEGFP-N1 as pEGFP-N1 group, and untreated MKN-28 as control group. The expression of ARHI was detected by Western blotting and fluorescence microscope. CCK-8 assay was used to analyze the cell proliferation, the wound-healing assay and transwell assay were performed to investigate the effects on migration and invasion. RESULTS: Compared with the pEGFP-N1 group and control group, proliferation, invasion and migration of the pEGFP-ARHI group were depressed (P < 0.05). CONCLUSION: Recombination eukaryotic expression pEGFP-ARHI could partially reverse the malignant phenotypes of gastric cancer cell MKN-28.

[Human papillomavirus genotype distribution in invasive squamous cell carcinoma of the uterine cervix in Mongolian women in inner Mongolia autonomy region].

OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV) and the HPV genotype distribution in invasive squamous cell carcinoma of the uterine cervix in the Mongolian women in Inner Mongolia autonomy region. METHODS: The prevalence data of HPV in our department were retrospectively reviewed. INNO-LiPA genotyping technique was used to detect HPV genotypes in the reserved carcinoma tissue specimens. RESULTS: Totally 63 tissue specimens were collected and detected. The prevalence of HPV was 93.7%. The positive rates of HPV among different clinical staging and different pathological grading were not significantly different (P >0.05). The prevalence of HPV16 was not significantly different among different age groups (P>0.05). HPV16 (69.8%), HPV18 (4.8%), HPV31 (4.8%), HPV39 (4.8%), and HPV52 (3.2%) were the 5 dominating HPV genotypes in all cases. CONCLUSIONS: HPV infection is closely correlated with invasive squamous cell carcinoma of the uterine cervix in Mongolia women. HPV16 is the most important genotype in invasive squamous cell carcinoma of the uterine cervix, followed by HPV18, 31, and 39. HPV infection dose not affect the progression and differentiation of invasive squamous cell carcinoma of the uterine cervix.