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In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC0.016 μg/mL) and low cytotoxicity (IC

Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.

Stromal antigen 2 (STAG2) is a subunit of the cohesion complex that plays an important role in the normal segregation of sister chromatids during mitosis or meiosis. However, the effect of STAG2 on the bladder cancer cell proliferation, migration, and invasion has not yet been fully clarified. In this study, we aimed to characterize STAG2 expression and functional significance in BC and adjacent normal tissue. Notably, STAG2 expression was markedly lower in BC cells and tumor tissues than their normal counterparts at the gene and protein levels. Moreover, clinicopathological analysis showed that the low STAG2 expression is associated with TNM stage. Functional analysis demonstrated that STAG2 overexpression attenuated cell proliferation via G1-phase arrest, invasion, and migration, and promoted apoptosis in BC cell lines, while the opposite was observed with STAG2 knockdown cells. Furthermore, STAG2 overexpression upregulated E-cadherin, caspase-3, and caspase-7 and downregulated vimentin, matrix metalloproteinase (MMP)2, and MMP9. Collectively, these data suggest that STAG2 acts as a tumor suppressor gene in bladder cancer and may be a potential therapeutic target in BC.

Background/Aims: In recent years the diagnosis and management of renal cancer has changed greatly, although the mechanism is still elusive. TMEM106a is a conserved type II transmembrane protein which is a key factor to regulate macrophage activation. Its inactivation in gastric cancer is frequently observed to be associated with poor prognosis. The role of TMEM106a in renal cancer remained unclear. Methods: TMEM106a expression profiling was performed in a panel of renal cancer cell lines and primary renal tissue cells. Then TMEM106a was overexpressed by a viral system in a renal cancer cell line with low level of TMEM106a. This stable cell line was assessed in multiple cell growth and migration assays. The results from TMEM106a overexpressing cell line were then confirmed with primary renal cells by siRNA knockdown of TMEM106a. Results: TMEM106a expression level was reduced in renal cancer cells compared to normal primary renal cells. Restoration of TMEM106a expression in TMEM106a-low renal cancer cells resulted in attenuated proliferation, reduced cell migration and enhanced caspase 3 dependent apoptosis compared to control cells. TMEM106a knockdown in primary renal cells led to increased colony formation compared to the control cells with scrambled siRNA transfection. Conclusion: TMEM106a is a novel tumor suppressor in renal cancer.

With the continuous progress of virtual simulation technology, medical surgery visualization system has been developed from two-dimensional to three-dimensional, from digital to network and intelligentization. The visualization system with mixed reality technology will also be used in all stage of medical surgery, such as case discussion, surgical planning, intraoperative guidance, post-operative evaluation, rehabilitation, so as to further promote high intelligence, high precision of medical surgery, and consequently improve effectiveness of treatment and quality of medical service. This paper discusses the composition and technical characteristics of medical operation visualization system based on mixed reality technology, and introduces some typical applications of mixed reality technology in medical operation visualization, which provides a new perspective for the application of mixed technology in medical surgery.

Flavonoids are a class of polyphenol antioxygen, despite various known biological activities and therapeutic potential, scattered but not much is known about their interactions with drug transporters. P-glycoprotein (P-gp) as a cellular defense mechanism by effluxing its substrates has been widely investigated. The aim of this study was to investigate the inhibitory effects of 75 flavonoids on P-gp in vitro and in vivo and to illuminate the structure-activity relationships of flavonoids with P-gp. Five flavonoids, including tangeretin, sinensetin, isosinensetin, sciadopitysin and oroxylin A exhibited significant inhibition on P-gp in MDR1-MDCKIIcells, which reduced the P-gp-mediated efflux of paraquat and taxol and consequently increased their cell toxicity. In addition, co-administration of digoxin with five flavonoids increased the AUC0-t of digoxin in different extents in rats, from 19.84% to 81.51%. Molecular docking assays elucidated the inhibitory effect of flavonoids might be related to Pi interactions, but not hydrogen bonds. The pharmacophore model suggested the hydrophobic groups in B benzene ring may play a vital role in the potency of flavonoids inhibition on P-gp. Taken together, our findings would provide the basis for a reliable assessment of the potential risks of flavonoid-containing food/herb-drug interactions in humans.

MicroRNAs (miRNAs) have been demonstrated to exhibit abnormal expression patterns in various types of human cancer. The aim of the present study was to identify a novel tumor suppressor microRNA (miR) and investigate its physiological function and mechanism in renal cell carcinoma (RCC). The expression levels of miRNA (miR)‑362‑3p expres were measured in 47 pairs of RCC and adjacent normal tissue samples, using reverse transcription-quantitative polymerase chain reaction analysis. In addition, miR‑362‑3p was transfected into renal cancer cells to investigate its role in the regulation of cell proliferation, migration, invasion, apoptosis and cell cycle. Identification of the target gene of miR‑362‑3p was performed using luciferase reporter assays and western blot analyses. The results demonstrated that the expression levels of miR‑362‑3p were downregulated in the RCC tissue samples, compared with the adjacent normal tissue samples. The upregulation of miR‑362‑3p using a synthesized mimic suppressed the proliferation, migration and invasion of the renal cancer cells, and induced cell apoptosis and G1 phase arrest. Further experiments demonstrated that the overexpression of miR‑362‑3p resulted in decrease expression levels of nemo-like kinase. These results suggested that miR-362-3p functions as a tumor suppressor in RCC, and may serve as a potential molecular target in the treatment of RCC.

Dysifragilone A, a sesquiterpene aminoquinone based on a rearranged avarone skeleton, has been previously isolated and identified from the South China Sea sponge Dysidea fragilis. In the present study, anti‑inflammatory activity and the underlying molecular mechanism of dysifragilone A were studied using the classical inflammation model of lipopolysaccharide (LPS)‑activated RAW264.7 macrophage cells and an MTT assay, Griess method, ELISA and western blotting were used. The results revealed that dysifragilone A significantly reduced the release of inflammatory mediators and inflammatory cytokines in activated RAW264.7 cells, including nitric oxide (NO), prostaglandin E2,(PGE2) and interleukin‑6 (IL‑6). The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2), and the enzymatic activity of iNOS and COX‑2 were also inhibited by dysifragilone A in a dose dependent manner. Further mechanistic investigations suggested that the anti‑inflammatory activity of dysifragilone A results from the suppression of p38 mitogen‑activated protein kinase (MAPK) activation in LPS‑activated macrophages; however, this was not associated with inhibition of the extracellular signal‑regulated kinase (ERK) or c‑Jun N‑terminal kinase (JNK) signaling pathways. Therefore, dysifragilone A and similar compounds may be anti‑inflammatories that have potential to be used in the clinic.

IMM-H004 is a novel neuroprotective agent and its glucuronide metabolite IMM-H004G has similar protective effects against cerebral ischemic injury in vivo and in vitro. A specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was established and validated for determination of IMM-H004 and IMM-H004G simultaneously in rat plasma and Ringer's solution. Plasma samples containing IMM-H004, IMM-H004G and internal standard propranolol were prepared by direct protein precipitation in a sample-to-solvent ratio of 1:2:6 (plasma: water: acetonitrile), whereas no protein precipitation was required for Ringer's solution samples. Separation was performed with a gradient mobile phase of methanol/water with 0.5% formic acid (v/v) on Eclipse Plus C18 column (2.1×50mm, 3.5μm) at a flow rate of 0.3mL/min. The detection was operated on a triple quadrupole mass spectrometer in positive ion multiple reaction monitoring (MRM) mode. The monitored transitions were 305.1→248.1 for IMM-H004, 481.3→305.1 for IMM-H004G and 260.1→183.1 for propranolol. The linear ranges of IMM-H004 and IMM-H004G were 5 to 3000ng/mL and 10 to 3000ng/mL for plasma method and 0.5 to 500ng/mL for Ringer's solution method. All the intra-day and inter-day precision and accuracy for the two analytes in rat plasma were below 7.5% and the intra-day precision and accuracy for analytes in Ringer's solution were within ±14.7%. There was no obvious matrix effect and the recoveries of the analytes were higher than 94.2%. IMM-H004 and IMM-H004G were stable during one analytic process. The established method was applied successfully to plasma pharmacokinetic and brain microdialysis studies of IMM-H004 and IMM-H004G in rats after a single intravenous administration of IMM-H004.

Cancer/testis (CT) antigens are promising targets for immunotherapy due to their restricted expression in the germ cells of the testis in healthy tissue and high immunogenicity. The aim of the present study was to determine whether transmembrane protein 31 (TMEM31) is a CT antigen and to investigate the pattern of TMEM31 expression during the progression of melanoma. The pattern of expression of human TMEM31 mRNA in multiple human tissues was determined through reverse transcription-polymerase chain reaction analysis. TMEM31 protein expression was analyzed in the human testis, in addition to 128 primary melanoma and 64 metastatic melanoma samples through immunohistochemistry analysis. TMEM31 was identified to be predominantly expressed in the testis and weakly expressed in the placenta. In addition, TMEM31 protein expression was detected in 120/190 (63.16%) melanoma samples (primary and metastatic). The intensity of TMEM31 staining in metastatic and primary melanomas was determined through semiquantitative integrated optical density (IOD) analysis, and identified to be significantly increased in metastatic melanoma compared with primary melanoma (0.24±0.03 vs. 0.09±0.01 IOD/area; P

Herein, Ni doped ZnO-TiO2composites were prepared by facile sol-gel approach and were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-visible diffuse reflectance spectroscopy (UV-Vis DRS), X-ray photoelectron spectroscopy (XPS), and photoluminescence spectroscopy (PL). The results indicated that the Ni ions can be incorporated into the lattice of TiO2structure and replace Ti. The introduction of Ni expanded light absorption of TiO2to visible region, increased amount of surface hydroxyl groups and physically adsorbed oxygen (as the electronic scavenges), and then enhanced separation rate of photogenerated carriers. The photodegradation test of reactive brilliant blue (KN-R) under simulated solar light indicated that Ni doped ZnO-TiO2composites have better photocatalytic activities, as compared to those of TiO2and ZnO-TiO2.

Bladder cancer exhibits high mortality as a result of limited therapeutic options and a high recurrence rate. Accordingly, novel treatments such as immunotherapy have emerged as promising therapeutic modalities to prolong overall patient survival and effect a disease cure, which has renewed enthusiasm for the identification of tumor-specific target antigens. Cancer-testis (CT) antigens are recognized as ideal targets for immunotherapy because of their expression features and high immunogenicity profiles. Here, we investigate the expression pattern of a novel CT antigen, testis-expressed 19 (TEX19), in patients with bladder carcinoma and among multiple human tissues. Six bladder cancer cell lines (T24, UM-UC-3, J82, 5637, SW780, and RT4) were also analyzed for TEX19 expression. Our results reveal that TEX19 expression in normal tissue is restricted to human testis. In addition, TEX19 mRNA expression was detected in 60 % (24/40) bladder cancer samples, whereas 58.20 % (110/189) were positive for TEXT19 protein expression. Compared to low-grade tumors, TEX19 exhibited increased expression in high-grade tumors, from 53.69 to 77.14 %, respectively (P = 0.011). TEX19 was also expressed in all six bladder cancer cell lines. Together, our findings suggest that TEX19 represents a novel CT gene and might play a role in the progression of bladder cancer and that this gene therefore provides a potential target for immunotherapy treatment strategies against bladder cancer.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway has been identified as an important pathway in renal cell carcinoma (RCC). We have reported a nonsense mutation in PIK3R1, which encodes the regulatory subunit of PI3K, in a metastatic RCC (mRCC), while the mutation was absent in the corresponding primary RCC (pRCC). To identify the function of PIK3R1 in RCC, we examined its expression in normal kidney, pRCC and mRCC by immunohistochemistry and real-time polymerase chain reaction. The expression of PIK3R1 significantly decreased in pRCC and was further reduced in mRCC compared with normal tissue. Besides, its expression levels were negatively correlated with T-category of tumor stage. Additionally, 786-O and A-704 cells with PIK3R1 depletion introduced by CRISPR/Cas9 system displayed enhanced proliferation, migration and epithelial-mesenchymal transition (EMT) and acquired a stem-like phenotype. Moreover, the PIK3R1 depletion promoted the phosphorylation of AKT in the cells. The knockdown of AKT by shRNA reduced p-GSK3β and CTNNB1 expression in the cells, while the depletion of CTNNB1 impaired stem-like phenotype of the cells. Overall, PIK3R1 down-regulation in RCC promotes propagation, migration, EMT and stem-like phenotype in renal cancer cells through the AKT/GSK3β/CTNNB1 pathway and may contribute to progression and metastasis of RCC.

Numerous attempts for detection of circulating tumor cells (CTC) have been made to develop reliable assays for early diagnosis of cancers. In this study, we validated the application of folate receptor α (FRα) as the tumor marker to detect CTC through tumor-specific ligand PCR (LT-PCR) and assessed its utility for diagnosis of bladder transitional cell carcinoma (TCC). Immunohistochemistry for FRα was performed on ten bladder TCC tissues. Enzyme-linked immunosorbent assay (ELISA) for FRα was performed on both urine and serum specimens from bladder TCC patients (n = 64 and n = 20, respectively) and healthy volunteers (n = 20 and n = 23, respectively). Western blot analysis and qRT-PCR were performed to confirm the expression of FRα in bladder TCC cells. CTC values in 3-mL peripheral blood were measured in 57 bladder TCC patients, 48 healthy volunteers, and 15 subjects with benign urologic pathologies by the folate receptor α ligand-targeted PCR. We found that FRα protein was overexpressed in both bladder TCC cells and tissues. The levels of FRα mRNA were also much higher in bladder cancer cell lines 5637 and SW780 than those of leukocyte. Values of FRα were higher in both serum and urine specimens of bladder TCC patients than those of control. CTC values were also higher in 3-mL peripheral blood of bladder TCC patients than those of control (median 26.5 Cu/3 mL vs 14.0 Cu/3 mL). Area under the receiver operating characteristic (ROC) curve for bladder TCC detection was 0.819, 95 % CI (0.738-0.883). At the cutoff value of 15.43 Cu/3 mL, the sensitivity and the specificity for detecting bladder cancer are 82.14 and 61.9 %, respectively. We concluded that quantitation of CTCs through FRα ligand-PCR could be a promising method for noninvasive diagnosis of bladder TCC.