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Background: CircRNAs and miRNAs are involved in the progression of tumor. CircMCTP2 is considered as a novel tumor promoter. However, the exact functions of circMCTP2 in bladder cancer are still unclear. This study was designed to explore the underlying mechanisms of circMCTP2-modulated tumor development in bladder cancer. Methods: The present study is an original research. The levels of circMCTP2 in a total of 39 bladder cancer specimens and cell lines were determined by RT-qPCR. The expression of FZD8 in T24 and RT-4 cells treated with miR-99a-5p mimics were examined using western blotting. In addition, the proliferative, migrative and invasive abilities of transfected cells were determined by CCK8 and Transwell assays. Furthermore, the apoptosis of transfected cells was evaluated using flow cytometry. Dual luciferase reporter assay was performed to elucidate the relationship between miR-99a-5p and circMCTP2/FZD8. Results: The levels of circMCTP2 were elevated in bladder cancer samples and cells, and this was related to worse survival rate. Downregulation of circMCTP2 suppressed growth and metastasis of cells, whereas the apoptotic rate of cells was enhanced. The levels of miR-99a-5rp was elevated after the downregulation of circMCTP2. Moreover, reverse correlation between the expression of miR-99a-5p and circMCTP2 was revealed in bladder cancer specimens. Additionally, FZD8 was the putative target of miR-99a-5p and the mimics of miR-99a-5p inhibited the proliferation, migration and invasion of bladder cancer cells via the FZD8/Wnt-b-catenin axis. Moreover, circMCTP2 regulated the growth and metastasis of bladder cancer cells potentially through regulating the miR-99a-5p/FZD8/Wnt-b-catenin axis. In summary, circMCTP2 was considered as an oncogenic factor through regulating the miR-99a-5p/FZD8/Wnt-b-catenin axis. Conclusions: This novel signaling could regulate the biological behaviours of bladder cancer cells, and these findings highlighted circMCTP2 as a critical target for treating bladder cancer. [ABSTRACT FROM AUTHOR]

Introduction: Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, originating from renal tubular epithelial cells in the kidney. Hypoxia proves to be a feature commonly observed in solid tumors, leading to increased resistance to treatment and tumor progression. Methods: scRNA‐seq data were procured from GSE159115 data set. We utilized UMAP and NMF algorithm for clustering and dimensionality reduction. The FindAllMarkers function was used to compare various groups and identify potential hypoxia marker genes. A series of in vitro experiments, including CFA, flow cytometry targeting cell cycle, CCK‐8, and EDU, was applied to investigate how ANGPTL4 regulated the ccRCC progression. Two cell lines of ccRCC cells, 786‐O and Caki, were used for si‐ANGPTL4 transfection. Results: We annotated a total of a total of 6 cell clusters, namely ccRCC malignant cells, T cells, endothelial cells, myeloid cells, smooth muscle cells, and B cells. We observed higher levels of hypoxia‐score in the ccRCC malignant cells, while lowest hypoxia‐score in T and B cells. We detected multiple hypoxia‐related subclusters of TME cells in ccRCC, among which S100A4 CD8+ T cells and nonhypoxia CD8+ T cells were found with a marked elevation of T cell inhibitory gene score. We identified that ANGPTL4+ endothelial cells might function as an integrative role in tumor angiogenesis. Multiple TME subclusters showed high potency in stratification of the prognosis of ccRCC patients. Moreover, by a series of in vitro experiment, we found ANGPTL4 regulated the ccRCC cell proliferation, probably through ERK/P38 pathway. Conclusion: We discerned multiple hypoxia‐related subclusters of TME cells in ccRCC, which displayed distinct functional features and great potency in predicting prognosis of ccRCC patients. We identified the role of ANGPTL4 in regulating ccRCC proliferation via ERK/p38 pathway. [ABSTRACT FROM AUTHOR]

This article discusses the role of FOXC1 (Forkhead Box C1) in regulating immune response genes and the tumor microenvironment in basal-like breast cancer (BLBC). The study found that FOXC1 can suppress the expression of interleukin-1β (IL-1β), a proinflammatory cytokine, by interfering with the interaction between the NF-κB transcription factor and the IL-1β promoter. FOXC1 overexpression also attenuated the expression of other inflammation-associated genes. These findings suggest that FOXC1 may have anti-inflammatory properties in cancer cells and provide insights into the molecular mechanisms underlying tumor immunosuppression. [Extracted from the article]

Ferroptosis is a form of programmed cell death with important biological functions in the progression of various diseases, and targeting ferroptosis is a new tumor treatment strategy. Studies have shown that sodium butyrate plays a tumor-suppressing role in the progression of various tumors, however, the mechanism of NaBu in endometrial cancer is unclear. Cell viability, clone formation, proliferation, migration, invasion abilities and cell cycle distribution were assessed by CCK8 assay, Clone formation ability assay, EdU incorporation, Transwell chambers and flow cytometry. The level of ferroptosis was assayed by the levels of ROS and lipid peroxidation, the ratio of GSH/GSSG and the morphology of mitochondria. Molecular mechanisms were explored by metabolome, transcriptome, RNA-pulldown and mass spectrometry. The in-vivo mechanism was validated using subcutaneous xenograft model. In this study, NaBu was identified to inhibit the progression of endometrial cancer in vitro and in vivo. Mechanistically, RBM3 has a binding relationship with SLC7A11 mRNA. NaBu indirectly downregulates the expression of SLC7A11 by promoting the expression of RBM3, thereby promoting ferroptosis in endometrial cancer cells. In conclusion, Sodium butyrate can promote the expression of RBM3 and indirectly downregulate the expression of SLC7A11 to stimulate ferroptosis, which may be a promising cancer treatment strategy. [ABSTRACT FROM AUTHOR]

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. [ABSTRACT FROM AUTHOR]

The phytochemical investigation on the fruits of Morinda citrifolia led to the isolation and characterization of a new anthraquinone, moricitrifone (1), along with seven known anthraquinones (2–8). The chemical structure of 1 was elucidated by extensive spectral analyses. The known compounds (2–8) were identified by comparing their spectral data with those reported in the literature. The antiproliferative activities of all isolated anthraquinones (1–8) against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 were evaluated in vitro. Compounds 1–8 exhibited remarkable antiproliferative activities with IC50 values ranging from 0.26 ± 0.05 to 16.58 ± 0.18 μM, which were comparable to those of doxorubicin. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer (TC) continues to increase worldwide. Aerobic glycolysis, the prominent feature of glucose metabolism in cancer progression, is associated with TC. We first demonstrated that HIF-1a is highly expressed in TC tissues and is positively correlated with the level of XIST in the serum of patients with TC. Then, we proved that XIST regulates the expression of HIF-1a through the XIST/miR-93/HIF-1a pathway, thereby regulating the level of glycolysis in TC cells. Knockdown of XIST inhibits glycolysis, proliferation, the cell cycle and metastasis of TC cells. Finally, we verified that artemisinin could target the degradation of HIF-1a and inhibit glycolysis in TC cells. Collectively, XIST levels in serum may be used as a tumor marker for TC promoted by HIF-1a, which could be treated using artemisinin. [ABSTRACT FROM AUTHOR]

Background and aims: The early diagnosis and intervention of oesophageal squamous cell carcinoma (ESCC) are particularly important because of the lack of effective therapies and poor prognosis. Comprehensive research on early ESCC at the single‐cell level is rare due to the need for fresh and high‐quality specimens obtained from ESD. This study aims to systematically describe the cellular atlas of human intramucosal ESCC. Methods: Five paired samples of intramucosal ESCC, para‐ESCC oesophageal tissues from endoscopically resected specimens and peripheral blood mononuclear cells were adopted for scRNA‐seq analysis. Computational pipeline scMetabolism was applied to quantify the metabolic diversity of single cells. Results: A total of 164 715 cells were profiled. Epithelial cells exhibited high intra‐tumoural heterogeneity and two evolutionary trajectories during ESCC tumorigenesis initiated from proliferative cells, and then through an intermediate state, to two different terminal states of normally differentiated epithelial cells or malignant cells, respectively. The abundance of CD8+ TEXs, Tregs and PD1+CD4+T cells suggested an exhausted and suppressive immune microenvironment. Several genes in immune cells, such as CXCL13, CXCR5 and PADI4, were identified as new biomarkers for poor prognosis. A new subcluster of malignant cells associated with metastasis and angiogenesis that appeared at an early stage compared with progressive ESCC was also identified in this study. Intercellular interaction analysis based on ligand–receptor pairs revealed the subcluster of malignant cells interacting with CAFs via the MDK–NCL pathway, which was verified by cell proliferation assay and IHC. This indicates that the interaction may be an important hallmark in the early change of tumour microenvironment and serves as a sign of CAF activation to stimulate downstream pathways for facilitating tumour invasion. Conclusion: This study demonstrates the changes of cell subsets and transcriptional levels in human intramucosal ESCC, which may provide unique insights into the development of novel biomarkers and potential intervention strategies. [ABSTRACT FROM AUTHOR]

Four new polyacetylene substances, sadivaethynes A–D, were isolated from the ethanol extract of the roots of Saposhnikovia divaricata (Turcz.) Schischk using repeated column chromatography. Structural elucidation of compounds 1–4 was established by 1D and 2D NMR spectra referring to the literature, together with high-resolution mass spectrometric analysis. All compounds were evaluated for cytotoxicity against two human cancer cell lines (MGC-803, Ishikawa) in vitro. [ABSTRACT FROM AUTHOR]

For real-time evaluation of the cell behavior and function under in vivo-like 3D environment, the 3D functionalized scaffolds simultaneously integrate the function of 3D cell culture, and electrochemical sensing is a convincing candidate. Herein, Fe3O4 nanoparticles as the nanozyme (peroxide oxidase mimics) were modified on graphene foam scaffold to construct a 3D integrated platform. The platform displayed a wide linear range of 100 nM to 20 μM and a high sensitivity of 53.2 nA μM−1 toward detection of hydrogen peroxide (H2O2) under the working potential of + 0.6 V (vs. Ag/AgCl). The obtained 3D scaffold also displayed satisfactory selectivity toward the possible interferents that appeared in the cell culture environment. Furthermore, the cells still maintained high cell viability (almost 100%) after their growth and proliferation on the scaffold for 7 days. With the superior performance on cell culture and electrochemical monitoring, the functions on the 3D culture of MCF-7 or HeLa cells and in situ monitoring of cell-released H2O2 was easily achieved on this 3D platform, which show its great application prospects on further cancer-related disease diagnosis or drug screening. A nanozyme-based three-dimensional graphene scaffold was successfully constructed for cell culture and identification of cancer cells through in situ electrochemical monitoring of the cell-released H2O2. [ABSTRACT FROM AUTHOR]

To investigate the effects of transmembrane protein 45A (TMEM45A) on biological characteristics and cisplatin (DDP) resistance of cervical cancer cells. TMEM45A in cervical cancer cells and normal cervical epithelial cells (HCerEpiC) were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. HPV genotypes were identified by multiplex PCR. SiHa and HeLa cells were divided into Blank, shCTL, shTMEM45A-1, and shTMEM45A-2 groups, followed by Cell Counting Kit-8 (CCK-8), EdU, Annexin V-FITC/PI staining, Wound healing, and Transwell invasion assays, as well as qRT-PCR and Western blotting. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) was employed to evaluate the impact of TMEM45A shRNA on cisplatin-resistant cervical cancer cells (SiHa/DDP and HeLa/DDP). Compared with HcerEpic cell, cervical cancer cells exhibited the upregulation of TMEM45A expression, especially in HPV-positive cell lines (CaSki, SiHa, HeLa). TMEM45A shRNA suppressed the proliferation of SiHa and HeLa cells, arrested cells at the S phase, and promoted cell apoptosis. TMEM45A shRNA inhibited the epithelial-mesenchymal transition (EMT), invasion, migration of SiHa and HeLa cells, accompanying by the downregulated Vimentin and N-cadherin with the upregulated E-cadherin. Moreover, SiHa/DDP and HeLa/DDP had higher TMEM45A expression than their parental SiHa and HeLa cells, respectively. And inhibiting TMEM45A can reduce the IC50 of SiHa/DDP cells and HeLa/DDP cells to cisplatin. Silencing TMEM45A can inhibit cell proliferation, invasion, migration and EMT, regulate cell cycle distribution, promote cell apoptosis, and reverse cisplatin resistance of HPV-positive cervical cancer cells, highlighting that inhibition of TMEM45A may be a therapeutic strategy for HPV-positive cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is a common gastrointestinal cancer and currently has the third-highest mortality rate. Research shows that the natural compound narciclasine has a variety of biological activities. The present study aimed to investigate the effect of narciclasine on gastric cancer cells and its molecular mechanisms and determine whether this compound could be a novel therapy for gastric cancer. Methods: MTT and clone assays were employed to detect the proliferation of gastric cancer cells. The cell apoptosis was detected by flow cytometry. The formation of autophagosomes and autophagosomal lysosomes was observed by transmission electron microscopy and laser confocal scanning microscopy. Western blotting was used to detect the expression of apoptosis, autophagy and Akt/mTOR pathway-related proteins. Results: In this study, we found that narciclasine could inhibit the proliferation of gastric cancer cells and promote apoptosis in gastric cancer cells. Further experiments showed that narciclasine promoted the levels of autophagy proteins LC3-II, Atg-5 and Beclin-1, reduced the expression of the autophagy transporter p62, and increased autophagic flux. By using the autophagy inhibitors 3-MA and CQ, it was shown that narciclasine could induce autophagy-mediated apoptosis in gastric cancer cells. Finally, we found that narciclasine had no significant effects on the total content of Akt and mTOR in gastric cancer cells, and it involved autophagy in gastric cancer cells by reducing the phosphorylation level of p-Akt and p-mTOR. Conclusions: Narciclasine can induce autophagy-dependent apoptosis in gastric cancer cells by inhibiting the phosphorylation level of Akt/mTOR and thus reduce the proliferation of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Background: Whether anesthesia methods affect malignant biological behavior of cancer remains unresolved. In this study, we aim to compare the effects of general anesthesia (GA) and local anesthesia (LA) on serum collected from primary hepatocellular carcinoma (HCC) patients presenting for radiofrequency ablation (RFA). Methods: From August 2020 to December 2020, a prospective, randomized, and controlled study was conducted at Renji Hospital, which is affiliated with Shanghai Jiaotong University School of Medicine. 25 qualified patients from 18 to 65 years of age undergoing RFA were enrolled in the study and randomly assigned into two groups: the GA group (n = 14) and the LA group (n = 11). Venous blood was drawn from all patients preoperatively and 1 hour postoperatively. The serum collected was then used for the culturing of HepG2 cells. The malignant biological behaviors of HepG2 cells, including invasion, migration and proliferation, were observed after 24 hours of exposure to patients' serum. ELISA was used to compare expression levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and lymphokines (IFN-γ, IL-2) in patients' serum from both groups. Results: HepG2 cells cultured with postoperative serum obtained from patients who received GA, but not LA, were associated with significantly increased cell invasion, migration and proliferation, compared to preoperative serum from the same patient group. Expression levels of pro-inflammatory cytokines were significantly higher, and lymphokines significantly lower in postoperative serum from GA patients compared to the corresponding preoperative serum. Conclusion: GA affects the serum milieu of patients with HCC, promoting the malignant biological behavior of a human HCC cell line. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvironment. Turning the TAMs against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically "cold" tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells' immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAMs to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAMs. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1's action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAMs both by blocking Nano-DOX-induced PD-L1 in the TAMs and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAMs with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX's action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAMs to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAMs, achieves enhanced activation of TAM-mediated anti-tumor response. [ABSTRACT FROM AUTHOR]

Background: Scavenger Receptor Class A Member 5 (SCARA5), also known as TESR, is expressed in various tissues and organs and participates in host defense. Recent studies have found SCARA5 to produce an anti-tumor effect for multiple tumors, although the mechanistic basis for the effect is unknown. Methods: Bioinformatics, methylation-specific polymerase chain reaction (MSP), quantitative real-time PCR, and immunohistochemistry were used to assess promoter methylation and expression of SCARA5 in lung cancer tissues and cell lines. The biological effect of SCARA5 on lung cancer cells was confirmed by the CCK8 assay, colony formation assay, and flow cytometry. GSEA, Western blot, RNA sequencing, and luciferase-based gene reporter assay were used to explore the mechanistic basis for the anti-tumor effect of SCARA5. Chemosensitivity assays were used to evaluate the anti-tumor effect of SCARA5 in conjunction with chemotherapeutic drugs. Results: We found SCARA5 to be downregulated in lung cancer cell lines and tissues with SCARA5 levels negatively related to promoter methylation. Ectopic expression of SCARA5 suppressed proliferation of lung cancer both in vitro and in vivo through upregulation of HSPA5 expression, which inhibited FOXM1 expression resulting in G2/M arrest of the A549 cell line. SCARA5 also improved susceptibility of A549 cells to chemotherapeutic drugs that damage DNA. Conclusion: SCARA5 was silenced in NSCLC due to promoter methylation and could be a potential tumor marker in NSCLC. [ABSTRACT FROM AUTHOR]

Fusobacterium nucleatum (Fn) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (M φ) was involved in CRC progress driven by Fn infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of Fn in M φ polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of M φ into the M2-like M φ phenotype by in vitro study. Histological observation from Fn -positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like M φ. Fn -induced M2-like M φ polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn -challenged M φ and CRC cells. In addition, Fn -challenged M2-like M φ conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics in vitro and significantly enhanced tumor growth in vivo , all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF- κ B signaling pathway mediated Fn -induced S100A9 expression and subsequent M2-like M φ activation. Collectively, these findings indicate that elevated S100A9 in Fn -infected CRC microenvironment participates in M2-like M φ polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF- κ B/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn -associated CRC. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. Methods: First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. Results: We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Conclusions: Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa. [ABSTRACT FROM AUTHOR]

Cell is the basic unit of structure and function of all living bodies. The study of intracellular drug concentration distribution is helpful to understand the drug efficacy of target site. Pemetrexed is a new multitarget folate antagonist with pyrrolidine group as its core structure. An ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed for rapid quantification of pemetrexed concentration in human breast cancer cells (MCF-7). Sample pretreatment was completed by protein precipitation using methanol. The optimized chromatographic separation was achieved on a ZORBAX SB-C18 column (2.1 × 150 mm, 3.5 μm). The column was equilibrated with initial mobile phase and eluted under gradient phases containing 0.1% formic acid in water (phase A) and in acetonitrile (phase B). The gradient program started at 5% B, increased to 95% B in 2 min, and then held at 95% B for 1.5 min. The linear range of pemetrexed in cells and nucleus was 2.0–200.0 ng/mL, while in the medium sample it was 50.0–5000.0 ng/ml, and the correlation coefficients were all greater than 0.99. The recovery was 47.50–67.55% (2.0–200.0 ng/mL) and 82.72–97.15% (50.0–5000.0 ng/mL), and the matrix effect was 98.10–100.62% (2.0–200.0 ng/mL) and 89.78–97.65% (50.0–5000.0 ng/mL). Interday precision and intraday precision (RSD%) were less than 15.0% (for LLOQ, less than 20%), and accuracy (RE%) was within ±15%; the deviation of stability was within ±15%, all meeting the requirements of biological sample analysis. The results of intracellular samples showed that the concentration of pemetrexed reached its peak at 3 h after administration. The concentration of pemetrexed in the nucleus continued to increase 2 h after administration and may have reached the maximum concentration at 6 h. [ABSTRACT FROM AUTHOR]

Fibroblasts in the stroma play a critical role in tumor evolution. In this study, we assessed the influence of colonic fibroblasts on colon cancer cells treated with 5-fluorouracil (5-FU), and mouse colon cancer cell lines MC38 and colonic fibroblasts NIH3T3 were used in this study. A sensitive and rapid UHPLC-MS/MS method for the quantitation of 5-FU from the cell and their medium has been successfully developed and validated. The cells were lysed with methanol, and the mixture was evaporated and then redissolved to extract intracellular 5-FU. The analysis was performed on UHPLC-MS/MS using an Atlantis T3-C18 column (3 μm, 2. 1 ∗ 100 mm) and gradient elution with acetonitrile and 0.1% formic acid in water. Method validation included the following parameters: the matrix effect range 88.82%–93.64% and the recovery range 93.52%–94.56%. The intraday and interday precision and accuracy were <11% and within ±6%, and the stability, specificity, carry-over, dilution effect, and linearity all conformed to the criteria. The method was applied to detect the concentration of 5-FU inside cells and cell culture medium. The preliminary results present that NIH3T3 could enhance the drug resistance of MC38 to 5-FU with a decreased intracellular concentration of 5-FU in MC38, which showed a positive relationship with NIH3T3 number. [ABSTRACT FROM AUTHOR]

A new sesquiterpenoid glycoside, consisting of one vetispirane-type, dmetelisproside A (1), together with two known megastigmane sesquiterpenoids, citroside A (2) and staphylionoside D (3) were isolated from the leaves of Datura metel L. The structures were determined by analysis of their MS and NMR data as well as by comparison with literature values. All isolates were evaluated for cytotoxicity toward SGC-7901, Hepg2, HeLa, MCF-7, and MDA-MB-231 cancer cell lines, and anti-inflammatory activity against nitric oxide (NO) in RAW 264.7 cells in vitro. Compounds 1 and 2 exhibited pronounced cytotoxicity against SGC-7901 and HeLa cells with IC50 values in the range of 21.43 to 29.51 μm. All three compounds displayed potential effects against NO production with IC50 values of 31.10, 34.25, and 44.31 μm, respectively. Thus, these isolated compounds in the leaves of Datura metel L were subjected to bioactivity substances for future studies on medicinal application. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that long non-coding RNAs (lncRNAs) serve important roles in carcinogenesis and that this type of gene may be used as biomarkers in cancer. A high level of lncRNA HOXA distal transcript antisense RNA (HOTTIP) is associated with unfavorable prognosis for patients with ovarian cancer (OC), but the mechanism of HOTTIP involved in OC development remains to be elucidated. The present study aimed to investigate the mechanism of HOTTIP in metastasis-associated OC cell behaviors. HOTTIP levels in ovarian cells were quantified by reverse transcription-quantitative PCR, cell proliferation was analyzed by colony formation assay, and apoptosis was assessed by flow cytometry. Cell migratory and invasive abilities were evaluated by wound healing and Transwell assays, respectively. The expression levels of mitogen-activated protein kinase kinase (MEK)/ERK pathway-associated proteins were detected by western blotting. The results demonstrated that knockdown of HOTTIP in OC cells significantly reduced the phosphorylation levels of MEK and ERK, inhibited the proliferation and invasion of OC cells and promoted their apoptosis. Furthermore, the effects of HOTTIP on cell migration and invasion were partly associated with the epithelial-mesenchymal transition (EMT) process. Proliferation, invasion and EMT of OC cells were enhanced following overexpression of HOTTIP; however, these effects were reversed by the MEK/ERK pathway inhibitor U0126. In conclusion, HOTTIP was demonstrated to promote the proliferation, migration and invasion of OC cells by activating the MEK/ERK pathway. Therefore, HOTTIP may serve as a potential therapeutic target for OC. [ABSTRACT FROM AUTHOR]

Fatty acid synthase (FASN) has been shown to be selectively up‐regulated in cancer cells to drive the development of cancer. However, the role and associated mechanism of FASN in regulating the malignant progression of salivary adenoid cystic carcinoma (SACC) still remains unclear. In this study, we demonstrated that FASN inhibition attenuated invasion, metastasis and EMT of SACC cells as well as the expression ofPRRX1, ZEB1, Twist, Slug and Snail, among which the level of PRRX1 changed the most obviously. Overexpression of PRRX1 restored migration and invasion in FASN knockdown cells, indicating that PRRX1 is an important downstream target of FASN signalling. Levels of cyclin D1 and c‐Myc, targets of Wnt/β‐catenin pathway, were significantly decreased by FASN silencing and restored by PRRX1 overexpression. In addition, FASN expression was positively associated with metastasis and poor prognosis of SACC patients as well as with the expression of PRRX1, cyclin D1 and c‐Myc in SACC tissues. Our findings revealed that FASN in SACC progression may induce EMT in a PRRX1/Wnt/β‐catenin dependent manner. [ABSTRACT FROM AUTHOR]

Background: Accumulating works show that lncRNAs play critical roles in the development of gastric cancer (GC). LncRNA HLA complex group 18 (HCG18) was implicated in the progression of bladder cancer and glioma, but its role in GC is unknown. Methods: RT‐PCR was used to detect HCG18 and miR‐141‐3p expression in GC specimen. GC cell lines (AGS and MKN‐28) were exploited as cell model. The biological effect of HCG18 on cancer cells was probed by CCK‐8, colony formation, flow cytometry, Transwell and wound‐healing experiments in vitro, and subcutaneous xenotransplanted tumor model and tail vein injection model in vivo. Interaction between HCG18 and miR‐141‐3p was determined by bioinformatics analysis, RT‐PCR, and luciferase reporter experiments. Downstream gene expression of miR‐141‐3p, including Wiskott–Aldrich syndrome protein interacting protein family member 1 (WIPF1), Yes associated protein 1 (YAP), and tafazzin (TAZ) were detected using Western blot. Results: HCG18 was markedly up‐regulated in GC specimens, while miR‐141‐3p was markedly down‐regulated. Down‐regulation of HCG18 inhibited viability, migration, and invasion of GC cells, while miR‐141‐3p transfection led to opposite effect. HCG18 could down‐regulate miR‐141‐3p through adsorbing it, and a negative association between HCG18 and miR‐141‐3p was found in GC specimens. HCG18 promoted WIPF1, YAP and TAZ expression, nonetheless, such influence was reversed by co‐transfecting with miR‐141‐3p. Conclusion: HCG18 was aberrantly up‐regulated in GC tissues, and it indirectly regulated the activity of Hippo signaling through counteracting miR‐141‐3p expression. [ABSTRACT FROM AUTHOR]

A phytochemical investigation on the stems of Mappianthus iodoides led to the isolation of a new naturally occurring prenylated isoflavone, mappianthone A (1), together with seven known analogues (2−8). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparison with data reported in the literature. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1−8 showed significant antiproliferative effects against several human cancer cell lines with IC50 values ranging from 0.16 to 12.68 μM. [ABSTRACT FROM AUTHOR]

Five new α-tetralone glycosides, juglanbiosides A-E (1–5), together with an α-tetralone derivative (15) and nine known 1,4-naphthoquinones (6–14) were isolated from the 95% EtOH extract of green walnut husks of Juglans mandshurica Maxim. Their structures were elucidated by comprehensive spectroscopic methods (1H, 13C NMR, DEPT, HSQC, HMBC, CD, HR-ESI-MS). In vitro cytotoxicities of all the isolated compounds were evaluated against BGC-823, HCT-15 and K562 cancer cell lines. [ABSTRACT FROM AUTHOR]

A new naturally occurring trinoreudesmane sesquiterpene, artahongkongol A (1), together with seven known eudesmane sesquiterpenes (2−8), was isolated from the stems and leaves of Artabotrys hongkongensis Hance. Among them, 1 is a rare trinoreudesmane sesquiterpene containing 12 carbon atoms on the carbon skeleton. All known compounds (2−8) were isolated from the genus Artabotrys for the first time. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1−8 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.57 to 15.68 μM. [ABSTRACT FROM AUTHOR]

Background: Both salinomycin (SAL) and sulforaphane (SFN) exert their antitumorigenic effects in various types of cancer We investigated whether combining salinomycin (SAL, an antibiotic ionophore) with sulforaphane (SFN, a phytochemical) exerted synergistic antiproliferative and proapoptotic activities in colorectal cancer (CRC) cells in vitro and in vivo by evaluating the proliferative and apoptotic responses of two CRC cell lines. Materials and Methods: The combination index (CI) was calculated using the Chou-Talalay method, and the effects of the synergistic combination (CI< 1) of lower doses of SAL and SFN were selected for further studies. Anti-tumor effect of the combination of SAL and SFN was tested both in vitro and in vivo. Results: Cotreatment effectively inhibited proliferation, migration and invasion and enhanced apoptosis. The xenograft model also showed similar results. Furthermore, we evaluated the molecular mechanism behind SAL- and SFN-mediated CRC cell apoptosis. The combination treatment induced apoptosis in Caco-2 and CX-1 cells by inhibiting the PI3K/Akt pathway, which increased the expression of the tumor suppressor protein p53. The treatment also decreased the expression of the survival protein Bcl-2 and increased the expression of the proapoptotic protein Bax, which increased the Bax/Bcl-2 ratio, as well as enhanced poly ADP-ribose polymerase (PARP) cleavage. Upon inhibiting the PI3K/Akt pathway with LY294002 prior to cotreatment, we detected enhanced PARP cleavage compared to that in the cotreatment only group. Conclusion: We investigated whether the combination of SAL and SFN had antiproliferative and proapoptotic effects in CRC cells both in vitro and in vivo. Cotreatment also significantly decreased migration and invasion compared to that of the control and SAL or SFN monotherapies. This novel combination of SAL and SFN might provide a potential strategy to treat CRC. [ABSTRACT FROM AUTHOR]

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2‐AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 μg kg−1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF‐7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF‐7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P =.0024; migration, 15.90% vs 3.25%, P =.0015; invasion, 8.17% vs 2.13%, P =.04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF‐7 cells. Clinical trial registration: NCT03108937. [ABSTRACT FROM AUTHOR]

A phytochemical investigation on the stems and leaves of Clausena emarginata led to the isolation of a previously undescribed carbazole alkaloid, clausemargine A (1), together with 11 known analogues (2–12). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2–12) were isolated from C. emarginata for the first time. All isolated compounds were evaluated for their their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–12 showed significant antiproliferative effects with IC50 values ranging from 0.28 to 15.18 μM. [ABSTRACT FROM AUTHOR]

Introduction: ephrinA1 plays important roles in tumor angiogenesis. Matrix metalloproteases (MMPs) can cleave ephrinA1 from the cell membrane into extracellular environment. However, how soluble ephrinA1 is modulated by hypoxia and whether MMPs participate in this hypoxic process remains to be investigated in detail. Methods: Thirty-seven patients with oral squamous cell carcinoma (OSCC) were included in the present study for HIF-1α, MMP-2, MMP-9 and ephrinA1 detection by immunohistochemistry. Serum samples from 35 patients were collected both preoperatively and postoperatively to confirm the existence of soluble ephrinA1 by ELISA. Block assay and Western blot analysis were further carried out to elucidate the proteolysis mechanism of ephrinA1 under hypoxic condition in vitro. Results: Our data demonstrated that HIF-1α, MMP-2, MMP-9 and ephrinA1 expressed positively, and correlated with microvessel density in OSCCs, except for MMP-9. The serum expression level of ephrinA1 in OSCC patients decreased significantly after surgical removal of the solid tumors. In vitro experiments indicated that GM6001, a MMP-specific inhibitor, could reduce hypoxia-induced soluble ephrinA1 secretion from SCC cells. Further Western blot analysis confirmed that both HIF-1α and MMP-2 were up-regulated by hypoxia in a similar time-dependent manner, with the MMP-9 expression unchanged during this course. Conclusion: These results suggested a possible novel mechanism that ephrinA1 secretion is mediated by HIF-1α/MMP-2 signaling cascade which may play pivotal roles in OSCC neovascularization in a paracrine manner. [ABSTRACT FROM AUTHOR]

A phytochemical investigation on the stems and leaves of Clausena lenis led to the isolation of a new furanocoumarin, clauselenisin A (1), together with five known analogues (2–6). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2–6) were isolated from C. lenis for the first time. All isolated compounds were evaluated for their their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–6 showed significant antiproliferative effects with IC50 values ranging from 0.36 to 16.48 μM. [ABSTRACT FROM AUTHOR]

Abstract We report here the synthesis, characterization of seventeen (E)-2-methyl-3-ferrocenyl- N -acrylamides. The single crystal structures of the key intermediate b and two target compounds d5 and d6 were confirmed by X-ray crystallographic analysis. Antitumor activity of all compounds was tested in vitro. Compound d1 was the most significant one against B16 F10 cell line, indicating that it could be a good candidate for further study. Furthermore, cancer cell apoptosis assay was performed and the result indicated that compound d1 effectively fueled B16 F10 cells apoptosis in a dose-dependent manner. Graphical abstract Image 1 Highlights • Total seventeen (E)-2-methyl-3-ferrocenyl- N -acrylamides were synthesized. • Compounds b , d5 and d6 were confirmed by X-ray crystallographic diffraction. • d1 exhibited significant antitumor activity and effectively fueled cells apoptosis. [ABSTRACT FROM AUTHOR]

Phytochemical investigation on the stems and leaves of Trigonostemon howii resulted in the isolation of a new abietane diterpenoid, trigohowimine A (1), along with seven known structurally diverse diterpenoids (2–8). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparison with data reported in the literature. New compound 1 was evaluated for its cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480. Compound 1 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.82 to 8.53 μM. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) is essential in regulation of cancer cell and cancer stem cells (CSCs) behaviour. Linc00662 is a newly identified human lung cancer related lncRNA. In this study, we aimed to explore the function of Linc00662 in human lung cancer. The expression level of Linc00662 was analysed by quantitative real-time PCR. Cell metastasis and invasive ability were detected by transwell and scratch wound healing assays. The stemness of CSCs was shown by tumorsphere formation assay and flow cytometry. The interaction between Linc00662 and Lin28 was confirmed by RNA immunoprecipitation and RNA pulldown assay. Overexpression of Linc00662 promoted the poor prognosis of lung cancer. Cell invasion, metastasis and CSCs stemness in H1299 and A549 could be influenced by Linc00662. Linc00662 had direct interaction with Lin28, and the Linc00662 function was dependent on Lin28. We demonstrate that overexpression of Linc00662 enhances lung cancer cell metastasis and CSC stemness by interacting with Lin28 in human lung cancer, which could be utilized as a potential diagnostic and therapeutic target for lung cancer patients. [ABSTRACT FROM AUTHOR]

Two novel γ -lactone derivatives, trigoheterophines A ( 1 ) and B ( 2 ), together with four known furan derivatives ( 3 – 6 ), were isolated from the stems and leaves of Trigonostemon heterophyllus . The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A ( 1 ) and B ( 2 ) represent an unusual type of γ -lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds ( 3 – 6 ) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . Compounds 1 – 6 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ -lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents. [ABSTRACT FROM AUTHOR]

Period 2 (per2) is a core circadian clock gene. Dysregulation of the per2 gene has been identified in a number of types of human cancer and may be associated with a poor prognosis. To confirm the influence of per2 gene on MNNG/HOS human osteosarcoma cells, small interfering (si)RNA against per2 or plasmids containing per2 were transfected into MNNG/HOS cells, and the proliferation, apoptosis and migration were observed. The present study demonstrated that per2 knockdown significantly enhanced MNNG/HOS cell proliferation and migration and protected MNNG/HOS cells from apoptosis. Per2 overexpression inhibited MNNG/HOS cell proliferation and migration and promoted apoptosis. Furthermore, the protein expression of phosphorylated (p)-protein kinase B (Akt) and Bcl-2 were inhibited in per2-overexpressing cells, while the expression of p27, p21 and cleaved caspase-3 was promoted. In contrast, the expression of p-Akt and Bcl-2 was promoted in per2-knockdown cells, and p27, p21 and cleaved caspase-3 were decreased. This initial study may provide an alternative therapeutic strategy for the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of chitinase-3-like protein 1 (YKL-40) gene RNA interference on the biological behaviors and enhanced chemosensitivity of endometrial cancer (EC) HEC-1A cells. YKL-40 small interfering (si)RNA was transduced into EC HEC-1A cells using a lentivirus. The experiment was divided into three groups: The experimental group was transfected with YKL-40 siRNA (si-YKL-40); the mock-treatment group was transfected with transfection reagent only; and the blank control group was left untreated. A reverse transcription-quantitative polymerase chain reaction was performed to investigate the mRNA expression levels of YKL-40. The biological behaviors, including cell proliferation, migration, invasion and apoptosis, were detected by MTT and Transwell assays, and flow cytometry (FCM) analysis, respectively. The results of the present study demonstrated that the mRNA expression levels of YKL-40 were downregulated within HEC-1A cells upon transfection with si-YKL-40 (P<0.05). The proliferative, migratory and invasive abilities of HEC-1A cells were inhibited by si-YKL-40 (P<0.05). The mRNA expression levels of YKL-40 were upregulated within HEC-1A cells following treatment with cisplatin (P<0.05). FCM analysis revealed that the average cellular apoptosis rate increased following the inhibition of YKL-40 gene expression via siRNA (P<0.05). Therefore, the YKL-40 gene may be associated with the proliferative, migratory, invasive and anti-apoptotic ability of HEC-1A cells. YKL-40 downregulation may enhance the sensitivity of human EC HEC-1A cells to chemotherapy. [ABSTRACT FROM AUTHOR]

Mitofusin 2 (Mfn2) is expressed in numerous human tissues and serves a pivotal role in cell proliferation. However, Mfn2 is considered as an anti-tumor gene, and is silenced in human malignant tumors, including those of breast cancer. However, the mechanisms contributing to Mfn2 silencing and the mechanism of its anti-tumor function in breast cancer remain unclear. In the present study, hypoexpression of Mfn2, and hypermethylation of its promoter, was confirmed in human breast cancer cells and in breast cancer tissues by reverse transcription-quantitative polymerase chain reaction (PCR) and methylation specific PCR, respectively. Chemical demethylation treatment with 5-aza-2'-deoxycytidine upregulated the mRNA expression level of Mfn2 in MCF-7 cells in a dose-dependent manner. In addition, overexpression of Mfn2 repressed the proliferation, migration and invasion of MCF-7 cells, mediated by inhibition of the Ras-extracellular signal-regulated kinase (ERK)1/2 signaling pathway. However, overexpression of Mfn2 with deletion of the p21Ras motif (Mfn2ΔRas) and protein kinase A (PKA) phosphorylation site (Mfn2ΔPKA) partially reduced the anti-tumor function of Mfn2, and inhibited the Ras-ERK1/2 signaling pathway. Taken together, the present study confirmed the anti-tumor effects of Mfn2 in human breast cancer and clarified that the mechanism of its anti-tumor functions includes promoter DNA methylation, the P21Ras binding site and PKA phosphorylation. [ABSTRACT FROM AUTHOR]

Five new carbazole alkaloids, clausehainanines A-E ( 1–5 ), together with seven known analogues ( 6–12 ) were isolated from the stems and leaves of C. hainanensis . Their structures were elucidated by extensive spectroscopic methods. Among them, compounds 1–5 were an unusual type of carbazole alkaloids, possessing diverse isopentenyl derivatives as substituents at C-2. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . Alkaloids 1–12 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.12 to 15.56 μM. These findings suggest that the discoveries of these carbazole alkaloids with significant cytotoxic activities isolated from C. hainanensis could be of great importance to the development of new anticancer agents. [ABSTRACT FROM AUTHOR]

The risk of seizure is increased following brain surgery such as cranioplasty. Patients with seizures that are treated with valproic acid (VPA) may have a decreased risk of further seizures. To verify microRNA (miR)-155 as a potential biomarker for the occurrence of seizures, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used. Computational analysis and luciferase reporter assay was performed to identify the putative target of miR-155. RT-qPCR and western blot analyses were used to determine the expression level of miR-155, sodium voltage-gated channel a subunit 1 (SCN1A) mRNA and protein. RT-qPCR analysis indicated that miR-155 levels in patients who experienced seizures increased 2.45-fold compared with patient who did not experience seizures, indicating miR-155 may be a potential biomarker for the occurrence of seizures. SCN1A was identified as a target gene of miR-155; the luciferase reporter assay revealed a negative regulatory relationship between miR-155 and SCN1A. The expression of SCN1A mRNA of patients receiving VPA was higher compared with the control group patients. Furthermore, the expression levels of SCN1A mRNA and protein were reduced or elevated following transfection with miR-155 mimics or inhibitors, respectively, compared with the scramble control. Furthermore, a concentration-dependent effect of miR-155 on the expression of SCN1A was observed. In conclusion, miR-155 may be associated with the risk of seizure and SCN1A may be a target gene of miR-155. Downregulation of microRNA-155 by preoperative administration of VPA may prevent postoperative seizure by upregulating the expression of SCN1A. [ABSTRACT FROM AUTHOR]

Three new dihydrobenzofuran neolignans, mappiodoinins A-C ( 1 - 3 ), together with nine known analogues ( 4  - 12 ) were isolated from the stems and leaves of Mappianthus iodoies . Their structures with the absolute configurations were elucidated by extensive spectroscopic methods. This is the first time to find dihydrobenzofuran neolignans from the genus Mappianthus. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW-480 in vitro . Neolignans 1 - 12 showed significant cytotoxic effects against various human cancer cell lines with IC 50 values ranging from 0.16 to 18.62 μM. [ABSTRACT FROM AUTHOR]

Twenty-six novel isosteviol derivatives coupled with two types of nitric oxide ( NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan-based derivatives ( 8a, 8b, 8c, 8d, 8e, 9e, and 9f) exhibited desirable cytotoxic activities, while NONOate-based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 ( 8a, IC50 = 0.48 ± 0.02 μ m; 8e, IC50 = 0.94 ± 0.01 μ m); compounds 8b and 8d were more potent on HCT116 ( IC50 = 3.39 ± 0.06 and 3.29 ± 0.03 μ m), HepG2 ( IC50 = 1.05 ± 0.03 and 5.37 ± 0.08 μ m), and SW620 ( IC50 = 1.33 ± 0.02 and 4.11 ± 0.05 μ m) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC50 = 4.76 ± 0.14 μ m. NO-releasing experiment of compounds 8a- e, 17a, 18a, 19a, and 21a reminded us that NO-releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities. [ABSTRACT FROM AUTHOR]

Double-stranded DNA breaks induce serine phosphorylation of histone H2A.X, producing γ-H2A.X foci that are then recognized by DNA damage response pathway proteins. Formation of γ-H2A.X is therefore critical for the repair of DNA double-stranded breaks and maintenance of genomic stability, and defects in the recognition or repair of double-stranded breaks can result in tumorigenesis. However, key details regarding the formation of γ-H2A.X and its possible role in tumorigenesis remain elusive. Here, we report a previously unknown phosphorylation site on H2A.X, Tyr39. Phosphorylation at this site is induced by ionizing radiation and is a prerequisite for γ-H2A.X formation. Increased phosphorylation of H2A.X at Tyr39 was observed in multiple cancer cell lines, and we found that H2 AX Tyr39 phosphorylation positively correlated with histological grade, tumor size and tumor node metastasis stage, and negatively correlated with survival. We also identified a potential role for eyes absent 2 ( EYA2) in regulating H2A.X Tyr39 phosphorylation. Our study supports an important role for H2 AX Tyr39 phosphorylation in γ-H2A.X formation and cancer progression. [ABSTRACT FROM AUTHOR]

DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients. [ABSTRACT FROM PUBLISHER]

Cancer cells and their stromal microenvironment are mutually supportive. Either destroying cancer cells or damaging stromal components cannot guarantee a satisfactory outcome in the long-term treatment. Herein, we showed that the tumor-stroma crosstalk was disturbed by nanoparticle-based photodynamic therapy (PDT) in pancreatic tumor models, leading to the persistent inhibition of extracellular matrix (ECM) secretion and the enhanced therapeutic effect. By employing a conditioned medium method, we found that the nanoparticulate PDT at a sub-lethal dosage down-regulated TGFβ signaling pathways, leading to the decrease in drug resistance, proliferation, and migration of the cancer cells. Meanwhile, pancreatic stellate cells (PSCs) were inactivated by PDT, hindering the secretion of ECM. Combining the results that PDT indiscriminately killed PSCs and cancer cells, we showed that the mutual support between the cancer cells and the stroma was interrupted. We further presented the inhibition of the crosstalk persistently enhanced tumor penetration in stroma-rich pancreatic tumor models. The loosened stroma not only facilitated tumor eradication by subsequent therapy but also improved the efficiency of gemcitabine treatment on monthly later recurrent tumors. Therefore, our work may boost the potential of PDT to be a valuable individual or adjuvant treatment for desmoplastic cancers. [Display omitted] [ABSTRACT FROM AUTHOR]

The study is aimed at studying the effects of soluble and insoluble oat β-glucan on colon carcinogenesis in mice. One hundred and twenty male Kunming mice were divided into normal control (NC), model control (MC), high doses (100 mg/kg body weight) of soluble (H-SOG) and insoluble β-glucan (H-IOG), and low doses (50 mg/kg body weight) of soluble (L-SOG) and insoluble β-glucan (L-IOG) groups. The mice except those in the NC group were given subcutaneous injections of DMH to induce colon cancer. The bile acid content was significantly reduced but the colonic short-chain fatty acid content was enhanced (p < .05) in mice administered β-glucan, moreover, the tumor cells apoptosis was significantly promoted (p < .05), compared to the MC group. The effect of high doses β-glucan was better than the low doses, but there is little difference between the SOG and IOG. Results suggested that both SOG and IOG exert favorable effects in preventing colon cancer in a doses-dependent manner while the specific mechanism maybe different. [ABSTRACT FROM AUTHOR]

Eight undescribed steroidal saponins named solasaponins A-H were isolated from the fruits of Solanum xanthocarpum , including an unusual 16,26-epoxy-furostanol saponin, two furostanol saponins, three isospirostanol saponins, two pseudo-spirostanol saponins. The structures of all compounds were elucidated by extensive spectroscopic data analyses (1D, 2D NMR, and HRESIMS) combined with physico-chemical analysis methods (acid hydrolysis, optical rotation, and IR). The cytotoxicities of all compounds in vitro against two human cancer cell lines (A-549 and HepG2) were evaluated by CCK-8 assay. [Display omitted] • Eight undescribed steroidal saponins were obtained from Solanum xanthocarpum fruits. • Solasaponins A with the undescribed 16,26-epoxy-furostanol carbon skeleton was disclosed. • Some compounds revealed significant cytotoxic activity (＜10 μ M). [ABSTRACT FROM AUTHOR]

Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH-sensitive copolymer poly(2-ethyl-2-oxazoline)-poly( d , l -lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28 nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin α v β 3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK-conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin α v β 3 -rich prostate cancers. [ABSTRACT FROM AUTHOR]

Here, we report a self-supported nanoporous gold microelectrode decorated with well-dispersed and tiny platinum nanoparticles as an electrochemical nonenzymatic hydrogen peroxide biosensor. Nanoporous gold was fabricated by electrochemical alloying/dealloying and then small-sized platinum nanoparticles were electrodeposited uniformly on them. This novel hybrid nanostructure endows the sensor with high sensitivity and selectivity towards the reduction of hydrogen peroxide with a low detection limit of 0.3 nM. The sensor has been successfully applied for the measurement of H2O2 release from a single isolated human breast cancer cell, demonstrating its great potential for further physiological and pathological applications. [ABSTRACT FROM AUTHOR]