Three-component reductive conjugate addition/aldol tandem reaction enabled by nickel/photoredox dual catalysis.

A three-component reductive cross-coupling of aryl halides, aldehydes, and alkenes by nickel/photoredox dual catalysis is disclosed. The key to success for this tandem transformation is to identify α-silylamine as a unique organic reductant, which releases silylium ions instead of protons to prevent unwanted protonation processes, and meanwhile serves as Lewis acid to activate aldehydes in situ. This dual catalytic protocol completes a traditional conjugate addition/aldol sequence that eliminates the requirement of organometallic reagents and metal-based reductants, thus providing a mild synthetic route to highly valuable ß-hydroxyl carbonyl compounds with contiguous 1,2-stereocenters.

Iridoid compounds from the aerial parts of Swertia mussotii Franch. with cytotoxic activity.

One new secoiridoid compound swertiamarin B (1), along with a known compound lytanthosalin (2), were isolated from ethanol extract of the aerial parts of Swertia mussotii. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. All compounds were first isolated from the Swertia genus. Their antitumor activities were evaluated for four human tumor cell lines (HCT-116, HepG2, MGC-803 and A549). Compounds 1 and 2 showed excellent cytotoxic activities toward the MGC-803 cell lines with IC50 values 3.61 and 12.04 µM, respectively.

Piezo1 regulates migration and invasion of breast cancer cells via modulating cell mechanobiological properties.

Cell migration and invasion are two essential processes during cancer metastasis. Increasing evidence has shown that the Piezo1 channel is involved in mediating cell migration and invasion in some types of cancers. However, the role of Piezo1 in the breast cancer and its underlying mechanisms have not been clarified yet. Here, we show that Piezo1 is high-expressed in breast cancer cell (BCC) lines, despite its complex expression in clinical patient database. Piezo1 knockdown (Piezo1-KD) promotes unconfined BCC migration, but impedes confined cell migration. Piezo1 may mediate BCC migration through the balances of cell adhesion, cell stiffness, and contractility. Furthermore, Piezo1-KD inhibits BCC invasion by impairing the invadopodium formation and suppressing the expression of metalloproteinases (MMPs) as well. However, the proliferation and cell cycle of BCCs are not significantly affected by Piezo1. Our study highlights a crucial role of Piezo1 in regulating migration and invasion of BCCs, indicating Piezo1 channel might be a new prognostic and therapeutic target in BCCs.

A function of fascin1 in the colony formation of mouse embryonic stem cells.

Fascin1 is known to participate in the migration of cancer cells by binding to actin filaments. Recent studies evidenced that fascin1 also modulates processes such as the tumorigenesis and maintenance of pluripotency genes in cancer stem cells. However, the function of fascin1 in embryonic stem cells remains unclear. In this article, we report that fascin1 is highly expressed and widely distributed in mouse embryonic stem cells (mESCs), which are regulated by JAK-STAT3 and ß-catenin. We found that the overexpression of fascin1 impairs the formation of mESC colonies via the downregulation of intercellular adhesion molecules, and that mimicking the dephosphorylated mutation of fascin1 or inhibiting phosphorylation with Gö6983 significantly enhances colony formation. Hyperphosphorylated fascin1 can promote the maintenance of pluripotency in mESCs via nuclear localization and suppressing DNA methyltransferase expression. Our findings demonstrate a novel function of fascin1, as a vital regulator, in the colony formation and pluripotency of mESCs and provide insights into the molecular mechanisms underlying embryonic stem cell self-organization and development in vitro.

Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning.

Aqueous solubility is an important physicochemical property of compounds in anti-cancer drug discovery. Artificial intelligence solubility prediction tools have scored impressive performances by employing regression, machine learning, and deep learning methods. The reported performances vary significantly partly because of the different datasets used. Solubility prediction on novel compounds needs to be improved, which may be achieved by going deeper with deep learning. We constructed deeper-net models of ~20-layer modified ResNet convolutional neural network architecture, which were trained and tested with 9,943 compounds encoded by molecular fingerprints. Retrospectively tested by 62 recently-published novel compounds, one deeper-net model outperformed four established tools, shallow-net models, and four human experts. Deeper-net models also outperformed others in predicting the solubility values of a series of novel compounds newly-synthesized for anti-cancer drug discovery. Solubility prediction may be improved by going deeper with deep learning. Our deeper-net models are accessible at http://www.npbdb.net/solubility/index.jsp.

Heat Stress-Induced Multiple Multipolar Divisions of Human Cancer Cells.

Multipolar divisions of heated cells has long been thought to stem from centrosome aberrations of cells directly caused by heat stress. In this paper, through long-term live-cell imaging, we provide direct cellular evidences to demonstrate that heat stress can promote multiple multipolar divisions of MGC-803 and MCF-7 cells. Our results show that, besides facilitating centrosome aberration, polyploidy induced by heat stress is another mechanism that causes multipolar cell divisions, in which polyploid cancer cells engendered by mitotic slippage, cytokinesis failure, and cell fusion. Furthermore, we also find that the fates of theses polyploid cells depend on their origins, in the sense that the polyploid cells generated by mitotic slippage experience bipolar divisions with a higher rate than multipolar divisions, while those polyploid cells induced by both cytokinesis failure and cell fusion have a higher frequency of multipolar divisions compared with bipolar divisions. This work indicates that heat stress-induced multiple multipolar divisions of cancer cells usually produce aneuploid daughter cells, and might lead to genetically unstable cancer cells and facilitate tumor heterogeneity.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Swertia mussotii extracts induce mitochondria-dependent apoptosis in gastric cancer cells.

Swertia mussotii (Gentianaceae) is a traditional Chinese medicinal plant grown in the Qinghai-Tibet Plateau. Three fractions from S. mussotii extract, named SWF50, SWF 70 and SWF100, were screened for in vitro anti-proliferative activity on two gastric cancer cell lines, MGC-803 and BGC-823 cells using MTT assay. Our results demonstrated that SMF70 showed an anti-proliferative effect in MGC-803 cells and SMF100 showed an anti-proliferative effect in BGC-823 cells in vitro. Moreover, both two fractions induced apoptosis via depolymerization of cytoskeletal filaments, increased cytoplasmic levels of ROS and Ca2+ and disrupted mitochondrial transmembrane potential. In addition, flow cytometry analysis indicated that both two fractions could induce cell apoptosis and arrest the cell cycle at S phase. Our results indicate that SMF70 induces apoptosis of MGC-803 cells and SMF100 induces apoptosis of BGC-823 cells via a mitochondrial-dependent pathway. Meanwhile, we also investigated antitumor effect of SMF70 in vivo, and exhibited effective tumor growth inhibition. Our findings demonstrate that S. mussotii extracts could be a potential new alternative therapeutic agent gastric cancer.

Changes of ferrous iron and its transporters after intracerebral hemorrhage in rats.

OBJECTIVE: Ferrous iron is a major source inducing oxidative stress after intracerebral hemorrhage (ICH). Divalent metal transporter1 (DMT1) is the important and well-known plasma membrane transport protein which was proved to be involved in the transport of free ferrous iron in mammals. Ferroportin 1 (FPN1) is the unique exporter of ferrous iron from mammalian cells. The role of DMT1 and FPN1 in brain after ICH is still not elucidated. Therefore, we measure the expression of DMT1 and FPN1, to explore the correlations between ferrous iron and its specific transporters after ICH. METHODS: Ninety-six Sprague-Dawley rats received intra-striatal infusions of 0.5 U type IV collagenase to establish ICH model. Ferrous iron content in brain was determined using Turnbull's method. DMT1 and FPN1 expression were examined by immunohistochemical staining and Real-Time quantitative polymerase chain reaction (RT-PCR). With the use of confocal laser microscopy, we determined the colocalization of DMT1 and FPN1 at 1, 3, 7 and 14 days after ICH. RESULTS: Ferrous iron deposition was shown in the perihematomal zone as early as 1 day after ICH; it reached a peak after 7 days and was not elevated within 14 days following ICH. The expression of the DMT1 upregulated and reached to peak at day 7 after ICH. FPN1 reached a plateau at 3 days post-ICH. Expression levels of DMT1 and FPN1 were in parallel with ferrous iron deposition. There was a positive correlation between FPN1 and DMT1. DMT1 mainly localized in the cytoplasm of glias and neurons. FPN1 were mostly distributed on the membrane of endothelial cells and glias. Confocal microscope showed that DMT1 colocalized with FPN1. CONCLUSIONS: DMT1 and FPN1 are positively influenced by ferrous iron status in brain after ICH. DMT1 and FPN1 attenuate iron overload after ICH via increasing transmembrane iron export.

Coexpression of the mutated BRCA1 mRNA and p53 mRNA and its association in Chinese prostate cancer.

The mutations of BRCA1 and p53 genes have been simultaneously characterized in many tumors. However, their coexpression and associations have not been investigated quantitatively in prostate cancer. In the present study, the expressions of the mutated BRCA1 mRNA and p53 mRNA were examined in 48 Chinese prostate cancer cases and 10 corresponding adjacent benign tissues with in situ hybridization. The 5-year survival rates of the corresponding patients after operation were investigated. The results showed that the positive expressions of the mutated BCRA1 mRNA and p53 mRNA are involved in prostate cancer (P < 0.05). Moreover, there is a closed negative association between the expressions of the mutated BRCA1 gene and p53 gene in the mRNA level with the progression, angiogenesis, metastasis, and survival rate of prostate cancer. Their coexpression and negative association suggest that the two altered tumor suppressor genes might interact functionally in prostate cancer to provide a potential signal determining a prognosis of the tumor metastasis and survival rate. Further work will be done to elucidate the interaction mechanisms in prostate cancer.

Preparation and drug release characteristics of Pingyangmycin-loaded dextran cross-linked gelatin microspheres for embolization therapy.

Gelatin microspheres (GMs) containing Pingyangmycin hydrochloride were prepared for the interventional embolization by a double-phase emulsified thermal gelation method using oxidized dextran (ox-dex) as the cross-linking agent. The average diameter of the microspheres was 82 microm with 74% ranging from 50-200 microm. Drug content and the characteristics of drug release in vitro and in vivo were evaluated using UV-spectroscopy and HPLC, respectively. The prepared microspheres showed a rather high percentage of encapsulation ranging from 85 to 88% and drug content at 7.2%. The results of in vitro experiments showed that about 65.5% of the total amount of the encapsulated drug was released after 6 h at 37 degrees C. Experiments conducted through artery perfusion and artery embolization in rabbits revealed that the local drug concentration was significantly higher than the systemic blood-drug concentration, with a high level of local drug concentration maintained for more than 120 min after artery embolization with the Pingyangmycin-loaded ox-dex-GMs. The results indicated that the external carotid artery embolization with Pingyangmycin-loaded ox-dex-GMs at reduced dosages prolonged the local drug concentration at a higher level, and could achieve the purpose of a localized targeting tumor therapy. Compared with other embolization materials, ox-dex-GMs are an excellent alternative interventional embolization material for the treatment of head and neck tumors.