Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR.

BACKGROUND: Fentanyl is an opioid analgesic and is widely used in ovarian cancer patients for pain management. Although increasing evidence has suggested the direct role of fentanyl on cancer, little is known on the effect of fentanyl on ovarian cancer cells. METHODS: Proliferation, migration and apoptosis assays were performed in ovarian cancer cells after fentanyl treatment. Xenograft mouse model was generated to investigate the in vivo efficacy of fentanyl. Combination index was analyzed for the combination of fentanyl and chemotherapeutic drugs. Immunoblotting approach was used to analyze signaling involved in fentanyl's action focusing on EGFR. RESULTS: Fentanyl at nanomolar concentration does-dependently increased migration and proliferation of a panel of ovarian cancer cell lines. Fentanyl at the same concentrations either did not or stimulated proliferation to a less extent in normal cells than in ovarian cancer cells. Consistently, fentanyl significantly promoted ovarian cancer growth in vivo. The combination of fentanyl with cisplatin or paclitaxel was antagonist in inhibiting cell proliferation. Although fentanyl did not affect cell apoptosis, it significantly alleviated ovarian cancer cell death induced by chemotherapeutic drugs. Mechanistically, fentanyl specifically activated EGFR and its-mediated downstream pathways. Knockdown of EGFR abolished the stimulatory effects of fentanyl on ovarian cancer cells. We finally demonstrated that the activation of EGFR by fentanyl is associated with opioid µ receptor system. CONCLUSIONS: Fentanyl activates ovarian cancer via simulating EGFR signaling pathways in an opioid µ receptor-dependent manner. The activation of EGFR signaling by fentanyl may provide a new guide in clinical use of fentanyl in ovarian cancer patients.

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade.

BACKGROUND: Substantial clinical and preclinical evidence have indicated the association between amide-linked local anesthesia and the long-term outcomes of cancer patients. However, the potential effects of local anesthesia on cancer recurrence are inconclusive and the underlying mechanisms remain poorly understood. METHODS: We systematically examined the effects of three commonly used local anesthetics in melanoma cells and analyzed the underlying mechanisms focusing on small GTPases. RESULTS: Ropivacaine and lidocaine but not bupivacaine inhibited migration and proliferation, and induced apoptosis in melanoma cells. In addition, ropivacaine and lidocaine but not bupivacaine significantly augmented the in vitro efficacy of vemurafenib (a B-Raf inhibitor for melanoma with BRAF V600E mutation) and dacarbazine (a chemotherapeutic drug). Mechanistically, ropivacaine but not bupivacaine decreased the activities of Ras superfamily members with the dominant inhibitory effects on RhoA and Ras, independent of sodium channel blockade. Rescue studies using constitutively active Ras and Rho activator calpeptin demonstrated that ropivacaine inhibited migration mainly through RhoA whereas growth and survival were mainly inhibited through Ras in melanoma cells. We further detected a global reduction of downstream signaling of Ras and RhoA in ropivacaine-treated melanoma cells. CONCLUSION: Our study is the first to demonstrate the anti-melanoma activity of ropivacaine and lidocaine but not bupivacaine, via targeting small GTPases. Our findings provide preclinical evidence on how amide-linked local anesthetics could affect melanoma patients.

Ropivacaine inhibits the migration of esophageal cancer cells via sodium-channel-independent but prenylation-dependent inhibition of Rac1/JNK/paxillin/FAK.

The direct anti-proliferative and pro-apoptotic effects of local anesthetics have been well documented in various cancers. However, whether local anesthetics affect cancer metastasis and their underlying molecular mechanisms are not well understood. In this work, we show that ropivacaine at the clinically relevant concentration significantly inhibits esophageal cancer cell migration. Interestingly, ropivacaine at the same concentration does not display inhibitory effects on esophageal cancer cell growth and survival. We further demonstrate that ropivacaine significantly decreases activities of GTPases including RhoA, Rac1 and Ras, and inhibits prenylation in esophageal cancer cells. In addition, the inhibitory effects of ropivacaine on GTPases activities and migration are abolished in the presence of geranylgeraniol and farnesol, demonstrating that ropivacaine inhibits GTPases activities via prenylation inhibition. Finally, we demonstrate that ropivacaine-inhibited esophageal cancer cell inhibition occurs independently of sodium channel but via suppressing Rac1/JNK/paxillin/FAK pathway. Our work demonstrates the potent anti-migratory effect of ropivacaine in esophageal cancer by attenuating prenylation-dependent migratory signalling events. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect metastasis.

A high-performance nanobridged MoO3 UV photodetector based on nanojunctions with switching characteristics.

Ultraviolet photodetectors (UVPDs) were fabricated via the in situ growth of orthorhombic MoO3 nanobelts among interdigital electrodes. Two types of nanojunction, touching and interpenetration, were formed between neighboring nanobelts at different growth conditions. The photoresponse mechanism of the UVPDs greatly depends on the type of nanojunction. Nanojunctions formed with touching nanobelts possess switching characteristics due to the barrier height variation along with the UV illumination. The UVPD with the touching structure exhibits low noise, high UV sensitivity and fast speed, having a dark current of 1.4 nA, an on/off ratio of over 100 and a response time of below 1 s, at an applied voltage of 10 V. The enhanced performance can be attributed to the switching characteristics of the touching nanojunction.

Dark current suppression of MgZnO metal-semiconductor-metal solar-blind ultraviolet photodetector by asymmetric electrode structures.

The application of asymmetric Schottky barrier and electrode area in an MgZnO metal-semiconductor-metal (MSM) solar-blind ultraviolet photodetector has been investigated by a physical-based numerical model in which the electron mobility is obtained by an ensemble Monte Carlo simulation combined with first principle calculations using the density functional theory. Compared with the experimental data of symmetric and asymmetric MSM structures based on ZnO substrate, the validity of this model is verified. The asymmetric Schottky barrier and electrode area devices exhibit reductions of 20 times and 1.3 times on dark current, respectively, without apparent photocurrent scarification. The plots of photo-to-dark current ratio (PDR) indicate that the asymmetric MgZnO MSM structure has better dark current characteristic than that of the symmetric one.

UV and IR dual light triggered cellulose-based invisible actuators with high sensitivity.

Actuators are widely used in bionic devices and soft robots, among which invisible actuators have some unique applications, including performing secret missions. In this paper, highly visible transparent cellulose-based UV-absorbing films were prepared by dissolving cellulose raw materials using N-methylmorpholine-N-oxide (NMMO) and using ZnO nanoparticles as UV absorbers. Furthermore, transparent actuator was fabricated by growing highly transparent and hydrophobic polytetrafluoroethylene (PTFE) film on regenerated cellulose (RC)-ZnO composite film. In addition to its sensitive response to Infrared (IR) light, the as-prepared actuator also shows a highly sensitive response to UV light, which is attributed to the strong absorption of UV light by ZnO NPs. Thanks to the drastic differences in adsorption capacity between the RC-ZnO and PTFE materials for water molecules, the asymmetrically- assembled actuator demonstrates extremely high sensitivity and excellent actuation performance, with a force density of 60.5, a maximum bending curvature of 3.0 cm-1, and a response time of below 8 s. Bionic bug, smart door and the arm of excavator made from the actuator all exhibit sensitive responses to UV and IR lights.

From Straw to Device Interface: Carboxymethyl-Cellulose-Based Modified Interlayer for Enhanced Power Conversion Efficiency of Organic Solar Cells.

Advanced interface materials made from petrochemical resources have been extensively investigated for organic solar cells (OSCs) over the past decades. These interface materials have demonstrated excellent performances in OSC devices. However, the limited resources, high-cost, and non-ecofriendly nature of petrochemical-based interface materials restrict their commercial applications. Here, a facile and effective approach to prepare cellulose and its derivatives as a cathode interface layer for OSCs with enhanced performance from rice straw of agroforestry residues is demonstrated. By employing this carboxymethyl cellulose sodium (CMC) into OSCs, a highly efficient inverted OSC is constructed, and a power conversion efficiency (PCE) of 12.01% is realized using poly[(2,6-(4,8-bis(5-(2-ethyl-hexyl)-thiophen-2-yl)-benzo[1,2-b:4,5-b'] dithiophene))-alt-(5,5-(1',3'-di-2-thienyl-5',7-bis(2-ethylhexyl)benzo[1',2'-c: 4',5'-c']dithiophene-4,8-dione): 3,9-bis(2-methylene-((3-(1, 1-dicyanomethylene)-6/7-methyl)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3-d: 2',3'-d']-s-indaceno[1,2-b: 5, 6-b']dithiophene as the active layer, which shows over 9.4% improvement in PCE compared to that of a device without the CMC layer (PCE = 10.98%), especially the enhancement in short-circuit current. The improved current densities and PCEs are attributed to the reduced work function, enhanced absorption, and improved interfacial contact by using CMC and ZnO as co-interface. This approach of fabricating interface materials from biorenewable sources for OSCs is simple, scalable, and cost-effective, representing a promising direction for the development of smart interface and green electronics.

AMPK Activation of Flavonoids from Psidium guajava Leaves in L6 Rat Myoblast Cells and L02 Human Hepatic Cells.

OBJECTIVE: To isolate the hypoglycemic bioactive components from leaves of Psidium guajava and evaluate their AMP-activated protein kinase (AMPK) activities. METHODS: A variety of column chromatography was used for the isolation of compounds, and nuclear magnetic resonance (NMR) and mass spectrum (MS) were used for the structure identification of compounds. AMP-activated protein kinase (AMPK) activity of compounds obtained from leaves of Psidium guajava was evaluated in L6 rat myoblast cells and L02 human hepatic cells by western blot. RESULTS: Six principal flavonoids largely present in the leaves of Psidium guajava, quercetin (1), quercetin-3-O-α-L-arabinofuranoside (2), quercetin-3-O-α-L-arabinopyranoside (3), quercetin-3-O-ß-D-galactopyranoside (4), quercetin-3-O-ß-D-glucopyranoside (5), and quercetin-3-O-ß-D-xylopyranoside (6), were obtained and compound 1-6 exhibited significant activity on AMPK activation both in L6 cells and L02 cells (p < 0.01) compared with Control. In particular, the effects of quercetin on AMPK activation were extremely significant compared with Control (p < 0.001). CONCLUSIONS: These findings demonstrated that these flavonoids had potential for the activation of AMPK and hypoglycemic activity.

FALEC exerts oncogenic properties to regulate cell proliferation and cell-cycle in endometrial cancer.

Focally amplified lncRNA on chromosome 1 (FALEC) is novel lncRNA located in a focal amplicon on chromosome 1q21.2, and has been identified as an oncogenic properties in a variety of human cancers. However, there was no report about the expression pattern and biological function of FALEC in endometrial cancer. In our research, FALEC expression was increased in endometrial cancer tissue samples and cell lines compared with corresponding paracancerous normal tissue samples and cell line, respectively. Furthermore, we investigated the clinical significance of FALEC in endometrial cancer patients, and found endometrial cancer patients with advanced clinical stage or large tumor size had higher levels of FALEC expression than those with early clinical stage or small tumor size. The in vitro studies showed silencing of FALEC expression inhibited cell proliferation and arrested cell cycle at G0/G1. In conclusion, FALEC is overexpressed in endometrial cancer tissues and cells, and involved in regulating cell proliferation and cell-cycle.

Local Anesthetic Drug Inhibits Growth and Survival in Chronic Myeloid Leukemia Through Suppressing PI3K/Akt/mTOR.

BACKGROUND: Apart from the known anesthetic and antiarrhythmic effects, recent studies also highlight the anticancer activities of local anesthetics. In line with the findings, our work shows that ropivacaine, an amide-linked local anesthetic drug, targets chronic myeloid leukemia (CML) via inhibiting PI3K/Akt/mTOR. MATERIALS AND METHODS: The effects of ropivacaine in CML cell lines and primary stem or progenitor cells were investigated using apoptosis, proliferation and colony formation assays. The effects of ropivacaine on proliferation and survival pathways were analyzed using Western blot. RESULTS: We demonstrate that ropivacaine dose and time dependently inhibits proliferation in CML cell lines via arresting cell at G2/M stage. Ropivacaine induces apoptosis in CML cells. In addition, the anti-CML activity of ropivacaine is mainly through growth arrest rather than apoptosis induction. We further demonstrate that ropivacaine induces apoptosis and inhibits colony formation in CD34 progenitor or stem cells derived from patients with blast phase-CML. Importantly, combination of ropivacaine with imatinib or dasatinib (Bcr-Abl tyrosine kinase inhibitors) is significantly more effective in targeting CML cell lines as well as blast phase-CML CD34 cells than imatinib or dasatinib alone. We further demonstrate that ropivacaine inhibits phosphorylation of essential molecules involved in PI3K/Akt/mTOR signaling pathways in CML cells. Akt overexpression significantly reverses the effects of ropivacaine, further confirming that ropivacaine acts on CML cells via inhibition of PI3K/Akt/mTOR. CONCLUSIONS: Our work provide rationales on clinical trials for the use of local anesthetics in CML by demonstrating the anti-CML effects of ropivacaine and the molecular mechanism of its action.

New limonoids isolated from the bark of Melia toosendan.

Two new limonoids, 12-ethoxynimbolinins G and H (compounds 1 and 2), and one known compound, toosendanin (Chuanliansu) (compound 3), were isolated from the bark of Melia toosendan. Their structures were elucidated by spectroscopic analysis and X-ray techniques. The absolute configuration of toosendanin (3) was established by single-crystal X-ray diffraction. Compounds 1-3 were evaluated for their cytotoxicity against five tumor cell lines.

Two new limonoids isolated from the fuits of Melia toosendan.

In the present study, two new limonoids, 1α, 7α-dihydroxyl-3α-acetoxyl-12α-ethoxylnimbolinin (1) and 1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12ß-ethoxylnimbolinin (2), together with other four known limonoids (3-6), were isolated from the fruits of Melia toosendan. Their structures were elucidated by means of extensive spectroscopic analyses (NMR and ESI-MS) and comparisons with the data reported in the literature. The isolated compounds were evaluated for their antibacterial activities. Compound 4 exhibited significant antibacterial activity against an oral pathogen, Porphyromonas gingivalis ATCC 33277, with an MIC value of 15.2 µg·mL(-1). Compound 2 was also active against P. gingivalis ATCC 33277, with an MIC value of 31.25 µg·mL(-1). In conlcusion, our resutls indicate that these compounds may provide a basis for future development of novel antibiotics.