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Micro-/nanorobots (MNRs) can be autonomously propelled on demand in complex biological environments and thus may bring revolutionary changes to biomedicines. Fluorescence has been widely used in real-time imaging, chemo-/biosensing, and photo-(chemo-) therapy. The integration of MNRs with fluorescence generates fluorescent MNRs with unique advantages of optical trackability, on-the-fly environmental sensitivity, and targeting chemo-/photon-induced cytotoxicity. This review provides an up-to-date overview of fluorescent MNRs. After the highlighted elucidation about MNRs of various propulsion mechanisms and the introductory information on fluorescence with emphasis on the fluorescent mechanisms and materials, we systematically illustrate the design and preparation strategies to integrate MNRs with fluorescent substances and their biomedical applications in imaging-guided drug delivery, intelligent on-the-fly sensing and photo-(chemo-) therapy. In the end, we summarize the main challenges and provide an outlook on the future directions of fluorescent MNRs. This work is expected to attract and inspire researchers from different communities to advance the creation and practical application of fluorescent MNRs on a broad horizon.

The study of chemical reactions in aqueous media is very important for its implications in several fields of science, from biology to industrial processes. However, modeling these reactions is difficult when water directly participates in the reaction, since it requires a fully quantum mechanical description of the system. Ab-initio molecular dynamics is the ideal candidate to shed light on these processes. However, its scope is limited by a high computational cost. A popular alternative is to perform molecular dynamics simulations powered by machine learning potentials, trained on an extensive set of quantum mechanical calculations. Doing so reliably for reactive processes is difficult because it requires including very many intermediate and transition state configurations. In this study we used an active learning procedure accelerated by enhanced sampling to harvest such structures and to build a neural-network potential to study the urea decomposition process in water. This allowed us to obtain the free energy profiles of this important reaction in a wide range of temperatures, to discover several novel metastable states, and improve the accuracy of the kinetic rates calculations. Furthermore, we found that the formation of the zwitterionic intermediate has the same probability of occurring via an acidic or a basic pathway, which could be the cause of the insensitivity of reaction rates to the solution pH.

The industrial production of commodity chemicals often requires extreme conditions of temperature and pressure. Yet, in industrial reactors the catalyst remains active for a long time notwithstanding the harsh operating conditions. This challenges a static picture of the catalytic process. To explain the long-term stability of the industrial catalysts we invoke instead a highly dynamical scenario. We illustrate this concept with an ab initio quality simulation of the Li2NH catalyzed decomposition of ammonia at T = 750 K. This process has been intensively studied for its possible use in a hydrogen-based economy. However, a full understanding of the way it works is still lacking. We show that when exposed to the reactants, the surface structure of the catalyst changes and a dynamic fluctuating steady state is activated allowing the reaction to proceed until the flow of reagents is discontinued. This interfacial reactive fluctuating state is induced by the reaction of ammonia with the surface imides. This discommensuration induces large fluctuations in the top surface layers, which now behave almost like an ionic liquid. In this activated environment, a series of reactions that eventually lead to the release of N2 and H2 molecules become possible.

Conotoxins are promising neuropharmacological tools and drug candidates due to their high efficiency and specificity in targeting ion channels or neurotransmitter receptors. In this study, a novel O

Purpose This study was performed to investigate the effect of miRNA let-7a-5p on the proliferation, invasion, and migration of human hepatoma cells as well as to determine BZW2 expression in these cells. Methods Western blotting and real-time quantitative polymerase chain reaction were used to detect changes in the expression of miRNA let-7a-5p and BZW2 protein and gene, respectively. A luciferase reporter gene assay was used to examine whether BZW2 is the target gene of miR-let-7a-5p. The effect of miR-let-7a-5p on the invasion, migration, and proliferation of human hepatoma Bel-7404 and HepG2 cells was determined using the transwell invasion assay, scratch test, and CCK-8 assay, respectively. Flow cytometry was used to assess the effect of miR-let-7a-5p and BZW2 expression on apoptosis of hepatoma cells. Results The luciferase reporter gene assay identified BZW2 as the target gene of miR-let-7a-5p. Moreover, increased expression of miR-let-7a-5p was found to significantly decrease BZW2 expression; inhibit proliferation, invasion, and migration; and promote apoptosis of hepatoma cells. Conclusion miR-let-7a-5p can inhibit proliferation, invasion, and migration as well as promote apoptosis of hepatoma cells by decreasing BZW2 expression.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by a loss of dopaminergic neurons in the substantia nigra of the brain. Numerous investigations have focused on the underlying mechanism involved in the progression of PD in recent decades. miR-132 is abnormal expression in many diseases including PD. However, the functional role and molecular mechanism of miR-132-5p in PD pathogenesis are still not elucidated. In our study, we found miR-132-5p was upregulated in 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP) model of PD. MTT assay and flow cytometric analysis revealed that inhibition of miR-132-5p increased cell survival ability and reduced MPTP-induced apoptosis of SH-SY5Y cells. Furthermore, inhibition of miR-132-5p could significantly suppressed mRNA and protein expression levels of LC3 and Beclin 1, indicating inhibition of miR-132-5p might restrain autophagy in PD. Subsequently, ULK1 was identified as a target of miR-132-5p and positively regulated by miR-132-5p at both mRNA and protein levels. Additionally, ectopic expression of ULK1 was able to reverse the effects of miR-132-5p inhibition. Taken together, our results demonstrated that miR-132-5p inhibition might exert a protective role in MPTP-treated PD models by targeting ULK1, indicating that miR-132-5p may be a prospective therapeutic target for PD.

α-Conotoxins, a group of small marine peptide toxins that target nAChRs with high potency and selectivity, are valuable pharmacological tools and potential drug leads. In this study, we reported the synthesis and physiological functions of a novel αM-superfamily conotoxin SIIID (CCGEGSSCPKYFKNNFICGCC) from a fish-hunting Conus striatus. Three SIIID isomers with different cystine connectivities were synthesized by solid-phase polypeptide synthesis and confirmed by mass spectrometry. Patch clamp experiments on HEK293 cells expressing nAChR subtypes showed that 1 μM SIIID (1-4, 2-5, 3-6) inhibited PNU-120596 and acetylcholine induced human α7 nAChR currents by 48.45%, which was higher than 5.08% of SIIID (1-5, 2-4, 3-6) and 9.57% of SIIID (1-6, 2-4, 3-5). Further study on the most active SIIID isomer showed that 10 μM SIIID inhibited PNU-120596 and acetylcholine induced human α7 nAChR currents by 76.33% but had no obvious effect on acetylcholine induced human α3β4 nAChR currents. In addition, SIIID inhibited PNU-120596 and acetylcholine induced human α7 nAChR currents with an IC

The study of liquid-liquid phase transition has attracted considerable attention. One interesting example of such phenomenon is phosphorus for which the existence a first-order phase transition between a low density insulating molecular phase and a conducting polymeric phase has been experimentally established. In this paper, we model this transition by an ab-initio quality molecular dynamics simulation and explore a large portion of the liquid section of the phase diagram. We draw the liquid-liquid coexistence curve and determine that it terminates into a second-order critical point. Close to the critical point, large coupled structure and electronic structure fluctuations are observed., Comment: 6 pages and 5 figures

Background This research aims to examine the mechanism of glycochenodeoxycholate (GCDA)-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCC). Extracellular signal-regulated kinase 1/2 (ERK1/2) were extensively expressed in liver cancer cells.Methods GCDA-induced survival of human liver carcinoma cells and chemoresistance was determined by CCK8 and flow cytometry, respectively. Functional of ERK1/2 and interaction of Bcl-2 family members was determined in western blot and immunofluorescence.Results Silencing ERK1/2 by RNA interference suppressed GCDA-stimulated survival and promoted apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. And such GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, who acts as an inhibitor to block phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, up-regulation of pro-survival protein Mcl-1 and decrease of pro-apoptotic protein Bim.Conclusions Our work verified the function of ERK1/2 in GCDA-induced chemoresistance in hepatocellular carcinoma cells. Disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for treating of GCDA-related proliferation and drug-resistance in liver cancer.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in adults. Basic leucine zipper and W2 domains 2 (BZW2) is a member of the basic-region leucine zipper (bZIP) superfamily of transcription factors. Here, we found that BZW2 expression was substantially increased in both human HCC tissues and cell lines, which was correlated with the clinical progression of patients with HCC. Silence of BZW2 in HCC cells by infecting with the lentivirus for delivering BZW2 shRNA (short hairpin RNA), prohibits cell progression, as determined by the suppressed cell proliferation, clonality, invasion, and increased cell apoptosis. Furthermore, overexpression of BZW2 promotes drug resistance of HCC cells, as shown by the attenuated suppression of cell viability and invasion following rapamycin (RAPA) treatment. Mechanistically, overexpression (or silence) of BZW2 in HCC cells significantly stimulates (or decreases) the activation of the PI3K/AKT/mTOR signaling pathway, which is responsible for HCC progression. Thus, increased BZW2 expression in HCC can induce HCC progression and drug resistance via stimulating the PI3K/AKT/mTOR pathway, which may represent a new therapeutic target for HCC.

Fluorescence cell staining has become an important tool in biology for sensing and imaging applications. Surprisingly, the introduction of halogen atoms, especially iodine atoms, into small molecules’ framework is able to enhance the cellular uptake of fluorescent objects. However, for these iodo-containing fluorescent probes, the inherent disadvantages, such as water insolubility, high toxicity, and aggregation-caused quenching, prevent them from extensive applications. Furthermore, iodination of organic molecules is really difficult to produce. In our research work, we synthesized fluorescence probes by a copolymerization method, by which the water-soluble copolymers of P-TPE, P-TPE-I1 P-TPE-I2, and P-TPE-I3 with different iodine element contents were synthesized. The study on fluorescence performances demonstrated that these polymers are of high fluorescence quantum yields and long fluorescence lifetimes (up to 15 ns). Both of these characteristics are very beneficial to fluorescence probes being used ...

White-light emitting materials have attracted extensive research interest in recent years, which is largely ascribed to their potential applications in lighting devices and display media. Scientists have reported that organic white-light emitters mostly depend on the integration of several components that simultaneously emit different colors of light. However, it is a challenge to rationally tune the ratios of colored luminescent dyes to produce white-light emitting materials since we still cannot find the general principles to guide their preparation. In this paper, we demonstrate that “equal is important”, which means that once the emission intensities from two complementary colored luminescent dyes are equally maintained, white light emission can be generated in a range of states, including in solids, solutions, and gels. During the research process, we also found that cationic fluorescent cores are highly sensitive to the polarity of solvents. Therefore, our results could inform the design of visual indicators for the polarity and electrical conductivity of solvents using fluorescence signals.

The combined molecular dynamics and coordinate driving (MD/CD) method is further refined in this work to automatically search reaction pathways for chemical reactions in solution. In this refined MD/CD method, the selective integrated tempering sampling based MD (SITS-MD) simulations are performed to efficiently sample conformers of the reactants in a realistic solution environment. Then, dozens of the reactant/solvent clusters from SITS-MD simulations were used in the subsequent CD step with the quantum mechanics/molecular mechanics (QM/MM) method to generate the reaction pathways. The present MD/CD method is able to search reaction pathways, in which solvent molecules may directly participate. This approach is applied to investigate two reactions without any prior knowledge of the reaction mechanism: Cope elimination of amine oxide in aqueous and dimethyl sulfoxide solutions, and dehydration of methanediol in aqueous solution. For both reactions, our calculations can locate a large number of low-energy reaction pathways. For the dehydration reaction in aqueous solution, free energy barriers for several reaction modes located by the MD/CD method have been obtained from the potential of mean force calculations. Our results show that the most likely reaction mode is the dehydration of methanediol catalyzed by two water molecules. These two illustrative applications demonstrate that the refined MD/CD method is a promising tool in predicting low-energy reaction pathways for reactions in solution.

Aims: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide, with a high mortality rate at advanced stages. In this study, we investigated the effect of niclosamide on cell growth and drug sensitivity in human HCC and elucidated the underlying mechanism. Methods: Three human HCC cell lines (HepG2, QGY-7703 and SMMC-7721) were used to evaluate the effect of niclosamide. Cell proliferation was measured by MTT assay and colony formation assay. Assessment of apoptosis was evaluated by flow cytometry and Hoechst staining. The mRNA and protein levels were analyzed by real-time PCR and western blot, respectively. Results: Niclosamide suppressed cell viability, inhibited clone formation, and induced cell apoptosis in HCC cells dose- and time-dependently. Furthermore, niclosamide synergized with cisplatin to promote the apoptosis of HCC cells. With niclosamide treatment, phospho-STAT3 (Y705) was inactivated and the downstream antiapoptotic proteins Mcl-1 and survivin were downregulated at both mRNA and protein levels in HCC cells. Conclusion: Niclosamide has effective function in anti-HCC and may be a single or combined drug treatment for HCC and acts via the STAT3 signaling pathway.

To explore the abnormal brain activity of early Parkinson’s disease with mild cognitive impairment (ePD-MCI) patients, the study analyzed the dynamic fluctuation of electroencephalogram (EEG) signals and the dynamic change of information communication between EEG signals of ePD-MCI patients. In this study, we recorded resting-state EEG signals of 30 ePD-MCI patients and 37 early Parkinson’s disease without mild cognitive impairment (ePD-nMCI) patients. First, we analyzed the difference of the complexity of EEG signals between the two groups. And we found that the complexity in the ePD-MCI group was significantly higher than that in the ePD-nMCI group. Then, by analyzing the dynamic functional network (DFN) topology based on the optimal sliding-window, we found that the temporal correlation coefficients of ePD-MCI patients were lower in the delta and theta bands than those in the ePD-nMCI patients. The temporal characteristic path length of ePD-MCI patients in the alpha band was higher than that of ePD-nMCI patients. In the theta and alpha bands, the temporal small world degrees of ePD-MCI patients were lower than that of patients with ePD-nMCI. In addition, the functional connectivity strength of ePD-MCI patients affected by cognitive impairment was weaker than that of ePD-nMCI patients, and the stability of dynamic functional connectivity network was decreased. This finding may serve as a biomarker to identify ePD-MCI and contribute to the early intervention treatment of ePD-MCI.

Background Conotoxins have become a research hotspot in the neuropharmacology field for their high activity and specificity in targeting ion channels and neurotransmitter receptors. There have been reports of a conotoxin acting on two ion channels, but rare reports of a conotoxin acting on three ion channels. Methods Vr3a, a proline-rich M-superfamily conotoxin from a worm-hunting Conus varius, was obtained by solid-phase synthesis and identified by mass spectrometry. The effects of synthesized Vr3a on sodium, potassium and calcium currents were tested on rat DRG cells by patch clamp experiments. The further effects of Vr3a on human Cav1.2 and Cav2.2 currents were tested on HEK293 cells. Results About 10 μM Vr3a has no effects on the peak sodium currents, but can induce a ~10 mV shift in a polarizing direction in the current-voltage relationship. In addition, 10 μM Vr3a can increase 19.61 ± 5.12% of the peak potassium currents and do not induce a shift in the current-voltage relationship. An amount of 10 μM Vr3a can inhibit 31.26% ± 4.53% of the peak calcium currents and do not induce a shift in the current-voltage relationship. The IC50 value of Vr3a on calcium channel currents in rat DRG neurons is 19.28 ± 4.32 μM. Moreover, 10 μM Vr3a can inhibit 15.32% ± 5.41% of the human Cav1.2 currents and 12.86% ± 4.93% of the human Cav2.2 currents. Conclusions Vr3a can simultaneously affect sodium, potassium and calcium currents. This novel triple-target conotoxin Vr3a expands understanding of conotoxin functions.

TsIIIA, the first μ-conotoxin from Conus tessulatus, can selectively inhibit rat tetrodotoxin-resistant sodium channels. TsIIIA also shows potent analgesic activity in a mice hotplate analgesic assay, but its effect on human sodium channels remains unknown. In this study, eight human sodium channel subtypes, hNa

Specific organelle imaging and long-term cellular tracking are of paramount importance in monitoring biological processes, pathological pathways, and therapeutic effects, etc. Herein, we report a novel macromolecule fluorescent probe (TPPA–DBO), which is synthesized from tris(4-(pyridin-4-yl)phenyl)amine (TPPA) and 1,8-dibromononane (DBO) with a gram scale by a simple method. TPPA–DBO demonstrates a highly specific nucleolus-targeting ability, which is very challenging in the bioimaging research field. We have shown that the green nucleolus-specificity probe TPPA–DBO has advantages over the commercially available nucleolus-staining probes such as DAPI, Hoechst dyes and SYTOs in terms of its AIE-performance, large Stokes shift (175 nm), excellent photostability, and promising usefulness in live cell imaging experiments. Surprisingly, after internalizing TPPA–DBO into the nucleus region for a period of time, some TPPA–DBO are reversely diffused from nucleolus into the cytoplasm, thus resulting in the staining of mitochondria with a redder emission color. This research result may provide a new concept of cellular tracker design and provide insight into biological questions, understanding disease mechanismss, and designing new therapeutic strategies.

Previous studies have indicated that each conotoxin precursor has a hyperconserved signal region, a rather conserved pro region and a hypervariable mature region, and nucleotide mutations are the main driven factor. However, in this study, we made an in-depth analysis on the M-superfamily conotoxin precursors and found that the diversity of the signal, pro and mature regions are more complicated than previous findings. Different conotoxin precursors can have same signal, pro and/or mature regions, especially different conotoxin precursors with same mature region but different signal and pro regions. In addition, insertions and deletions (indels) were detected in conotoxin precursors. Indels are infrequent in the signal region but frequent in the pro and mature regions. In contrast to deletions that dominate in the pro region, insertions dominate in the mature region. The number of amino acids is crucial for the physiological functions of mature conotoxins, therefore indels, especially insertions in the mature region, play an important role in the sequence and function diversity of conotoxins.

The newly emerged pathogenic bacteria leads to the bactericides generations one by one, which is definitely a long-term and costly process. For the small organic molecule used as antibacterial materials, photostability, biomembrane penetrating ability, and long-term antibacterial ability still are questionable. In this work, we synthesized the multiple-cation-charged aggregation-induced emission (AIE)-active polymer 1,2-diphenyl-1,2-bis(4-(pyridin-4-yl)phenyl) ethane–1,8-dibromooctane (DBPE-DBO). Due to the incorporating the dark toxicity from positively charged polymers, and the phototoxicity from generation of singlet oxygen, as well as AIE-active fluorescence performance, DBPE-DBO could be employed as an efficient bacteria targeting, imaging, and killing materials. Interestingly, DBPE-DBO was less toxic to the normal mammalian cells, which leads us to verify that DBPE-DBO could be used as a very cell-membrane permeable nucleus imaging probes. Thus, our research results may provide a new concept for the...

Fluorescence-tunable materials are becoming increasingly attractive because of their potential applications in optics, electronics, and biomedical technology. Herein, a multicolor molecular pixel system is realized using a simple copolymerization method. Bleeding of two complementary colors from blue and yellow fluorescence segments reproduced serious multicolor fluorescence materials. Interestingly, the emission colors of the polymers can be fine-tuned in the solid state, solution phase, and in hydrogel state. More importantly, the positive fluorescent polymers exhibited cell-membrane permeable ability and were found to accumulate on the cell nucleus, exhibiting remarkable selectivity to give bright fluorescence. The DNA/RNA selectivity experiments in vitro and in vivo verified that [tris(4-(pyridin-4-yl)phenyl)amine]-[1,8-dibromooctane] has prominent selectivity to DNA over RNA inside cells.

A set of multiple cation-doped linear polymers (abbreviated as OPY-1,2-BE, OPY-1,4-BB, OPY-1,8-BO, OPY-1,4-OBB) synthesized from a dipyridine derivative (OPY) and dibrominated compounds were employed as fluorescent probes for adenosine triphosphate (ATP) sensing. Among them, OPY-1,8-BO is particularly able to recognize ATP over its related compounds adenosine diphosphate (ADP), adenosine monophosphate (AMP), and other phosphate anions, with very desirable switch off–on performances. The interesting phenomenon of aggregate-induced emission (AIE) is proposed as the main reason for the ATP sensing, which is due to the ATP being more negative than the polymers and therefore there is more opportunity for connections with the multiple cation doped polymers through electrostatic attractions. Cell imaging measurements were carried out and demonstrated that even though these probes bear the same OPY core and only slightly different linkers, they are able to image different cell environments. The controlled cell imaging verified that the OPY-1,8-BO probe has ATP-specific recognition in living cells.

Fluorescence imaging, especially specific organelle imaging, has become a significant technology to comprehending cell transplantation, migration, division, fusion, and lysis. In this paper, we designed and synthesized a water soluble and fluorescent polymer named as Poly(AA-TPA-d), which was pH-responsive by the fluorescence channel due to the presence of poly acrylic acid as the polymer backbone. The research results demonstrated that Poly(AA-TPA-d) exhibits novel aggregation-induced-emission (AIE) property. Additionally, due to the hydrogen bond formation and C=O···π interactions between methyl acrylate groups, Poly(AA-TPA-d) was of excellent hydrogel formation ability. Moreover, Poly(AA-TPA-d) displayed good bio-compatibility with the living MPC5 cells and highly specific cytoplasm-targeting ability by MTT assay and cell staining experiment respectively.

Background The aim of this in vitro study was to measure the enhanced anticancer effects of Res (resveratrol) on PA (paclitaxel) in HepG2 human liver cancer cells. Methods The MTT (thiazolyl blue tetrazolium bromide, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), flow cytometry, qPCR (real-time quantitative polymerase chain reaction) and western blot assay were used for cells growth inhibitory effects, cells apoptosis (DNA content of sub-G1), mRNA and protein expressions, respectively. Results The 10 μg/mL of Res had no growth inhibitory effect on Nthy-ori 3–1 normal cells or HepG2 cancer cells meanwhile the 5 or 10 μg/mL of PA also had no growth inhibitory effect on Nthy-ori 3–1 normal cells. Where as PA-L (5 μg/mL) and PA-H (10 μg/mL) had the growth inhibitory effects in HepG2 cancer cells, and Res increase these growth inhibitory effects. By flow cytometry experiment, after Res (5 μg/mL) + PA-H (10 μg/mL) treatment, the HepG2 cells showed the most apoptosis in cells as compared to other treatments groups, and after additionally treated with Res, both the apoptosis cells of two concentrations PA were raised. As PA raised it also raised the mRNA and protein expressions of caspase-3, caspase-8, caspase-9, Bax (Bcl-2 assaciated X protein), p53, p21, IκB-α (inhibitor of NF-κB alpha), Fas (factor associated suicide), FasL (factor associated suicide ligand), TIMP-1 (tissue inhibitor of metalloproteinases 1), TIMP-2 (tissue inhibitor of metalloproteinases 2) and decrease Bcl-2 (B cell leukemia 2), Bcl-xL (B cell leukemia extra large), HIAP-1 (cIAP-1, cellular inhibitor of apoptosis 1), HIAP-2 (cIAP-2, cellular inhibitor of apoptosis 2), NF-κB (nuclear factor kappa B), COX-2 (cyclooxygenase 2), iNOS (inducible nitric oxide synthase), MMP-2 (metalloproteinase 2), MMP-9 (metalloproteinase 9), EGF (epidermal growth factor), EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), Fit-1 (VEGFR-1, vascular endothelial growth factor receptor 1). Meanwhile, the 5 μg/mL of Res could enhance these mRNA expressions changes as compared to the control cells. Conclusion From these results, we can conclude that Res could raise the anticancer effects of PA in HepG2 cells, Res could be used as a good sensitizing agent for PA.

μ-conotoxins are a group of marine Conus peptides that inhibit sodium currents, so μ-conotoxins are valuable in sodium channel research and new analgesic drug discovery. Here, a novel μ-conotoxin TsIIIA was identified from a worm-hunting Conus tessulatus. TsIIIA was chemical synthesized according to its amino acid sequence GCCRWPCPSRCGMARCCSS and identified by mass spectrum. Patch clamp on rat dorsal root ganglion cells showed that 10 μM TsIIIA specifically inhibit TTX-resistant sodium currents but has no effect on TTX-sensitive sodium currents. TsIIIA inhibits TTX-resistant sodium currents by a dose-dependent mode with an IC50 of 2.61 μM. Further study showed 10 μM TsIIIA has no obvious effect on the current-voltage relationships, conductance-voltage relationships and voltage-dependence of steady-state inactivation of TTX-resistant sodium channels. Mice hotplate analgesic assay indicated that TsIIIA obviously increase the pain threshold at 0.5-4 h. In addition, TsIIIA has better analgesic effects than Ziconotide, indicating that TsIIIA was a valuable lead compound for development of new analgesic drug.

In this work, we fabricated a novel triphenylamine-derivative (DNDT)-modified nanographene oxide by following a simple gram-scale method. The product showed interesting optical properties and good potential for use in bioimaging applications. This fluorescent carbon material could be readily internalized by HepG2 cells and was clearly visualized to accumulate mainly in the nucleus.

The effective polymerization process is very desirable in the field of macromolecule science. In this study, we present a facile synthetic method via aldol addition and condensation (AAC) that leads to the formation of fluorescent linear and branched polymers by cross coupling triphenylamines (TPA) and cyclohexanones (CYC) via CC bond formation. The methodology has the advantage of easy operations, mild reaction conditions, and high yield. Via the analysis of NMR, FT-IR, GPC, PL, UV, SEM, and theoretical calculation, the structure, physical properties, and optical behaviors of both polymers were well-characterized. The understanding of cell transplantation, migration, division, fusion, and lysis is a very challenging task. In this study, the linear polymer (LP) exhibits excellent biocompatibility and low cytotoxicity, which can be readily internalized by living cells in a noninvasive manner. The images of MPC5 cells indicate that LP can be a promising emissive fluorescence probe for bioimaging application.

Glycochenodeoxycholate (GCDA) is closely associated with carcinogenesis and chemoresistance of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3), a transcription factor, is involved in various human tumors. Whether GCDA induces chemoresistance through STAT3 and the mechanism of action remains elusive. In this study, we firstly found that the expression level of STAT3 has a positive correlation with chemoresistance of HCC cells. Moreover, GCDA can upregulate the expression of STAT3 protein. Hence, we suspect that GCDA may induce chemoresistance of HCC cells via STAT3. Mechanistically, GCDA stimulates phosphorylation of STAT3 at Ser727 site and mediates pSer727-STAT3 protein to translocate and aggregate in the nucleus, which is important for cell survival. When Ser727 of STAT3 mutated to Asp, the capacity of STAT3 to accumulate in the nucleus was attenuated, STAT3-induced cell survival was impaired and GCDA-induced chemoresistance was abolished. In addition, while activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was inhibited by PD98059, phosphorylation of STAT3 at Ser727 induced by GCDA was suppressed. Taken together, these data demonstrate that GCDA-enhanced survival of liver cancer cells may occur through the activation of STAT3 by phosphorylation at Ser727 site via mitogen-activated protein kinase/ERK1/2 pathway, which may contribute to the progression of human liver cancer and chemoresistance.

In this paper, one probe (TPPA-VCh) with fluorescence and Surface-enhanced Raman Scattering (SERS) two readout signals, which has high sensitivity and specificity to glutathione in both vitro and cell image applications, is designed and synthesized. Furthermore, the quenched emissions and intensified SERS signals is obtained by loading TPPA-VCh on the surfaces of gold nanoparticles.

Fluorescent probes are powerful tools for investigating reactive oxygen species (ROS) in living organisms. The overproduced “primary” ROS of superoxide anions (O2˙−) cause a chain of oxidative damage. In order to monitor O2˙− level fluctuations in living cells, we synthesized two reaction-type probes of TPA-DHP-1,2,3 and TPA-PPA-1,2,3, which were composed of an electron-rich triphenylamine (TPA) and the very active functional groups of dihydropyridine (DHP) and pyridinium (PPA). Intriguingly, DHP and PPA were able to carry out easy proton abstractions and nucleophilic reactions in the presence of O2˙−, resulting in the corresponding products with sharp wavelength shifts, and elevated fluorescence intensities. Therefore, undesirable background fluorescence interference can be reduced during the monitoring and imaging process. Meanwhile, the developed dual-channel monitoring strategy not only provides observations of the O2˙− level fluctuations, but could also be employed to image the dynamic accumulation process of probes in the different cell organelles. Therefore, the design could provide a simple, accurate and universal platform for biological applications in future research work.

NIMA-related expressed kinase 2 (NEK2) participates in the carcinogenesis and progression of certain types of cancer, however, its expression and roles in the development of hepatocellular carcinoma (HCC) remains unknown. Here, we found that NEK2 expression was significantly upregulated in both human HCC tissues and cell lines, and increased NEK2 expression in HCC was significantly correlated with clinical progression of HCC in patients. Knockdown of NEK2 in HCC cells inhibited HCC progression, as determined by the suppressed cell proliferation, invasion and metastasis. Furthermore, knockdown of NEK2 inhibited drug resistance of HCC cells, as shown by the promoted suppression of cell viability in 5-fluorouracil (5‑FU)‑treated HCC cells. Mechanistically, protein phosphatase 1 (PP1)/Akt and Wnt signaling activation are significantly inhibited by NEK2 knockdown, which is responsible for the HCC progression and involved in NEK2‑induced cancer cell abnormal biological behavior. Thus, enhanced NEK2 expression in HCC promotes HCC progression and drug resistance by promoting PP1/Akt and Wnt pathway activation, which may represent a new therapeutic target for HCC.

Nicotine is a major carcinogen in cigarettes, which can enhance cell proliferation and metastasis and increase the chemoresistance of cancer cells. Our previous data found that nicotine promotes cell survival in lung cancer by affecting the expression of antiapoptotic protein Mcl-1, suggesting that the Mcl-1 may be a therapeutic target for patients with lung cancer. In this study, we found that the effects of drug resistance on nicotine-induced lung cancer cell lines were shown to influence the phosphorylation of Mcl-1. Moreover, nicotine induces Mcl-1 phosphorylation exclusively at the T163 site, which results in enhancement of the antiapoptotic activity of Mcl-1 and increased cell survival. Meanwhile, nicotine can reduce the sensitivity of H1299 cells to CDDP via enhancement of the binding of Mcl-1 to Bak, which inhibits the proapoptotic effect of Bak and ultimately leads to increased survival and drug resistance of lung cancer cells. Thus, nicotine-induced cell survival and chemoresistance may occur in a mechanism by stimulating Mcl-1 phosphorylation and its interaction with Bak, which may contribute to improving the efficacy of chemotherapy in the treatment of human lung cancer.

Objective Glycochenodeoxycholate acid (GCDA) is a toxic component in bile salts. It plays an important role in the development and progression of liver cancer. In this study, we investigated the underlying mechanism of GCDA in hepatocarcinogenesis and chemotherapy resistance. Materials and methods Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and clonality by Ki-67 and colony-formation assay. Apoptosis was examined by flow cytometry. Real-time polymerase chain reaction (PCR) and western blot analysis were used to measure messenger RNA and protein levels, respectively. Short hairpin RNA was used to silence signal transducer and activator of transcription 3 (Stat3) expression. Results Bile salts (GCDA) promoted the proliferation of hepatocellular carcinoma (HCC) cells (HepG2 and QGY-7703), and GCDA treatment reduced the chemosensitivity of 5-fluorouracil (5FU) in HepG2 and QGY-7703 cells. GCDA upregulated the expression of antiapoptosis proteins Mcl-1/Survivin/Bcl-2. GCDA had no discernible effect on basal protein level or subcellular localization of phosphorylated Stat3. 5FU increased the apoptosis of HepG2 cells with silenced Stat3 expression, but GCDA-induced chemoresistance was not reversed. Conclusions GCDA-reduced HCC cell chemosensitivity may occur by upregulating antiapoptosis proteins Mcl-1/Survivin/Bcl-2. Stat3 may be a target for enhancing the chemosensitivity of hepatocellular carcinoma cells, but GCDA-induced chemoresistance is independent of Stat3.

Gold nanorods (AuNRs) have attracted widespread attention in the last few decades due to their potential applications in cancer photothermal therapy (CPTT). However, the utilization of AuNRs is restricted because of their high toxicity for cells and tissues. Numerous methods have been developed to solve this problem, among which the most convenient one is to coat AuNRs with biocompatible materials or replace their original toxic surfactant such as the hexadecyl-trimethyl ammonium bromide (CTAB). Organic polymers (OPs) are intensively researched due to their low toxicity and easy access to modification with functional groups (e.g., targeting molecules), pharmaceuticals (e.g., chemo drugs) and imaging agents (e.g., radioactive elements). Herein, this mini review summarized recent progress in detoxification and functionalization of AuNRs exploiting OPs coatings and their applications in CPTT. To begin with, we introduced current major approaches used to modify AuNRs with typical OPs. Then, applications of OPs coated AuNRs in CPTT were discussed. At the end of the review, we proposed a brief outlook for the future development of modification and functionalization of AuNRs with organic materials.