Multifunctional Carbon Nanodots for Antibacterial Enhancement, pH Change, and Poisonous Tin(IV) Specifical Detection.

In recent years, antibiotic-based carbon nanodots have been extensively developed and studied, because of their excellent synergistic fluorescence and antibacterial properties. These antibacterial carbon nanodots have also been developed with various new applications, such as heavy iron detection, pH sensitivity, temperature response, and bacterial count detection in various environments. In this article, using vancomycin hydrochloride as the only precursor, vancomycin hydrochloride carbon nanodots were rapidly synthesized by a one-step microwave method. The diameter of the vancomycin hydrochloride carbon nanodots was concentrated at 0.899 ± 0.40 nm with a uniform size and excitation-dependent fluorescence. Vancomycin hydrochloride carbon nanodots showed better antibacterial activity than the original vancomycin hydrochloride with low biological toxicity and good stability. In the pH range of approximately 7-13, there was a good linear relationship between the fluorescence intensity of the carbon nanodots and the pH value (R2 = 0.98516). Moreover, vancomycin hydrochloride carbon nanodots could quickly and specifically detect poisonous Sn4+ through changes in their fluorescence intensity, with a detection limit of approximately 5.2 µM. Multifunctional vancomycin hydrochloride carbon nanodots have good application prospects in the fields of antibacterial, toxic Sn4+ detection, and pH-sensitive aspects.

Carbon nanodots constructed by ginsenosides and their high inhibitory effect on neuroblastoma.

BACKGROUND: Neuroblastoma is one of the common extracranial tumors in children (infants to 2 years), accounting for 8 ~ 10% of all malignant tumors. Few special drugs have been used for clinical treatment currently. RESULTS: In this work, herbal extract ginsenosides were used to synthesize fluorescent ginsenosides carbon nanodots via a one-step hydrothermal method. At a low cocultured concentration (50 µg·mL- 1) of ginsenosides carbon nanodots, the inhibition rate and apoptosis rate of SH-SY5Y cells reached ~ 45.00% and ~ 59.66%. The in vivo experiments showed tumor volume and weight of mice in ginsenosides carbon nanodots group were ~ 49.81% and ~ 34.14% to mice in model group. Since ginsenosides were used as sole reactant, ginsenosides carbon nanodots showed low toxicity and good animal response. CONCLUSION: Low-cost ginsenosides carbon nanodots as a new type of nanomedicine with good curative effect and little toxicity show application prospects for clinical treatment of neuroblastoma. It is proposed a new design for nanomedicine based on bioactive carbon nanodots, which used natural bioactive molecules as sole source.

Experimental Study on the Enhanced Oil Recovery Mechanism of an Ordinary Heavy Oil Field by Polymer Flooding.

It is widely known that in the water flooding development process of ordinary heavy oil, the fingering phenomenon is obvious, there are a lot of unswept areas, and absolutely, the recovery is really very low. In addition, for some shallow and thin ordinary heavy oil reservoirs limited by the geological conditions of the reservoir, the thermal recovery technology also has serious heat loss and high development cost. Therefore, there is an urgent need to transform the development and further improve the enhanced oil recovery (EOR). In this paper, the mechanism of EOR by polymer flooding was investigated for high-porosity and high-permeability terrestrial ordinary heavy oil reservoirs. Through laboratory experiments, we analyzed the characteristics of oil-water relative permeability curves, mobility control ability, and microscopic seepage characteristics during polymer flooding of ordinary heavy oil reservoirs. On this basis, the effect of the mobility ratio on seepage characteristics and the mechanism of EOR enhancement were clarified. The results show that the polymer can effectively improve the mobility control effect of the displacing fluid. As the polymer solution and ordinary heavy oil have the characteristics of high viscosity and low mobility, there is a minimum mobility ratio in the process of polymer flooding. Namely, the characteristics of dual low mobility exist in the process of polymer flooding for the ordinary heavy oil. It effectively enhances the profile control and plugging ability of the polymer, thus expanding the sweep volume of larger pores and improving the displacement efficiency of smaller pores. Based on the two factors mentioned above, it is found that the dual low mobility characteristics can improve the recovery of ordinary heavy oil by polymer flooding. Therefore, it is proposed that an enhanced profile control and plugging effect due to the dual low mobility characteristics is an important EOR mechanism for ordinary heavy oil development by polymer flooding.

A novel promising neuroprotective agent: Ganoderma lucidum polysaccharide.

Nervous system diseases (NSDs) are characterized by a wide range of symptoms, a complex pathophysiology, an unclear etiology, a great deal of variation in treatment response, and lengthy therapy cycles, all of which pose considerable hurdles to clinical treatment. A traditional valuable medicine known as Ganoderma lucidum (GL) has a significant role to play in preserving health and treating diseases. Ganoderma lucidum polysaccharides (GLP) is one of the cardinal effective active ingredients of GL, which has a number of pharmacological actions, including liver protection, immune regulation, antioxidant activity, anticancer activity, antibacterial activity, and antiviral activity. Recently, studies on the structural characterization and biological functions of GLP were presented in this article to review the progress of researches about GLP on NSDs and summarize the potential mechanisms of action. These studies were anticipated to provide new research ideas for GLP as a novel promising neuroprotective agent and provide a reference for better development and utilization of GLP.

A Novel Conductive Antibacterial Nanocomposite Hydrogel Dressing for Healing of Severely Infected Wounds.

Wound infections are serious medical complications that can endanger human health. Latest researches show that conductive composite materials may make endogenous/exogenous electrical stimulation more effective, guide/comb cell migration to the wound, and subsequently promote wound healing. To accelerate infected wound healing, a novel medical silver nanoparticle-doped conductive polymer-based hydrogel system (Ag NPs/CPH) dressing with good conductivity, biocompatibility, and mechanical and antibacterial properties was fabricated. For the hydrogel dressing, Ag NPs/CPH, polyvinyl alcohol (PVA), and gelatin were used as the host matrix materials, and phytic acid (PA) was used as the cross-linking agent to introduce conductive polyaniline into the matrix, with antibacterial Ag NPs loaded via impregnation. After a series of analyses, the material containing 5 wt% of PVA by concentration, 1.5 wt% gelatin, 600 µL of AN reactive volume, and 600 µL of PA reactive volume was chosen for Ag NPs/CPH preparation. XPS and FTIR analysis had been further used to characterize the composition of the prepared Ag NPs/CPH. The test on the swelling property showed that the hydrogels had abundant pores with good water absorption (≈140% within 12 h). They can be loaded and continuously release Ag NPs. Thus, the prepared Ag NPs/CPH showed excellent antibacterial property with increasing duration of immersion of Ag NPs. Additionally, to evaluate in vivo safety, CCK-8 experiments of HaCat, LO2 and 293T cells were treated with different concentrations of the Ag NPs/CPH hydrogel soaking solution. The experimental results showed the Ag NPs/CPH had no significant inhibitory effect on any of the cells. Finally, an innovative infection and inflammation model was designed to evaluate the prepared Ag NPs/CPH hydrogel dressing for the treatment of severely infected wounds. The results showed that even when infected with bacteria for long periods of time (more than 20 h), the proposed conductive antibacterial hydrogel could treat severely infected wounds.

A Novel Temperature-Dependent Hydrogel Emulsion with Sol/Gel Reversible Phase Transition Behavior Based on Polystyrene-co-poly(N-isopropylacrylamide)/Poly(N-isopropylacrylamide) Core-Shell Nanoparticle.

As a kind of temperature-responsive hydrogel, polystyrene-co-poly(N-isopropylacrylamide)/poly(N-isopropylacrylamide) (PS-co-PNIPAM/PNIPAM) core-shell nanoparticles prepared by two-step copolymerization are widely studied and used because of their specific structures and properties. Unlike most reports about the steady stability of PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion, in this work, the PS-co-PNIPAM/PNIPAM core-shell nanoparticle hydrogel emulsion (symbolized as PS/PNIPAM hydrogel emulsion), which is prepared after the second step of synthesis and without washing out a large number of PNIPAM polymer segments, shows a reversible temperature-dependent sol-gel transition characteristic during the temperature range of 34-80 °C. The PS/PNIPAM hydrogel emulsion is a normal solution at room temperature, and it changes from a sol to a gel statue when the temperature approaches up to low critical solution temperature (LCST). As the temperature continues to increase, the gel (core-shell nanoparticles as the crosslinkers and the linear PNIPAM chain as the 3D gel network) of the PS/PNIPAM hydrogel emulsion gradually shrinks and drains linearly. Compared with most crosslinked hydrogels, the hydrogel here can be arbitrarily changed in shape according to use needs, which is convenient for use, transportation, and storage. Here a new route is provided for the preparation of a PS/PNIPAM core-shell hydrogel nanoparticle system, as well as a new supramolecular crosslinking sol-gel system for application in biomedical materials, sensors, biological separation, drug release, macromolecular adsorption, and purification.

Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-ß responses by Mfn2-mediated ubiquitin degradation of MAVS.

Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-ß production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-ß generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a 'fine tuning' of antiviral innate immunity in response to influenza infection under stress.

Bioinspired mineral hydrogels as nanocomposite scaffolds for the promotion of osteogenic marker expression and the induction of bone regeneration in osteoporosis.

Osteoporosis is one of the most prevalent age-related diseases worldwide and is characterized by a systemic deterioration of bone strength (bone mineral density and bone quality) with a resulting increase in fragility fractures. Due to the complex osteoporotic pathological environment, it is a huge challenge to induce bone regeneration under osteoporosis conditions. In this study, we successfully nanoengineer a bioinspired mineralized hydrogel from the supramolecular assembly of nano-hydroxyapatite, sodium carbonate, and polyacrylic acid, termed as CHAp-PAA. The resultant nanocomposite hydrogels can maintain their initial morphology and mechanical properties under physiological conditions, while exhibiting good primary stability, biocompatibility, bioactivity, and osteoconductivity. We demonstrate that this optimized hydrogel scaffold has shown superior performance for bone marrow stem cells (BMSCs) proliferation, differentiation, and extracellular matrix production in vitro. Remarkably, the mineralized CHAp-PAA hydrogels could be used as scaffolds for the critical-sized bone defect (6.0 mm diameter and 10.0 mm depth) in the osteoporotic rabbit model. Without the delivery of additional therapeutic agents or stem cells, these CHAp-PAA hydrogel scaffolds can improve bone ingrowth and accelerate new bone formation even in complex osteoporotic pathological environments. Therefore, this work presents a type of bioinspired multifunctional mineral hydrogel that offers an alternative strategy to manage osteoporosis. STATEMENT OF SIGNIFICANCE.

Tianma Gouteng granules decreases the susceptibility of Parkinson's disease by inhibiting ALOX15-mediated lipid peroxidation.

ETHNOPHARMACOLOGICAL RELEVANCE: Tianma Gouteng granules (TG), a clinical prescription of traditional Chinese medicine, has been clinically applied to treat Parkinson's disease (PD) in combination with Madopar, as included in the Chinese Pharmacopoeia (2015). TG has the potential to decrease the susceptibility of PD pharmacologically, however the mechanisms need detailed demonstration. AIM OF THE STUDY: To evaluate the pharmacological activities, as well as the possible mechanism of TG in diverse models of PD. MATERIALS AND METHODS: 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice, were utilized as PD animal models. Rotarod, locomotor activity, inclined plane and traction tests were used for behavioral assessment. Immunohistochemistry was used for tyrosine hydrolase determination. Western blot were conducted for detection of 4-HNE and 15-lipoxygenase-1 (ALOX15). The interactions of ALOX15 with the components in TG were predicted by molecular docking approach. RESULTS: Lipid peroxidation was involved in dopaminergic neuron damage in 6-OHDA-induced rat models. In MPTP-treated mice, the inhibition of lipid peroxidation improved behavioral and pathological symptoms of PD. The lipid peroxidation-related protein, ALOX15 was found to be the key factor in PD process in diverse PD models including 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice. TG treatment significantly relieved behavioral and pathological symptoms of MPTP-induced PD mouse models with a potential mechanism of alleviating ALOX15-induced lipid peroxidation. Moreover, the results of molecular docking analysis show that compounds in TG might have interactions with ALOX15. CONCLUSIONS: TG effectively improved the behavioral and dopaminergic neuron damage in diverse PD models. The mechanism of this action may be related to the direct inhibition of ALOX15 and the relief of lipid peroxidation.

Polystyrene@poly(ar-vinylbenzyl)trimethylammonium-co-acrylic acid core/shell pH-responsive nanoparticles for active targeting and imaging of cancer cell based on aggregation induced emission.

Doubly charged pH-responsive core/shell hydrogel nanoparticles with green fluorescence were prepared and were shown to be viable bioprobes for active targeting tumor tissue and imaging of cancer cells. Via emulsionfree copolymerization hydrogel nanoparticles as VANPs were prepared, the core of which was polystyrene (Ps) and the shell was comprised of strongly positive electrolyte (ar-vinylbenzyl)trimethylammonium (VBTAC) with weak negative electrolyte acrylic acid (AA). Through conventional amidation, the shell was conjugated with cell-specific folic acid (FA), denoted as VANPs-FA. Then, negatively charged sulfonated 9,10-distyrylanthracene derivatives (SDSA) based on aggregation induced emission (AIE), was binding tightly to positively charged VBTAC of VANPs-FA shell. The prepared double charged fluorescent core/shell hydrogel nanoparticles abbreviated as VANPs-FS, showed excitation/emission wavelengths at ~420/528 nm. Dynamic light scattering (DLS) measurements were performed to determine the size and surficial zeta potential of VANPs-FS. Under proper ratio of VBTAC to AA, the VANPs-FS was stable (~ 64.63 nm, -20.2 mV) at high pH (> 7), started to aggregate (~ 683.0 nm, -3.2 mV) at pH around 6, and can redispers at low pH (< 5). The MTT analysis proved that VANPs-FS had good biocompatibility and low cytotoxicity. The targeting effectiveness of VANPs-FS was confirmed by confocal laser scanning microscopy (CLSM). Graphical abstract Detailed synthetic route of VANPs-FS (top) and schematic cancer tumor-target aggregation of pH-sensitive VANPs-FS with enhanced retention and rapid cancer cell imaging (bottom).

Dissection of mechanisms of Chinese medicinal formula Si-Miao-Yong-an decoction protects against cardiac hypertrophy and fibrosis in isoprenaline-induced heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese herbal formulation. SMYAD first appeared in the Eastern Han Dynasty according to the "Shen Yi Mi Zhuan". Then the formula was recorded in the "Yan Fang Xin Bian" edited by medical scientist Bao Xiangao in the Qing Dynasty. This well-known prescription has been traditionally used for gangrene and vascular vasculitis. It is mainly used for cardiovascular and endocrine diseases in current clinical applications and research. AIM OF STUDY: In this study, the potential mechanisms of SMYAD against cardiac fibrosis and hypertrophy in the ß-adrenoceptor agonist isoprenaline induced heart failure model were investigated. MATERIALS AND METHODS: The heart failure animal model was established via injected isoprenaline in rats. Echocardiography was used to detect the structure and function of the heart. HE staining and Masson's trichrome staining was performed to assess myocardial tissue morphology. The serum biochemical indexes were detected by dedicated biochemical kit. BNP was tested by ELISA kit. The levels of mRNA were detected by RT-qPCR. Cardiomyocyte morphology was assessed by immunofluorescence. Phosphorylated and total p38, Akt were analyzed by Western blot. The production of reactive oxygen species (ROS) was tested by CM-H2DCFDA probe. Formula identification of chemical constituents of SMYAD in plasma was disclosed through ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS). RESULTS: SMYAD was able to improve the heart function in ISO induced heart failure rat model via protecting rat from developing cardiac hypertrophy and fibrosis. SMYAD also decreased plasma expression of these biochemical indexes. It was found that SMYAD could regulate cardiac hypertrophy and fibrosis makers' mRNA levels in vitro and vivo. In addition, SMYAD inhibited the phosphorylation of p38 and Akt, which are key mediators in the pathological process of ISO-induced cardiac hypertrophy and myocardial fibrosis. It also showed that the components of SMYAD in rat plasma exerted myocardial cell protective activity. CONCLUSION: In summary, SMYAD may comprise more than one active ingredient to the pursuit of combination therapies instead of specifically target a single disease-causing molecule. These experimental results suggest that SMYAD may be a potential drug candidate in diseases of cardiac hypertrophy and myocardial fibrosis caused by ß-adrenoceptor abnormalities.

Formation of colloidal alloy semiconductor CdTeSe magic-size clusters at room temperature.

Alloy semiconductor magic-size clusters (MSCs) have received scant attention and little is known about their formation pathway. Here, we report the synthesis of alloy CdTeSe MSC-399 (exhibiting sharp absorption peaking at 399 nm) at room temperature, together with an explanation of its formation pathway. The evolution of MSC-399 at room temperature is detected when two prenucleation-stage samples of binary CdTe and CdSe are mixed, which are transparent in optical absorption. For a reaction consisting of Cd, Te, and Se precursors, no MSC-399 is observed. Synchrotron-based in-situ small angle X-ray scattering (SAXS) suggests that the sizes of the two samples and their mixture are similar. We argue that substitution reactions take place after the two binary samples are mixed, which result in the formation of MSC-399 from its precursor compound (PC-399). The present study provides a room-temperature avenue to engineering alloy MSCs and an in-depth understanding of their probable formation pathway.

Target discovery of chlorogenic acid derivatives from the flower buds of Lonicera macranthoides and their MAO B inhibitory mechanism.

Chlorogenic acids (CGAs), exhibiting health benefits in many foods, also played an important role for their broad bioactive properties in nature. Obtaining more diverse CGAs was helpful to discover their potential edible and medical value. In this study, 11 CGAs, including four new (1-4) and seven known compounds (5-11), were obtained from the flower buds of Lonicera macranthoides Miq.-Hazz. The possible targets of all isolated CGAs were predicted using the ligand-based reverse screening and compound-target network, suggesting that MAO B (monoamine oxidase B) was the primary target of these CGAs. Subsequently, 7 out of 11 CGAs were confirmed to possess inhibitory effects by in vitro assay. The detailed interaction mechanism between compound and MAO B was also announced by molecular docking and molecular dynamics simulation.

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases.

Chinese medicine is a national treasure that has been passed down for thousands of years in China. According to the statistics of the World Health Organization, there are currently four billion people in the world who use Chinese medicine to treat diseases, accounting for 80% of the world's total population. However, the obscurity of its theory, its unmanageable quality, its complex compositions, and the unknown effective substances and mechanisms are great obstacles to the internationalization of Chinese medicine. Here, we propose a new strategy for the development of Chinese medicine: the clinical prescription (C)-protein (P)-small-molecule (S)-disease (D) strategy, namely the CPSD strategy. The strategy uses clinical prescriptions as the source of medicine and uses computer simulation technology to find small-molecule drugs targeting therapeutic proteins for treating specific diseases so as to deepen awareness of the value of Chinese medicine. At the same time, this article takes cardiovascular drug development as an example to introduce the application of CPSD, which will be instrumental in the further development, modernization, and internationalization of Chinese medicine.

Two new triterpenoids from Gardenia jasminoides fruits.

A new cycloartane triterpenoid, named gardenolic acid C (1), a new ursane triterpenoid, named 3ß,16ß,21ß,23,24-pentahydroxy urs-12,18,20-trien-28-oic acid γ-lactone (2), together with three know triterpenoids, gardenolic acid A (3), gardenolic acid B (4), and 3α,16ß,23,24-tetrahydroxy-28-nor-ursane-12,17,19,21-tetraen (5) were isolated from the fruits of Gardenia jasminoides Ellis. The structures of these compounds were elucidated by analyses of spectroscopic data. All isolates were evaluated for their neuroprotective effects in vitro.

Detection of Various Biomarkers and Enzymes via a Nanocluster-Based Fluorescence Turn-on Sensing Platform.

The profiling of disease-related biomarkers is an essential procedure for the accurate diagnosis and intervention of metabolic disorders. Therefore, the development of ultrasensitive and highly selective fluorogenic biosensors for diverse biomarkers is extremely desirable. There is still a considerable challenge to prepare nanocluster-based fluorescence turn-on probes capable of recognizing multiple biomolecules. We herein provide a novel nanocluster-based chemical information processing system (CIPS) for the programmable detection of various metabolites and enzymes. This CIPS consists of biocatalytic reactions between substrates and their respective oxidases to generate H2O2, which was then employed to synthesize bright fluorescent silver nanoclusters (Ag NCs). Utilizing this system, we are able to accurately probe a series of substrates/corresponding oxidases with high sensitivity and specificity, including glucose/glucose oxidase, uric acid/uric acid oxidase, sarcosine/sarcosine oxidase, choline/choline oxidase, xanthine/xanthine oxidase, and lactic acid/lactic acid oxidase. Furthermore, this metabolite profiling CIPS can be integrated with binary logic operations, which create an intelligent tool for the high-throughput screening of various diseases in vitro (e.g., diabetes, gout, prostate cancer, cardiovascular disease, and lactic acidosis).

Green, fast, and large-scale synthesis of highly fluorescent Au nanoclusters for Cu2+ detection and temperature sensing.

Gold nanoclusters have attracted widespread attention because of their unique optical and physical properties. However, traditional synthesis methods are complicated and require additional reducing agents, while the yield is often very low. Such resource and time-consuming synthesis processes limit their further application. Herein, a rapid sonochemical route is used to synthesize fluorescent Au nanoclusters in large quantities using glutathione (GSH) both as a capping and reducing agent. These Au nanoclusters are synthesized quickly (∼40 min) due to the presence of ultrasonic waves, and show orange red photoluminescence (Em = 598 nm), small size (∼2 nm) and good dispersion in aqueous solution. Moreover, GSH, as a protecting agent on the surface of resultant Au nanoclusters, has many functional groups including carboxyl and amino groups because of which the nanoclusters show high photo-, storage-, metal- and pH-stability. A stable Au nanoclusters-based nano-sensor is designed for highly sensitive and selective label-free detection of Cu2+ with a low limit of detection of 7 ppb (based on S/N = 3). The fluorescent probe can be used in versatile nanothermometry devices, because their photoluminescence intensity correlates strongly with temperature and varies considerably over a wide temperature range (20-80 °C). Therefore, the novel fluorescent sensing probe has great application prospects in Cu2+ detection and temperature sensing.

Red emitting and highly stable carbon dots with dual response to pH values and ferric ions.

The authors describe strongly red-emitting carbon dots (CDs) which were obtained via microwave synthesis using phenylenediamine as the carbon source. The structural and optical properties of the resultant CDs are studied in some detail. The CDs possess (a) longwave emission (peaking at 620 nm under 470 nm excitation), (b) a quantum yield of ~15%, (c) a size of typically 3.8 nm; and (d) good photostability. The CDs have a pH-dependet response that covers the pH 5 to 10 range, and their fluorescence is quenched by ferric ions. The CDs can detect ferric ions in aqueous samples in the 0 to 30 µM concentration range with a lower detection limit of 15 nM. The CDs were also used to image pH values and ferric ions in E. coli bacteria. Graphical abstract The red-emitting carbon dots with high stability are synthesized which show dual response to pH-values and ferric ions in aqueous solution and biological media simultaneously.

Design, synthesis and structure-activity relationship of a focused library of ß-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer.

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a ß-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor (21l) with best eEF2K enzymatic activity (IC50 of 5.5 µM) and anti-proliferative activity (MDA-MB-231 cells, IC50 of 12.6 µM, MDA-MB-436 cells, IC50 of 19.8 µM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo. These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer.

Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

OBJECTIVES: Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms. MATERIALS AND METHODS: Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms. RESULTS: We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1. CONCLUSIONS: These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy.