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Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 μM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,β-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

Compounds 1-3, the rare examples of 9,11-seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi. Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1. 1-3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC50 values in the range of 2.9-3.9 μM.

Substrate stiffness, as a critical mechanical factor, has been proven to be an important regulator of biological responses, cellular functions, and disease occurrence. However, the effects of substrate stiffness on the phenotypes and drug responses of neural cells remain largely unknown. In this study, polydimethylsiloxane (PDMS) substrates with different stiffnesses were employed to establish the mechanical microenvironment of tissues of different organs. We studied the influences of stiffness on neural cell phenotypes, including cell viability, cell cycle, cytoskeleton structures, cell stiffness, and drug responses of neural cells for hormesis and therapeutic efficacy in neurodegenerative disorders (NDD). The results showed that the greater the range of maximum stimulatory responses, the bigger the width of the stimulatory dosage and the higher the range of maximum neuroprotective activities of hormetic chemicals in neural cells grown on the soft substrate commensurable to the stiffness of the brain, indicating that neural cells on a rigid substrate are resistant to hormetic and neuroprotective effects of hormetic chemicals against 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. The sensitivity of neural cells on the soft substrate to drug response was attributed to the increased cell viability rate, cell cycle progression, actin stress fibers, focal adhesion formation, and decreased cell stiffness. The promoting effect of the soft substrate and the enhanced hormetic and neuroprotective effect of hormetic chemicals on soft substrates in PC12 cells were confirmed to be mediated by the upregulated EGFR/PI3K/AKT signaling pathway by RNA-Seq and bioinformatics analysis. This study demonstrates that the biomechanical properties of the neural microenvironment play important roles in cell phenotypes and drug responses of neural cells in vitro and suggests that substrate stiffness should be considered in the anti-NDD drug design and treatment.

Acute lung injury (ALI) involves series of inflammatory pathologies and cause high morbidity. Salviplenoid A (SA) was a new sesquiterpenoid from the traditional inflammatory herb Salvia plebeia. In our previous study, SA exhibited antiinflammatory activity in RAW264.7 cells. However, the extensive effects of SA in human cells and in vivo and the active mechanisms are unclear. Thus, in this study, we sought to access its effects in vitro and in vivo and to investigate its mechanisms. SA was proved to inhibit the induction of proinflammatory cytokines in human cell types, including pulmonary epithelial cells and endothetial cells. It also depressed monocyte adhesion. Moreover, SA potently attenuated the acute lung inflammation in the LPS-induced mouse model shown by down-regulation of proinflammatory mediators, inhibition of polymorphonuclear neutrophil infiltration, and alleviation of related symptoms like alveolar congestion and mucus secretion. Further evaluation confirmed that SA regulated NF-κB pathway by inhibiting the IκB-α phosphorylation. And it markedly mediated Nrf2/HO-1 pathway by activating the Nrf2/HO-1 expression and promoting Nrf2 nuclear translocation. Therefore, SA could attenuate acute lung inflammation via suppressing NF-κB and activating Nrf2, which provide a theoretical basis for the potential application of SA in clinic.

Static magnetic field (SMF) has a potential as a cancer therapeutic modality due to its specific inhibitory effects on the proliferation of multiple cancer cells. However, the underlying mechanism remains unclear, and just a few studies have examined the effects of SMF on metastasis, an important concern in cancer treatment. In this study, we evaluated the effects of moderate SMF (~150 mT) on the proliferation and migration of 4T1 breast cancer cells. Our results showed that SMF treatment accelerated cell proliferation but inhibited cell migration. Further, SMF treatment shortened the telomere length, decreased telomerase activity, and inhibited the expression of the cancer-specific marker telomerase reverse transcriptase (TERT), which may be related to expression upregulation of e2f1, a transcription repressor of TERT and positive regulator of the mitotic cell cycle. Our results revealed that SMF repressed both, cell migration and telomerase function. The telomerase network is responsive to SMF and may be involved in SMF-mediated cancer-specific effects; moreover, it may function as a therapeutic target in magnetic therapy of cancers.

The phytochemical investigation of the roots of Croton crassifolius led to the isolation of 16 new halimane furanoditerpenoids, crohalifuranes A-P (1-16), along with 15 known analogues, 17-31. The new structures including their absolute configurations were elucidated by NMR and MS data analysis, comparison of experimental and calculated electronic circular dichroism data, single-crystal X-ray diffraction data, and chemical methods. Crohalifuranes A (1) and B (2) are tetranor- and 19-nor-halimane diterpenoids featuring a rare decahydroacenaphthene core, respectively, which might be derived from the accompanying crassifoliusin A by loss of the furan ring or the C-19 substituent. Crohalifurane C (3) represents the first example of a 20-nor-halimane diterpenoid, and crohalifurane D (4) is characterized by an unusual 6,20-δ-lactone moiety. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide in RAW264.7 cells, and 2 and 23 exhibited moderate inhibition on NO production with IC50 values of 17.2 ± 1.3 and 23.7 ± 1.4 μM, respectively.

Two new lathyrane diterpenoids, euphanoids A and B (1 and 2), along with five known compounds (3–7) were isolated from the roots of Euphorbia kansuensis. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by single crystal X-ray diffraction. All of the isolates were screened for the inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 1 and 2 showed pronounced inhibition on NO production with IC50 values of 4.7 and 9.5 μM, respectively, being more active than the positive control, quercetin (IC50 = 10.8 μM).

A ratiometric sensor through the built-in correction gains stronger anti-interference ability and more accurate analysis results compared with a single-signal sensor. Herein, a novel ratiometric assay platform coupled with fluorescence (FL) and scattering has been constructed for the selective and accurate quantization of Br−/I−. The ratiometric sensor is based on a metal–organic nanosystem, which is constructed via coordination bonding-induced self-assembly between non-conjugated polymer nanoparticles (NC-PNPs) and Hg(II), consequently displaying fluorescence and strong second-order scattering (SOS) signals. In the response system, the NC-PNPs function as a signal unit, and the Hg(II) ion serves as a recognition element. Upon the introduction of Br−/I−, the high affinity with Hg(II) makes Br−/I− snatch Hg(II) from the NC-PNP–Hg(II) nanosystem, causing the nanocomplex to disassemble. The target-triggered disaggregation results in a decrease in the SOS intensity, and meanwhile the Hg–Br− or Hg–I− compounds produced in situ reduce the FL intensity of the NC-PNPs via static quenching, suggesting the feasibility of ratiometric Br−/I− detection. Finally, the FL–SOS dual-signal strategy towards Br−/I− is successfully applied to real water/food samples. The ratiometric analytical platform coupled with FL and SOS offers a new perspective for applications based on target-induced aggregation and disaggregation behavior.

Developing novel luminescent materials for sensitive and rapid detection of phosphate (Pi) is vital in clinical diagnoses and water-quality monitoring. Herein, a lanthanide coordination polymer (NH2-BDC–TbGMP CPs)-based ratiometric fluorescent probe is designed for quick and visual detection of Pi. The NH2-BDC–TbGMP CPs are prepared via the self-assembly of 2-aminoterephthalic acid (NH2-BDC) and guanine monophosphate (GMP) with terbium ions (Tb3+). After the formation of NH2-BDC–TbGMP CPs, the inherent fluorescence of NH2-BDC is quenched via static quenching, while the nonluminous Tb3+ can emit strong green fluorescence due to the antenna effect between Tb3+ and GMP. In the presence of Pi, Pi can competitively combine with Tb3+ to interrupt the interaction of the NH2-BDC–TbGMP CP system, further causing a decrease in the fluorescence of Tb3+ and an increase in the emission of NH2-BDC. Accordingly, the ratiometric fluorescence sensing of Pi can be achieved by continuously recording the variations of two fluorescence signals. The corresponding fluorescence intensity ratio of Tb3+ to NH2-BDC (F547/F425) is linearly correlated with the Pi concentration in the range of 0.5 to 100 μM, with a detection limit of 0.13 μM. This strategy offers a simple, rapid, and sensitive method for the ratiometric fluorescence and visual sensing of Pi, which shows great application potential for water-quality monitoring.

Jatrofolianes A (1) and B (2), which are two highly modified lathyrane diterpenoids, were isolated from Jatropha gossypiifolia. 1 incorporates an unusual transannular 1,3-dioxolane moiety, forming a unique 5/6/5/8/3 ring system, while 2 possesses a new 10,11:13,14-diseco-lathyrane skeleton with a 12-membered macrocyclic lactone ring. Their structures were determined by spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction. 2 showed significant multidrug resistance (MDR) reversal activity to cancer cells HepG2/ADR and HCT-15/5-FU at 10 μM.

The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms are related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer.

Colorectal cancer (CRC) is one of the most common cancer types and a leading cause of cancer-associated mortality in China. Increased thioredoxin reductase 1 (TrxR1) levels have been previously identified as possible target for CRC. The present study revealed that the natural product hydroxytyrosol (HT), which exhibits a polyphenol scaffold, is a potent inhibitor of TrxR1. Inhibition of TrxR1 was indicated to result in accumulation of reactive oxygen species, inhibit proliferation and induce apoptosis and G1/S cell cycle arrest of CRC cells. Using a C-terminal mutant TrxR1 enzyme activity assay, TrxR1 RNA interference assay and HT binding model assay, the present study demonstrated the core character of the selenocysteine residue in the interaction between HT and TrxR1. HT can serve as polyphenol scaffold to develop novel TrxR1 inhibitors for CRC treatment in the future.

A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (–)-fusaspoid A (1a/1b) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.

Ammonia concentration together with pH values are important and closely linked indexes for aqueous systems. Rapid on-site determination of ammonia or pH is of great significance to environmental monitoring. In this work, a pH-switchable nanoprobe based on biomass carbon dots (CDs) is developed using a smartphone as a simple and handy instrument. The CDs demonstrate sensitive pH response in wide linear ranges of 6.1–13.6, and 2.0–13.6 with colorimetric and fluorescent channels, respectively. It is the pH-induced aggregation that governs the color and fluorescence switch. With the pH evolution caused by the dissolution of ammonia, the smartphone-integrated nanoprobe is applied to ammonia detection with a broad range of 0.5–300 mM. Moreover, the headspace single drop microextraction strategy can concentrate ammonia from matrix, offering a remarkably high selectivity for ammonia determination. Finally, the practical applications of this method for ammonia analysis obtained satisfactory results.

Ratiometric sensing suffers from less interference and can obtain more accurate results than single-signal assay. Here, a new ratiometric optical sensing strategy for H2O2 detection is developed by etching silver nanoparticles (AgNPs) to deactivate fluorescence resonance energy transfer (FRET) and reduce Rayleigh scattering based on a hyphenated technique of fluorescence and second-order Rayleigh scattering (SRS). The ratiometric detection of H2O2 is achieved through exploiting a hybrid system fabricated by fluorescent carbon dots and silver nanoparticles (CDs/AgNPs). In the CDs/AgNPs system, the fluorescence of CDs is quenched because of FRET, and the scattering is strong due to the intrinsic high light-scattering power of AgNPs. With the introduction of H2O2, the AgNPs are etched and the CDs are released from the AgNP surface, resulting in the fluorescence enhancement and scattering decline. As a result, ratiometric sensing of H2O2 can be achieved based on the CDs/AgNPs system by simultaneous collection of fluorescence and SRS signals. The sensing system is further used for H2O2-generation bioanalysis, and as a proof-of-concept, ratiometric assay of glucose and evaluation of glucose oxidase activity are performed successfully. This work provides a new perspective for sensing applications of plasmonic nanoparticles.

A simple and label-free fluorescence turn-on method is proposed for the discrimination and detection of epinephrine (Ep) and dopamine (DA) via polyethyleneimine (PEI)-initiated in situ copolymerization and excitation wavelength switch. The PEI solution in the presence of Ep, DA and the mixture of Ep and DA are denoted as PEp-PEI, PDA-PEI and MEp+DA, respectively. In this study, PEI aqueous solution medium initiates the auto-oxidization of Ep and DA and the bioinspired copolymerization. These resultant copolymers emit yellow-green fluorescence color with a fluorescence emission maximum at 515 nm. Interestingly, these fluorescent copolymers exhibit distinct different excitation spectra, although Ep and DA are structurally very similar. PDA-PEI exhibits only one excitation peak at 385 nm, and PEp-PEI shows dual-excitation mode with two significant excitation peaks at 328 nm and 405 nm, respectively. MEp+DA also shows dual-excitation mode with two excitation peaks at 330 nm and 395 nm, respectively. Thus, individual Ep, DA, and their mixture can be discriminated based on the different excitation spectral shapes and peak locations of PEp-PEI, PDA-PEI and MEp+DA. Furthermore, the quantitative analysis of Ep and DA in mixture can also be achieved by switching excitation wavelength between 330 and 395 nm and monitoring the fluorescence emission intensity of MEp+DA at 515 nm. The fluorescence intensity of MEp+DA only related to the concentration of Ep when excited at 330 nm. Moreover, the concentration of DA can also be calculated by subtracting the fluorescence intensity of PEp-PEI from the total fluorescence intensity when excited at 395 nm. The resultant method has been used to simultaneously detect Ep and DA in human urine samples. The proposed fluorescence system is facile, eco-friendly, low-cost, and time-saving, and also provides a new and simple path for discriminating analogues.

The development of ratiometric fluorescent strategy is very significant and challenging in bioanalysis. Herein, graphitic carbon nitride (g-C3N4) nanosheets and cobalt oxyhydroxide (CoOOH) nanoflakes are exploited for ratiometric fluorescence assay of alkaline phosphatase (ALP) activity. In the g-C3N4/CoOOH nanohybrid, g-C3N4 nanosheets serve as a signal unit and the CoOOH nanoflakes function as a recognition element, and initially, the fluorescence of g-C3N4 is quenched by the CoOOH nanoflakes. In the absence of target, the CoOOH nanoflakes of the nanohybrid system are able to oxidize o-phenylenediamine (OPD), and the resultant oxidation product (OxOPD) quenches the blue emission of g-C3N4 and meanwhile emits orange fluorescence which acts as another signal element. However, an efficient redox reaction between ascorbic acid (AA) and CoOOH can cause decomposition of the CoOOH nanoflakes, and additionally, ALP can catalytically hydrolyze L-ascorbic acid-2-phosphate (AAP) to generate AA. Thus, in the presence of target, the CoOOH nanoflakes are destroyed by AA preferentially and the OPD is rarely oxidized to OxOPD, accompanied with strong blue emission of g-C3N4 and weak orange fluorescence from OxOPD. Target-dependent dual-signal change made the ratiometric assay possible, and also AA-induced signal variation was investigated and attributed to the stronger reducing capacity of AA than OPD. The ratiometric sensing platform for ALP activity assay provides a new perspective for the applications of two-dimensional nanomaterials to develop novel and sensitive biosensors.

The Red-emitting nitrogen-doped carbon dots (N-CDs) are synthesized using o-phenylenediamine by a one-step method, and can serve as a fluorescent probe for "turn off" detection of hematin in human red cells. The red-emitting N-CDs can be obtained only in acidic conditions and the emission of the red-emitting N-CDs is pH-dependent, indicating proton-controlled synthesis and emission. The red-emitting N-CDs are 2.7 nm in mean size and have a uniform dispersion and exhibit a high quantum yield (12.8%) and great optical properties. The developed sensing system for hematin displays a linear response from 0.4 to 32 μM with a detection limit of 0.18 μM. Importantly, this fluorescent probe demonstrates a good potential practicability for the quantitative detection of hematin in complex matrixes. Graphical abstract ᅟ.

Apoferritin caged a huge amount of photocatalysts and enhanced H2 generation capability under homogeneous acidic conditions., We took advantage of the iron binding affinity of apoferritin to immobilize iron–sulfur clusters into apoferritin up to 312 moieties per protein, with a loading rate as high as 25 wt%. The photocatalytic hydrogen generation activity in acidic aqueous solutions was achieved with TONs up to 31 (based on a single catalyst moiety) or 8.3 × 103 (based on a single protein) upon 3 h of visible light irradiation. The present study provides a versatile strategy to construct uniform protein/photocatalyst supramolecular systems with FeFe-H2ase activity.

Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development.

Developing a multifunctional platform for the selective detection and effective removal of toxic ions is a major challenge when addressing heavy metal contamination in environmental science. Herein, novel nonconjugated polymer nanoparticles (PNPs) called mercaptosuccinic acid-thiosemicarbazide PNPs (MT-PNPs) with appealing fluorescence and stability are synthesized via facile one-step hydrothermal treatment for attractive sensing and simultaneous removal of mercury(II). Interestingly, aggregation-induced fluorescence switch-off and scattering enhancement are found upon the addition of Hg2+, rendering MT-PNPs as a ratiometric sensor for selective and accurate Hg2+ monitoring. A wide linear range (0.1-1471 μM) and a low detection limit (95 nM) are obtained. This dual-signal opposite responses triggered by Hg2+ originate from the formation of MT-PNP-Hg2+ congeries via the multisite binding between S,N,O-containing groups of MT-PNPs and mercury. Meanwhile, target-induced aggregation renders an effective Hg2+ separation from contaminative aqueous media by MT-PNPs, which exhibits a satisfactory absorption efficiency of 90.42% within 50 min. Upon the simple Na2S treatment, the MT-PNPs can be regenerated and reused. This work thus delivers an applicable method for the ratiometric detection and effective removal of mercury with the novel nonconjugated PNPs, offering potential in tackling the problem of heavy metal ion pollution for environmental monitoring and remediation.

Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101's antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.

Thirteen new jatrophane diterpenoids, euphoresulanes A–M (1–13), and seven known analogues (14–20) were isolated from the whole plants of Euphorbia esula. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of 1, 6, and 10 were confirmed by single crystal X-ray diffraction. Compounds 1–20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent cancer cell line HepG2/ADR, and 1, 2, 4, 6, and 8 exhibited comparable activity to the positive drugs. Euphoresulane H (8), the most active MDR modulator, could enhance the efficacy of anticancer drug adriamycin to ca. 33 folds at 5 μM. The structure–activity relationship (SAR) study revealed that the acyloxy substitution at C-9 is essential to the activity and presence of H-2 was favorable.

Ascorbic acid (AA) is an important diet-derived antioxidant to human body. Thus, efficient and accurate detection of AA is of considerable significance in food analysis. Herein, smartphone assisted colorimetric and fluorescent triple-channel signal sensor has been developed for AA monitoring based on oxidase-like CoOOH nanoflakes. CoOOH nanoflakes can efficiently catalyze the oxidation of p-phenylenediamine (p-PD) into reddish brown p-PDox. The carbon dots (C-dots) are further introduced, of which the fluorescence can be quenched by p-PDox. However, in the presence of AA, the CoOOH nanoflakes is reduced and thus collapsed. As a result, the oxidation of p-PD is restrained, and thus the fluorescence of C-dots keeps strong. Based on AA induced light color, low absorbance, and strong fluorescence, triple-channel signal sensor has been proposed for AA determination. The AA assay shows a dynamic response range from 0.5 to 10 μM with a detection limit of 0.09 μM. The method assay allows detection of AA in real samples such as fruit juices. Combination with portable smartphone, the developed sensor is potential for AA determination in resource-poor settings.

A fluorescence method for the determination of picric acid (PA) using phosphorus-doped carbon dots (P-CDs), synthesized from β-cyclodextrin and sodium pyrophosphate, is described. The P-CDs are very uniform and monodisperse with a diameter of about 2.8 nm. Under an excitation of 350 nm, the P-CDs emit bright blue fluorescence with an emission peak at 440 nm. The as-synthesized P-CDs serve as a sensitive, selective, and label-free fluorescent probe for the detection of PA. Based on an inner filter effect between PA and P-CDs, a linear response is obtained for PA from 0.1 to 10 μM with a detection limit of 82 nM. Finally, this sensing system has been demonstrated to have practicability for PA detection in the environmental water samples.

Motivation Finding driver genes that are responsible for the aberrant proliferation rate of cancer cells is informative for both cancer research and the development of targeted drugs. The established experimental and computational methods are labor-intensive. To make algorithms feasible in real clinical settings, methods that can predict driver genes using less experimental data are urgently needed. Results We designed an effective feature selection method and used Support Vector Machines (SVM) to predict the essentiality of the potential driver genes in cancer cell lines with only 10 genes as features. The accuracy of our predictions was the highest in the Broad-DREAM Gene Essentiality Prediction Challenge. We also found a set of genes whose essentiality could be predicted much more accurately than others, which we called Accurately Predicted (AP) genes. Our method can serve as a new way of assessing the essentiality of genes in cancer cells. Availability and implementation The raw data that support the findings of this study are available at Synapse. https://www.synapse.org/#! Synapse: syn2384331/wiki/62825. Source code is available at GitHub. https://github.com/GuanLab/DREAM-Gene-Essentiality-Challenge. Supplementary information Supplementary data are available at Bioinformatics online.

The various synthetic routes of carbon dots (C-dots) feature a considerable step toward their potential use in sensors and biotechnology. Herein, by coupling pyrophosphate introduction with high-energy phosphate bond design, the fluorescence performance of C-dots is improved greatly. The introduction of pyrophosphate acts as the nucleus growth-inhibitor to protect C-dots from assembling and growing into large carbon particles. The high-energy phosphate bond is designed as an energy-donor to provide energy for synthesizing C-dots. The C-dots exhibit enhanced fluorescence with a high quantum yield of 24.8%. Then the C-dots are employed as the fluorescent probe to develop hydrogen peroxide (H2O2)-related biosensors. The mechanism is based on the fluorescence quenching of C-dots caused by the highly reactive OH and Fe3+ during the Fenton reaction. A wide linear range (0.5–100 μM) and a low detection limit (0.195 μM) are achieved for H2O2 detection. Moreover, the probe can be applied to H2O2-related biosensing in the presence of oxidase. As a proof-of-concept, a glucose sensor is developed with glucose oxidase. The presented glucose sensor exhibits good selectivity and high sensitivity with a detection limit of 0.254 μM. Additionally, the practical application of the proposed biosensor has been confirmed by detecting glucose in human serum samples.

Seven new diterpenoids, eupholenes A-G (1-7), including two presegetanes (1 and 2), four jatrophanes (3-6), and one paraliane (7), along with 19 known analogues (8-26) were obtained by anti-liver fibrosis bioassay-guided isolation of Euphorbia sieboldiana. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, ECD calculations, and single-crystal X-ray diffractions. Euphorbesulin A (10), a presegetane diterpenoid (5/9/5 ring system), was identified as a promising anti-liver fibrosis agent that could inhibit the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I in TGF-β1-stimulated LX-2 cells at a micromolar level. Mechanistic study revealed that 10 suppressed liver fibrosis via inhibition of TGF-β/Smad signaling pathway, and its potential target was TGF-β type I receptor. These findings suggested that presegetane diterpenoid could serve as a new type of structural motif in future anti-liver fibrosis drug development.

Isotactic polypropylene/poly(l-lactide) blends were toughened by blending polyethylene-glycidyl methacrylate (EGMA) as compatibilizer and dicumyl peroxide (DCP) as compatibilization accelerator. Isotactic polypropylene (iPP)/poly(l-lactide) (PLLA)/EGMA/DCP blends showed remarkably improved impact toughness and excellent flexibility, moderate levels of strength, and modulus. Reactive compatibilization between iPP and EGMA as well as PLLA and EGMA was studied using Fourier transform infrared spectroscopy. The “salami”-like phase structure of the dispersed domains in the iPP/PLLA/EGMA ternary blends was observed. With the further addition of DCP, the EGMA phase evolved from occluded sub-inclusions into an interface boundary. The significant increase in impact strength of iPP/PLLA/EGMA/DCP blends was ascribed to the effective interfacial compatibilization. This study provides a new route to prepare a cost-effective material with partial biodegradability, good impact toughness, and tensile strength. Meanwhile, a deep insight into the optimization of properties of multicomponent blends by morphology transition was proposed.

Using carbon dots as the reductant and stabilizer, a visible and fluorescent method was developed for melamine detection in raw milk with one-step synthesized silver nanoparticles. In this work, carbon dots (C-dots) were applied to reduce silver ions and stabilize the nanoparticles, resulting in the formation of silver nanoparticles (AgNPs). As a result, the inherent fluorescence emission of C-dots was significantly reduced after the formation of AgNPs. However, in the presence of melamine, silver ions could interact with the nitrogen atoms in amine and triazine groups of melamine. With 0–2 μM melamine, aggregated AgNPs were found after the reduction by C-dots, resulting in color and absorbance changes. With further increase of melamine (2–20 μM), both formation and aggregation of AgNPs were inhibited, and the fluorescence was gradually increased. This optical platform was optimized for melamine detection and then was applied to detecting melamine in raw milk samples. The results for melamine assay based on visible and fluorescent method showed the requisite sensitivity with a low detection limit of 30 nM, as well as high selectivity.

The degradation of rapeseed oil methyl ester (RME) under accelerated conditions was investigated by use of total fluorescence spectroscopy (TFS). This technique provides an easy and quick analysis of natural antioxidants (e.g. vitamin E, chlorophylls, etc.) and of oxidation products (e.g. hydroperoxides and oligomers) of RME at their characteristic excitation and emission wavelengths. In the result it was proven that similar to the specification related Rancimat-test (EN 14112) the oxidation stability of RME could be determined by fluorescence signals of the oxidation products. Additionally a quick and direct determination of the degradation degree and the oxidation stability of RME by fluorescence spectroscopy is enabled by use of the correlation between the Rancimat- and the fluorescence-measurement.

We have demonstrated a fluorescence approach for rapid, environment-friendly, and selective detection of Cu2+ in aqueous media using a kind of easily prepared and autofluorescent polymer nanoparticles (PNPs) as a sensor. The PNPs were synthesized by crosslinking hyperbranched polyethyleneimine (hPEI) with formaldehyde in water solution, and they emitted strong intrinsic fluorescence without the conjugation to any external fluorescent agent. The Cu2+ assay was on the basis of the principle that Cu2+ can be adsorbed on the surface of the PNPs, resulting in the fast and remarkable fluorescence quenching through electron transfer. The developed sensor was applied to the analysis of copper ions in environmental water samples with satisfactory results. Furthermore, the fluorescence of the PNPs-Cu2+ system can restore upon addition of cysteine (Cys) because of its ability to remove Cu2+ from the surface of PNPs. Based on the fluorescence “on-off-on” conversion, a reversible IMPLICATION logic gate was designed by using Cu2+ and Cys as the two inputs, and fluorescence intensity of the PNPs as the output signal.

In this work, novel water-soluble and blue fluorescent carbon dots (C-dots) were synthesized using one-pot hydrothermal method with malonic acid and urea, and were then used as a label-free fluorescent probe for selective, sensitive, and rapid determination of picric acid (PA). The sizes of the as-prepared C-dots were mainly distributed in the range of 1.5–3.0 nm with an average diameter of 2.5 nm. Moreover, the C-dots displayed blue fluorescence with an emission peak at 395 nm (320 nm excitation), which also showed good stability and anti-photobleaching ability. Interestingly, the fluorescence of C-dots could be selectively quenched by PA within 10 s. Based on this phenomenon, a label-free fluorescence assay was proposed for specific determination of PA. The fluorescence intensity of probe showed a linear response to PA in the concentration range of 0.1 to 26.5 μM with a low detection limit of 51 nM (S/N = 3). Finally, the resultant fluorescent probe was successfully applied to the detection of PA in real water samples.

Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.

Twenty new ingol diterpenoids, euphornans A–T (1–20), representing a rare class of C-19-oxidated and H-2, H-3 β-oriented ingols, were isolated from the seeds of Euphorbia marginata. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, ECD analysis, and single crystal X-ray diffraction. Compounds 1–20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent MDR cancer cell line HepG2/ADR, and 11, 14, and 18 were identified as potent MDR modulators that could enhance the efficacy of anticancer drug adriamycin to ca. 20 folds at 5 μM. The Pgp inhibition mechanism and brief structure–activity relationships (SARs) of these compounds were also discussed.

Rapid and sensitive detection of surfactants has attracted more and more attention since surfactants not only cause water pollution but also affect the health of human beings. Luminescent metal-organic frameworks combining unique optical property and inherent permanent porosity for guest-host encapsulation are widely used in fluorescence detection. Here we report a ratiometric fluorescent probe (denoted as UiO-66-NH

Copper is an essential mineral nutrient for the human body. However, excessive levels of copper accumulated in the body can cause some diseases. Therefore, it is great significant to establish a sensitive bioprobe to recognize copper ions (Cu2+) in vivo. In our work, nitrogen-doped carbon dots (N-CDs) and gold nanoclusters (Au NCs) are selected as luminescent nanomaterials and the Au NCs/N- CDs nanohybrids is successfully synthesized by coupling method. The Au NCs/N-CDs exhibited characteristic dual-emission peaks at 450 and 620 nm when excited by a single-wavelength of 380 nm. When different amounts of Cu2+ are introduced, the fluorescence intensity of the Au NCs is gradually weakened and fluorescence intensity of the N-CDs is almost unchanged, which can facilitate the visual detection of Cu2+. The Au NCs/N-CDs nanohybrid possesses good selectivity to Cu2+ with a limit of detection (LOD) is 3.5 μM and linear detection range of 10–150 μM. Visualization detection of Cu2+ is implemented by using nanoprobe in water samples. Furthermore, the ratiometric nanoprobe is utilized to the toxicity test of liver cancer cells, indicating excellent biocompatibility and low toxicity. This nanoprobe has been used to the intracellular fluorescence imaging. Moreover, this method is expected to be used to monitor the changes of Cu2+ concentration in hepatocytes.

The stem and root barks of Daphne giraldii Nitsche, also known as “Zushima”, is a traditional Chinese medicine with a long history of treating a variety of diseases such as rheumatism arthralgia, quadriplegia, headache, stomachache, waistache, and bruises. Chromatographic fractionation of the EtOH extracts of “Zushima” has led to the isolation of 26 flavonoids, including ten flavonols (1, 2, and 4–11), one flavone (12), two dihydroflavones (13 and 14), a dihydroflavonol (15), six flavans (3 and 16–20), three chalcones (21–23), and three 1,3-diarylpropanes (24–26). Daphgiflavones A−C (1–3) were new flavonoids. Their structures were elucidated by spectroscopic analysis. All compounds were evaluated for anti-inflammatory properties by testing their inhibitory activities against nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages. Compounds 8, 11, 21, and 23 exhibited significant inhibition on NO production with IC50 values ranging from 2.26 to 6.88 μM, being more active than the positive control quercetin (IC50: 14.16 μM).

Based on the 7-nitro-1,2,3-benzoxadiazole (NBD) unit, many fluorescent probes have been developed for the differential detection of biothiols. Among them, however, the use of fluorescent probes for rapid simultaneous identification of biothiols in vivo has been rarely reported. In this work, a simple fluorescent probe (NC-NBD) is rationally designed and developed according to the different reactivity of biothiols, which can simultaneously distinguish homocysteine (Hcy), cysteine (Cys), and glutathione (GSH) by adjusting two different fluorescence signals (green and yellow). The probe NC-NBD can discriminatively detect biothiols using two fluorescence channels with fast response (120–360 s), which is suitable for real-time monitoring of biothiols in biological systems. As expected, the probe NC-NBD with excellent performance is able to determine the levels of Cys/Hcy and GSH in human serum samples, and therefore has potential applications in biological specimens. The robust probe shows low toxicity and high sensitivity when applied to living cells, and successfully achieves rapid sequence distinguishing of biothiols and intracellular imaging by using two different fluorescence signals. The probe can provide an effective tool for the real-time monitoring of intracellular biothiols.

This paper presents a comprehensive study of the self-assembly dynamics and the biosensing efficacy of Tobacco mosaic virus-like particle (TMV VLP) sensing probes using an impedimetric microsensor platform. TMV VLPs are high surface area macromolecules with nanorod structures constructed from helical arrangements of thousands of identical coat proteins. Genetically modified TMV VLPs express both surface attachment-promoting cysteine residues and FLAG-tag antibody binding peptides on their coat protein outer surfaces, making them selective biosensing probes with self-assembly capability on sensors. The VLP self-assembly dynamics were studied by the continuous monitoring of impedance changes at 100Hz using interdigitated impedimetric microsensors. Electrical impedance spectroscopy revealed VLP saturation on impedance sensor surface with the coverage of 68% in self-assembly process. The VLP-functionalized impedance sensors responded to 12ng/ml to 1.2μg/ml of target anti-FLAG IgG antibodies in the subsequent enzyme-linked immunosorbent assays (ELISA), and yielded 18-35% total impedance increases, respectively. The detection limit of the target antibody is 9.1ng/ml using the VLP-based impedimetric microsensor. These results highlight the significant potential of genetically modified VLPs as selective nanostructured probes for autonomous sensor functionalization and enhanced biosensing.

Nine new melodinus-type alkaloids, melohemsines A-I (1–9), together with eight known ones were isolated from Melodinus hemselyanus. The structures of the new alkaloids, including their absolute configurations, were elucidated on the basis of comprehensive spectroscopic and electronic circular dichroism (ECD) analyses and X-ray diffraction. Compound 1 is the first melodinus-type alkaloid with a 6/6/5/5/6/3 hexacyclic ring skeleton system. Compounds 2–3 are the first natural melodinus-type alkaloids with a reduction in two carbon units at C-20.

An unprecedented indole alkaloid melosline A (1), with 6/5/6/6 tetracyclic ring skeleton, together with a new alkaloid melosline B (2) and one known compound (3) were isolated from the leaves and twigs of Alstonia scholaris. The new structures were elucidated by comprehensive spectroscopic analysis. The absolute configuration of compound 1 was confirmed by comparison of experimental data with calculated electronic circular dichroism (ECD). Compound 1 exhibited moderate cytotoxicity against MCF-7 cancer cell lines. (C) 2017 Elsevier Ltd. All rights reserved.

Controlled-synthesis of carbon nanodots (CNDs) with tunable properties has always been challenging. Here, novel CNDs (blue-emitting CNDs (b-CNDs) and green-emitting CNDs (g-CNDs)) with tunable redox abilities and emission are synthesized via one-pot hydrothermal method. The redox ability of CNDs is regulated by surface state tailoring. The abundant reductive groups on the surfaces endow the b-CNDs appealing reducibility, whereas g-CNDs with fewer surface functional groups are deficient in reducibility. Using HAuCl4 indicator, the distinct reducibility of CNDs is visually identified. Gold salts are reduced to Au nanobelts under reduction and stabilization of b-CNDs, causing plasmons-induced color changes, whereas g-CNDs have no reduction effect on Au3+. The size-evolution process of Au nano-species can guide not only plasmonic absorbance alteration but also fluorescence (FL) and second-order scattering (SOS) changes. Therefore, based on the plasmonic morphology-induced SOS increasement and the Forster resonance energy transfer-induced FL switch off, the b-CNDs contribute to a ratiometric sensor coupled with FL and SOS for Au3+ detection. The ratiometric strategy displays a better sensitivity and selectivity and a broader linear range than single-signal SOS or FL method. The regulation of redox CNDs and ratiometric assay of Au3+ provide a new prospect for the preparation and application of versatile CNDs.

Eight previously undescribed diterpenoids, euphoroyleans A−H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A−H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 μM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking.

Four new tetracyclic triterpenoids (1–4) were isolated from the leaves and twigs of Jatropha gossypiifolia. Their structures were elucidated by MS and NMR data analysis, together with the Mo2(OAc)4-induced CD data. Jagabeoeuphols A-C (1–3) are rare 19(10 → 9)abeo-euphane-type triterpenoids possessing a Δ5(10) group and a 7,8-epoxide moiety, and jagoseuphone A (4) is a typical euphane-type triterpenoid. The inhibitory effects of 1–4 on nitric oxide production induced by lipopolysaccharide in RAW264.7 cells were evaluated, and 4 exhibited moderate inhibitory activity with an IC50 value of 20.1 μM.