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Dimethyl indole Dye IDE was applied to the detection of Lys and Arg level in living cells and zebrafish larvae successfully, and it will be a useful fluorescence indicator for pH changes by Lys and Arg.

A new method for the O-alkylation of secondary and tertiary cinnamyl alcohols with primary alcohols by employing CuSO4·5H2O and neocuproine as catalysts was developed, and PEG-modified secondary and tertiary cinnamyl alcohols can be achieved directly.

Recently, we published a paper on the detection of superoxide (O2•-) with a water-soluble fluorescent probe (ACS Sens. 2018, 3, 59-64), and Francesco Tampieri et al. provided comments on our publication, mostly on the detection medium (deionized water) we used. Herein we present our responses to the addressed questions to explain that although KO2 decomposes in aqueous environment, the results we obtained did not affect the general trend, since evidence from the literature afforded the correlation between KO2 in aqueous media as a surrogate of superoxide and enzymatically produced O2•- for the probes wherein the deprotection pathway operated. Moreover, fluorescence imaging on cells and zebrafish embryos under PMA stimulation confirmed the effectiveness of our probe to detect superoxide using KO2 as a convenient source. The detailed studies from Francesco Tampieri and coauthors are scientifically meaningful for the reliable evaluation of fluorescent probes using KO2 as a surrogate of superoxide.

Novel cyanine-based fluorescent probes for the detection of H2S were developed. The probes developed are stable under physiological conditions. The water soluble fluorescent probe 2 displayed ultrafast and specific response to H2S displaying NIR fluorescence of 115-fold turn-on with the detection limit of 11 nM without assistance of organic solvent or surfactant. Cell imaging experiments indicated that probe 2 was cell-permeable and was able to detect H2S sensitively in lysosomes. Moreover, our probe was able to detect H2S intrinsically produced H2S through enzymatic/non-enzymatic biosynthetic pathway from Cys/GSH. Moreover, we applied probe 2 to detect H2S in living mice and demonstrated the fast metabolism of H2S. Thus, probe 2 shows great promise as a reporter for H2S.

Hypoxia is considered as a key microenvironmental feature of solid tumors. Luminescent transition metal complexes particularly those based on iridium and ruthenium have shown remarkable potentials for constructing sensitive oxygen‐sensing probes due to their unique oxygen quenching pathway. However, the low aqueous solubility of these complexes largely retards their sensing applications in biological media. Moreover, it remains difficult so far to use the existing complexes typically possessing only one luminescent domain to quantitatively detect the intratumoral hypoxia degree. Herein, an Ir(III) complex showing red emissions is designed and synthesized, and innovatively encapsulated within a hydrophobic pocket of Cyanine7‐modified cyclodextrin. The Ir(III) complex enables the oxygen detection, while the cyclodextrin is used not only for improving the water solubility and suppressing the luminescence quenching effect of the surrounding aqueous media, but also for carrying Cyanine7 to establish a ratiometric oxygen fluorescence probe. 2D nuclear magnetic resonance is carried out to confirm the host–guest structure. The oxygen‐responsive ability of the resulting ratiometric probe is evaluated through in vitro cell and multicellular experiments. Further animal studies about tumor oxygen level mapping demonstrate that the probe can be successfully used for quantitatively visualizing tumor hypoxia in vivo., Cyanine7labeled β‐cyclodextrin is used to encapsulate an hydrophobic oxygen sensitive Iridium complex to form a sensitive ratiometric fluorescence probe that can be used for quantitatively detecting the hypoxia degrees of both cytoplasm and nucleus of cancer cells in vitro. Owing to the outstanding sensitivity, it can also be used for quantitatively mapping the oxygen levels of tumors in vivo.

Objectives 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is useful for the detection of cancerous lesions, and FDG uptake is related to the apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) of extracranial tumors. The purpose of our study was to investigate the ability of FDG PET/CT in distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma multiforme (GBM) and to explore the relationship between 18F-FDG uptake and the ADC in patients with PCNSL. Methods We reviewed 92 patients (40 with PCNSL and 52 with GBM) who underwent FDG PET/CT scans at disease onset. The maximum standardized uptake value (SUVmax), tumor to normal contralateral cortex activity (T/N) ratio, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of tumor lesions were calculated. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic performance for FDG PET-related parameters to differentiate PCNSL from GBM. Twenty-eight patients with PCNSL (with 34 lesions) also underwent diffusion-weighted imaging. Pearson’s correlation analysis was used to assess the relation between SUV- and ADC-derived parameters. Results The SUVmax, T/N ratio, SUVmean, and TLG values were significantly higher in PCNSL than in GBM. Comparative ROC analysis indicated that the SUVmax had a greater area under the curve (AUC) of 0.910 than the T/N ratio (0.905, P = .85), SUVmean (0.836, P = .0006), or TLG (0.641, P Conclusions The SUVmax and T/N ratio may be reliable measures for differentiating PCNSLs from GBMs. Additionally, FDG metabolism indices were inversely proportional to the rADCs of PCNSL lesions.

Introduction The objective of this study was to synthesize an N-methyl- d -aspartate receptor (NMDAR) radiotracer [18F]-GE-179 in one-pot and evaluate its in vivo binding for NMDAR activation after brain ischemia reperfusion injury. Methods [18F]-GE-179 was auto-synthesized using a quick one-pot method from a stable disulfide precursor and purified using semi-preparative high-performance liquid chromatography (HPLC) with ethanol/aqueous NaH2PO4 as the eluent. Dynamic micro-positron emission tomography (PET)/computed tomography (CT) study of [18F]-GE-179 was successfully performed using a rat model of middle cerebral artery occlusion (MCAO, induced by transient occlusion into the left MCA). A simplified reference tissue model method was used to calculate the [18F]-GE-179 non-displaceable binding potential (BPND) for intracranial NMDAR activation assessment. Immunofluorescence staining of NMDAR NR1 subunit in brain slices containing lesion was also performed. Results [18F]-GE-179 was successfully prepared in a yield of 23–30% in a formulation that could be injected directly after dilution. Localized radioactivity accumulation was observed in the animal model of MCAO. Significantly higher (p = 0.0003–0.0404) BPND relative to equivalent contralateral was found in the ipsilateral caudate putamen, Acb core/shell, cortex cingulate, amygdala, hypothalamus, and superior colliculus. Immunofluorescence staining showed elevated NMDAR expression in the affected hemisphere. Conclusions [18F]-GE-179 was synthesized using a one-pot process with a markedly improved yield. Preliminary in vivo micro-PET study visualized excessive NMDAR stimulation successfully in a rodent model of MCAO, which was consistent with results of in vitro immunofluorescence staining. The study demonstrates that [18F]-GE-179 is a promising PET probe for the detection of functional NMDAR alterations.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Many studies have shown a significant increase in the marker signal of the receptor for advanced glycation end-products (RAGE) with the malignant progression of tumor growth, metastasis and recurrence of breast cancer, including TNBC of primary tumors and lymph node metastases. Azeliragon is a RAGE inhibitor and it has been shown to actively inhibit the TNBC cell line, SUM149 (IC50 = 5.292 ± 0.310 μM). In order to develop a new anti-TNBC agent, we designed, synthesized and screened 26 Azeliragon triazole analogues to determine their anti-TNBC activities in vitro. The most active compound was KC-10 with an IC50 value of 0.220 ± 0.034 μM.

We report herein the design and synthesis of a series of optimized phthalazine compounds as novel hedgehog signaling pathway inhibitors. The 4-methylamino-piperidine moiety of Taladegib was replaced by different four, five or six-membered azacycle or azaspirocycle building blocks. The in vitro Gli-luciferase assay results demonstrate that the scaffold hopping in this region afforded significant influences on Hh pathway inhibition. Pyrrolidin-3-amine moiety was found to be the best linker between pharmacophores phthalazine and fluorine substituted benzoyl group. Meanwhile the optimization of 1-methyl-1H-pyrazol by different aromatic rings was also investigated and the SAR was described. Many new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 23b showed the highest inhibitory potency with an IC50 value of 0.17 nM, which was 35-fold more potent than the lead compound Taladegib and 23-fold more potent than the marketed drug Vismodegib. The selected compounds 23a and 23b also possess potent antitumor activities against medulloblastoma cells proliferation in vitro. In vivo efficacy of 23b in a ptch+/-p53-/- mouse medulloblastoma allograft model also indicated encouraging results.

Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT. Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum). Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively). Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation.

PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in high throughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD

Novel cyanine-based fluorescent probes for the detection of H

Anti‑apoptotic and anti‑inflammatory treatments are imperative for skeletal muscle regeneration following injury. Baicalin is well known and has previously been investigated for its role in the treatment of injury and inflammatory diseases. Therefore, the present study aimed to investigate the effects of baicalin in inhibiting apoptosis of C2C12 myoblasts and preventing skeletal muscle injury. A cell counting kit‑8 (CCK‑8) assay and Annexin V/PI staining were initially performed to measure cell viability and apoptosis under conditions of H2O2 exposure with or without baicalin. Subsequently, oxidative activity, mitochondrial function, mitochondrial apoptogenic factors and caspase proteins were analyzed to examine the mechanism underlying the effect of baicalin on inhibiting apoptosis in C2C12 myoblasts. Furthermore, BALB/C mice with skeletal muscle injuries were established, and the potential application of baicalin for anti‑apoptotic and anti‑inflammatory effects was examined via small animal β‑2‑[18F]‑fluoro‑2‑deoxy‑D‑glucose (18F‑FDG) positron emission tomography (PET) imaging and pathological examination. The CCK‑8 assay and Annexin V/PI staining revealed cell death in the C2C12 myoblasts induced by H2O2, which was apoptotic, and this was effectively reversed by treatment with baicalin. H2O2 increased the reactive oxygen species and malondialdehyde levels in C2C12 myoblasts, which was caused by mitochondrial dysfunction, decreased expression of cytochrome c and apoptosis‑inducing factor from cytosolic and mitochondrial fractions, and activated expression of caspase‑3 and caspase‑9; however, treatment with baicalin reversed these effects. In addition, small animal PET imaging revealed that treatment with baicalin decreased the accumulation of FDG by ~65.9% in the injured skeletal muscle induced by H2O2. These pathological results also confirmed the protective effect of baicalin on injured skeletal muscle. Taken together, the results of the present study indicated that baicalin effectively inhibited the apoptosis of C2C12 myoblasts and protected skeletal muscle from injury, which may have potential therapeutic benefits for patients in a clinical setting.

We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33 nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/−p53−/− mouse medulloblastoma allograft model also indicated encouraging results.

Novel bis[3H]-naphtho[2,1-b]pyrans 1a–1g and bis[2H]-naphtho[1,2-b]pyrans 2a–2g were prepared efficiently. Such thiophene-linked bispyrans display distinct color change under continuous UV irradiation with up to 110 nm of bathochromic shift between the finally generated colored forms and initially generated forms. They also show high colorability, as well as good fatigue-resistance.

A novel series of chalcone derivatives were synthesized and their biological activities against HIF-1 were evaluated. Among these compounds, 5d exhibited clearly inhibitory effects on HIF-1 by downregulating the expression of HIF-1α under hypoxic conditions. Meanwhile, it also significantly suppressed VEGF-induced migration and invasion of Hep3B and HUVEC cells in nontoxic concentrations. Additionally, tube formation assay demonstrated its anti-angiogenesis activity. Moreover, the in vivo study indicated that compound 5d could retard tumor growth of Hep3B xenograft models and reduced CD31 and MMP-2 expression in tumor tissues. Finally, in acute intravenous toxicity, 5d was well tolerated and was found to be non-toxic up to 200 mg/kg in Swiss mice. These findings support the further investigation on the anti-invasive and anti-angiogenic potential of this class of compounds as HIF-1 inhibitor.

The co-existence and similar properties of amino acids make the detection of individual amino acids challenging. Herein we discovered that probe 1 may act as a smart example to classify and differentiate basic amino acids (Arg/Lys/His), thiol-containing amino acids (Cys/HCy), and GSH through different sensing mechanisms in selected environments.

We sought to quantify the effectiveness of a gifted and talented (GT) program, as was provided to university students who demonstrated a talent for learning English as a foreign language (EFL) in China. To do so, we used propensity score matching (PSM) techniques to analyze data collected from a tier-1 university where an English talent (ET) program was provided. Specifically, we provided (a) a step-by-step guide of PSM analysis using the R analytical package, (b) the codes for PSM analysis and visualization, and (c) the final analysis of baseline equivalence and treatment effect based on the matching sample. Collectively, the results of descriptive statistics, visualization, and baseline equivalence indicate that PSM is an effective matching technique for generating an unbiased counterfactual analysis. Moreover, the ET program yields a statistically significant, positive effect on ET students&rsquo, English language proficiency.

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [(18)F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [(11)C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [(11)C]-TKF can be made by reaction precursor with [(11)C]MeOTf or (11)CH₃I, but [(11)C]MeOTf will give us higher labeling yields and specific activity. [(11)C]-TKF presented better brain uptake in normal mouse than [(18)F]-THK523 (3.23% ± 1.25% ID·g(-1) vs. 2.62% ± 0.39% ID·g(-1) at 2 min post-injection). The acute toxicity studies of [(11)C]-TKF were unremarkable.

Energy metabolism abnormity is one of the most significant hallmarks of cancer. As a result, large amino acid transporter 1 (LAT1) is remarkably overexpressed in both blood-brain-barrier and glioma tumor cells, leading a rapid and sufficient substrate transportation. 3CDIT and 4CDIT are originally synthesized by modifying the existing most potent LAT1 substrate. 3CDIT is selected as its higher glioma-targeting ability. Since the microenvironment variation in tumor cells is another important feature of cancer, a great disparity in adenosine-5'-triphosphate (ATP) and glutathione (GSH) levels between extracellular and intracellular milieu can provide good possibilities for dual-responsive drug release in tumor cells. Doxorubicin (DOX) is successfully intercalated into the ATP aptamer DNA scaffolds, compressed by GSH-responsive polymer pOEI, and modified with 3CDIT to obtain 3CDIT-targeting pOEI/DOX/ATP aptamer nanoparticles (NPs). Enhanced NP accumulation and rapid GSH & ATP dual-responsive DOX release in glioma are demonstrated both in vitro and in vivo. More efficient therapeutic effects are shown with 3CDIT-targeting pOEI/DOX/ATP aptamer NPs than free DOX and no systemic toxicity is observed. Therefore, glioma-targeting delivery and GSH & ATP dual-responsive release guarantee an adequate DOX accumulation within tumor cells and ensure a safe and efficient chemotherapy for glioma.

We report herein the design and synthesis of a series of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Gli-luciferase assay demonstrated that changing piperazine ring of Anta XV to different four, five or six-membered heterocyclic building blocks afforded significant influences on Hh pathway inhibition. In particular, compound 10e with piperidin-4-amine moiety was found to possess 12-fold higher Hh inhibitory activities comparing to the lead compound in vitro. In vivo efficacy of 10e in a ptch(+/-)p53(-/-) mouse medulloblastoma allograft model also indicated encouraging results.

Automatic gain control (AGC) has been used in many applications. The key features of AGC, including a steady state output and static/dynamic timing response, depend mainly on key parameters such as the reference and the filter coefficients. A simple model developed to describe AGC systems based on several simple assumptions shows that AGC always converges to the reference and that the timing constant depends on the filter coefficients. Measures are given to prevent oscillations and limit cycle effects. The simple AGC system is adapted to a multiple AGC system for a TV tuner in a much more efficient model. Simulations using the C language are 16 times faster than those with MATLAB, and 10 times faster than those with a mixed register transfer level (RTL)-simulation program with integrated circuit emphasis (SPICE) model.

To investigate the effects and related mechanisms of 2-methylthio-adenosine-5'-triphosphate (2-MeSATP), an important extracellular agonist that activates receptors for purine nucleotides (P2XR), on ventricular arrhythmias in rabbits with chronic heart failure (CHF).The male New Zealand rabbits were divide into control (n=12), CHF (n=12) and CHF+2-MeSATP groups (2-MeSATP, n=12). CHF was induced by isoproterenol injection (0.3 mg·kg⁻¹·d⁻¹ for 3 weeks) and rabbits were observed 6 months later. The main cardioelectrophysiological parameters and ventricular arrhythmias were tested by recording monophasic action potential (MAP) with burst-pacing (BCL) in rabbits in vivo. The transient outward potassium current (Ito) was recorded via whole-cell patch clamp technique and the fluorescence intensity of intracellular free Ca²⁺ was detected with Flup-3/AM loading by the laser scanning confocal microscope in enzymatically dissociated single rabbet ventricular myocytes.CHF rabbits developed severely clinical CHF signs and symptoms, reduced left ventricular ejection fraction and fractional shortening as well as enlarged end-diastolic dimension. Compared with CHF group, APA and MaxdV/dt were significantly increased, while APD20, APD50 and APD90 were significantly reduced in 2-MeSATP group (all P0.01). Moreover, 2-MeSATP could obviously shorten BCL induced ventricular arrhythmias, and decrease deducibility and persistence time of ventricular arrhythmias with burst-pacing in 2-MeSATP group in vivo (all P0.05). With voltage clamp model, 2-MeSATP could significantly increase the current density of Ito in different command potential in CHF ventricular myocytes (all P0.01). When holding potential was set at -50 mV and command potential was set at +50 mV, the current densities of Ito increase was more significant in 2-MeSATP group than that in CHF group ((11.79 ± 4.51) pA/pF vs. (7.94 ± 3.53) pA/pF, P0.01). 2-MeSATP could completely change the I-V curve upward without changing the I-V curve direction in CHF ventricular myocytes. The fluorescence intensities of intracellular free Ca²⁺ increase was more significant in 2-MeSATP group compared to CHF group ((1 291.98 ± 123.31) µmol/L vs. (793.59 ± 114.65) µmol/L, P0.01).2-MeSATP as a potent agonist acting on P2XR could significantly shorten APD, increase heart rate and improve cardiac performance as well as decrease the susceptibility of ventricular arrhythmias in this rabbit CHF model. Our results suggest that Ito increase and sarcoplasmic reticulum uptake Ca²⁺ enhancement as well as dynamic balance of intracellular Ca²⁺ cycling sustenance might linked to the beneficial effects of 2-MeSATP in this CHF model.

This study examined how Chinese College students’ use of the computer-based Self-Access Language Learning Centre affects their English learning. The study investigated whether the gender difference influences students’ perceptions of the Self-Access Centre and whether students’ use of the Centre helps improve their English learning. Data was collected through questionnaires and a survey given to 120 sophomores at a technology university in Hubei, China. The data showed 1) no significant relationship between gender and students’ perceptions of the use of SAC and 2) significant correlations between students’ satisfaction of the SAC environment and their Oral English improvement, between students’ beliefs of learning better in the SAC and the improvement in their listening ability. Based on the research results, it was suggested that to provide a relaxed and material-rich environment and to improve learners’ autonomous learning can help improve the effectiveness of students’ use of the SAC.