Phloretin Inhibits Quorum Sensing and Biofilm Formation in Serratia marcescens.

This study investigated the antivirulence capacity and mechanism of apple-skin-derived phloretin against Serratia marcescens NJ01, a vegetable spoilage bacterium. At 0.5 to 2 mg/mL doses, phloretin considerably inhibited the secretion of acyl homoserine lactones (AHLs), indicating that phloretin disrupted quorum sensing (QS) in S. marcescens NJ01. The dysfunction of QS resulted in reduced biofilms and the decreased production of protease, prodigiosin, extracellular polysaccharides (EPSs), and swimming and swarming motilities. Dysfunctional QS also weakened the activity of antioxidant enzymes and improved oxidative injury. The improved oxidative injury changed the composition of the membrane, improved membrane permeability, and eventually increased the susceptibility of biofilm cells to amikacin, netilmicin, and imipenem. The disrupted QS and enhanced oxidative stress also caused disorders of amino acid metabolism, energy metabolism, and nucleic acid metabolism, and ultimately attenuated the ability of S. marcescens NJ01 to induce spoilage. Our results indicated that phloretin can act as a potent drug to defend against spoilage by S. marcescens.

L-Cysteine-Modified Transfersomes for Enhanced Epidermal Delivery of Podophyllotoxin.

The purpose of this study was to evaluate L-cysteine-modified transfersomes as the topical carrier for enhanced epidermal delivery of podophyllotoxin (POD). L-cysteine-deoxycholic acid (LC-DCA) conjugate was synthesized via an amidation reaction. POD-loaded L-cysteine-modified transfersomes (POD-LCTs) were prepared via a thin membrane dispersion method and characterized for their particle size, zeta potential, morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and in vitro release. Subsequently, in vitro skin permeation and retention, fluorescence distribution in the skin, hematoxylin-eosin staining and in vivo skin irritation were studied. The POD-LCTs formed spherical shapes with a particle size of 172.5 ± 67.2 nm and a zeta potential of -31.3 ± 6.7 mV. Compared with the POD-Ts, the POD-LCTs provided significantly lower drug penetration through the porcine ear skin and significantly increased the skin retention (p < 0.05). Meaningfully, unlike the extensive distribution of the POD-loaded transfersomes (POD-Ts) throughout the skin tissue, the POD-LCTs were mainly located in the epidermis. Moreover, the POD-LCTs did not induce skin irritation. Therefore, the POD-LCTs provided an enhanced epidermal delivery and might be a promising carrier for the topical delivery of POD.

Microemulsion-Based Keratin-Chitosan Gel for Improvement of Skin Permeation/Retention and Activity of Curcumin.

Curcumin (Cur) is a kind of polyphenol with a variety of topical pharmacological properties including antioxidant, analgesic and anti-inflammatory activities. However, its low water solubility and poor skin bioavailability limit its effectiveness. In the current study, we aimed to develop microemulsion-based keratin-chitosan gel for the improvement of the topical activity of Cur. The curcumin-loaded microemulsion (CME) was formulated and then loaded into the keratin-chitosan (KCS) gel to form the CME-KCS gel. The formulated CME-KCS gel was evaluated for its characterization, in vitro release, in vitro skin permeation and in vivo activity. The results showed that the developed CME-KCS gel had an orange-yellow and gel-like appearance. The particle size and zeta potential of the CME-KCS gel were 186.45 ± 0.75 nm and 9.42 ± 0.86 mV, respectively. The CME-KCS gel showed desirable viscoelasticity, spreadability, bioadhesion and controlled drug release, which was suitable for topical application. The in vitro skin permeation and retention study showed that the CME-KCS gel had better in vitro skin penetration than the Cur solution and achieved maximum skin drug retention (3.75 ± 0.24 µg/cm2). In vivo experimental results confirmed that the CME-KCS gel was more effective than curcumin-loaded microemulsion (Cur-ME) in analgesic and anti-inflammatory activities. In addition, the CME-KCS gel did not cause any erythema or edema based on a mice skin irritation test. These findings indicated that the developed CME-KCS gel could improve the skin penetration and retention of Cur and could become a promising formulation for topical delivery to treat local diseases.

A dicyanoisophorone-based ICT fluorescent probe for the detection of Hg2+ in water/food sample analysis and live cell imaging.

Mercury ions are notoriously difficult to biodegradable, and its abnormal bioaccumulation in the human body through the food chain can cause various diseases. Therefore, the quantitative and real-time detection of Hg2+ is very extremely important. Herein, we have brilliant designed and synthesized (E)-O-(4-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-en-1-yl)vinyl)phenyl) O-phenyl carbonothioate (ICM-Hg) as a selective fluorescent probe for Hg2+ detection in real samples and intracellular staining. ICM-Hg displayed high specificity toward Hg2+ by activating the intramolecular charge transfer (ICT) process, resulting in distinguished color change from colorless to bright yellow along with noticeable switch on yellow fluorescence emission. The fluorescent intensity of ICM-Hg at 585 nm shows a well linear relationship in the range of Hg2+ concentration (0-45 µM), and the detection of limit for Hg2+ is calculated to be 231 nM. Promisingly, ICM-Hg can efficiently detect Hg2+ in real samples including tap water, tea, shrimp, and crab with quantitative recovery as well as the intracellular fluorescence imaging.

Efficient gas chromatographic separation of xylene and other aromatic isomers by using pillar[6]arene-based stationary phase.

The separation of aromatic isomers, in particular xylene isomers, represents a big issue in chemical and petroleum industries, owing to their similar molecular sizes and boiling points. In this work, the investigation ofpillar[6]arene derivative modified by long alkyl chains (P6A-C10) as a stationary phase for high-resolution gas chromatographic (GC) separations of xylene isomers is presented. Pillar[n]arenes are a new class of macrocyclic hosts that can accommodate specific guests due to their highly symmetrical and rigid pillar architectures with π-electron rich cavities. The P6A-C10 column showed high-resolution performance towards xylene isomers, with peculiar advantages if compared with the commercial HP-5, HP-35, DB-17, and PEG-20Mcolumns.A quantum chemistry calculation has been performed, showing a difference in non-covalent interactions with the P6A-C10 pillar framework, which leads to specific selectivity for xylene isomers.Furthermore, the P6A-C10 column exhibited good repeatability.

Co-assembled Nanocarriers of De Novo Thiol-Activated Hydrogen Sulfide Donors with an RGDFF Pentapeptide for Targeted Therapy of Non-Small-Cell Lung Cancer.

Hydrogen sulfide releasing agents (or H2S donors) have been recognized gasotransmitters with potent cytoprotective and anticancer properties. However, the clinical application of H2S donors has been hampered by their fast H2S-release, instability, and lack of tumor targeting, despite the unclear molecular mechanism of H2S action. Here we rationally designed an amphiphilic pentapeptide (RGDFF) to coassemble with the de novo designed thiol-activated H2S donors (CL2/3) into nanocarriers for targeted therapy of non-small-cell lung cancer, which has been proved as a one-stone-three-birds strategy. The coassembly approach simply solved the solubility issue of CL2/3 by the introduction of electron-donating groups (phenyl rings) to slow down the H2S release while dramatically improving their biocompatible interface, circulation time, slow release of H2S, and tumor targeting. Experimental results confirmed that as-prepared coassembled nanocarriers can significantly induce the intrinsic apoptotic, effectively arrest cell cycle at the G2/M phase, inhibit H2S-producing enzymes, and lead to mitochondrial dysfunction by increasing intracellular ROS production in H1299 cells. The mouse tumorigenesis experiments further confirmed the in vivo anticancer effects of the coassembled nanocarriers, and such treatment made tumors more sensitive to radiotherapy then improved the prognosis of tumor-bearing mice, which holds great promise for developing a new combined approach for NSCLC.

Synthesis, biological evaluation, and molecular docking of novel hydroxyzine derivatives as potential AR antagonists.

Prostate cancer (PCa) is a malignant tumor with a higher mortality rate in the male reproductive system. In this study, the hydroxyazine derivatives were synthesized with different structure from traditional anti-prostate cancer drugs. In the evaluation of in vitro cytotoxicity and antagonistic activity of PC-3, LNCaP, DU145 and androgen receptor, it was found that the mono-substituted derivatives on the phenyl group (4, 6, 7, and 9) displayed strong cytotoxic activities, and compounds 11-16 showed relatively strong antagonistic potency against AR (Inhibition% >55). Docking analysis showed that compounds 11 and 12 mainly bind to AR receptor through hydrogen bonds and hydrophobic bonds, and the structure-activity relationship was discussed based on activity data. These results suggested that these compounds may have instructive implications for drug structural modification in prostate cancer.

Silk peptide-hyaluronic acid based nanogels for the enhancement of the topical administration of curcumin.

The present study focused on the development of Cur-loaded SOHA nanogels (Cur-SHNGs) to enhance the topical administration of Cur. The physiochemical properties of Cur-SHNGs were characterized. Results showed that the morphology of the Cur-SHNGs was spherical, the average size was 171.37 nm with a zeta potential of -13.23 mV. Skin permeation experiments were carried out using the diffusion cell systems. It was found that the skin retention of Cur-SHNGs was significantly improved since it showed the best retention value (0.66 ± 0.17 µg/cm2). In addition, the hematoxylin and eosin staining showed that the Cur-SHNGs improved transdermal drug delivery by altering the skin microstructure. Fluorescence imaging indicated that Cur-SHNGs could effectively deliver the drug to the deeper layers of the skin. Additionally, Cur-SHNGs showed significant analgesic and anti-inflammatory activity with no skin irritation. Taken together, Cur-SHNGs could be effectively used for the topical delivery of therapeutic drugs.

Synthesis, bioactivity, and molecular docking of novel arylpiperazine derivatives as potential AR antagonists.

Prostate cancer is one of the malignant tumors and the second most common malignant tumor in men. Clinically used androgen receptor (AR)-targeted drugs can antagonize androgen and inhibit tumor growth, but these drugs can cause serious resistance problems. To develop novel AR antagonists, 22 kinds of arylpiperazine derivatives were designed and synthesized, and the derivatives 5, 8, 12, 19, 21, 22, 25, and 26 not only showed strong antagonistic potency (>55% inhibition) and binding affinities (IC50 <3 µM) to AR, but also showed stronger inhibitory activity to LNCaP cells versus PC-3 cells. Among them, derivative 21 exhibited the highest binding affinity for AR (IC50 = 0.65 µM) and the highest antagonistic potency (76.2% inhibition). Docking studies suggested that the derivative 21 is primarily bound to the AR-LBP site by the hydrophobic interactions. Overall, those results provided experimental methods for developing novel arylpiperazine derivatives as potent AR antagonists.

Dithienylethene-Bridged Fluoroquinolone Derivatives for Imaging-Guided Reversible Control of Antibacterial Activity.

The emerging field of photopharmacology has offered a promising alternative to guard against the bacterial resistance by effectively avoiding antibiotic accumulation in the body or environment. However, the degradation, toxicity, and thermal reversibility have always been an ongoing concern for potential applications of azobenzene-based photopharmacology. Developing novel photopharmacological agents based on a more matched switch is highly in demand and remains a major challenge. Herein, two novel dithienylethene-bridged dual-fluoroquinolone derivatives have been developed by introducing two fluoroquinolone drugs into both ends of the dithienylethene (DTE) switch, in which the fluoroquinolone acts as a fluorophore except for the pharmacodynamic component. For comparison, two monofluoroquinolone-DTE hybrids were also prepared by a similar strategy. As expected, these resultant DTE-based antibacterial agents displayed efficient photochromism and fluorescence switching behavior in dimethyl sulfoxide. Moreover, improved antibacterial activities compared to those of monofluoroquinolone derivatives and a maximum fourfold active difference against Escherichia coli (E. coli) for open and closed isomers and photoswitchable bacterial imaging for Staphylococcus aureus and E. coli were observed. The molecular docking to DNA gyrase gave a rationale for the discrepancies in antibacterial activity for both isomers. Therefore, these fluoroquinolone derivatives can act as interesting imaging-guided photopharmacological agents for further in vivo studies.

Design, Synthesis, and Biological Evaluation of 4-Arylamino Pyrimidine Derivatives as FAK Inhibitors and Tumor Radiotracers.

Focal adhesion kinase (FAK) is considered a promising target for the diagnosis and treatment of cancer. In this work, a series of N,N'-(4-((5-bromo-2-(phenylamino)pyrimidin-4-yl)amino)-1,3-phenylene)diacetamide derivatives were synthesized and evaluated as FAK inhibitors and radiotracers. The studied compounds, possessing the same phenylene-diacetamide chain, exhibited high to moderate enzyme inhibition values (IC50) ranging from 3.7 to 108.0 nM. Compound 13a, which exhibits high FAK enzyme inhibition with an IC50 value of 3.7, could effectively suppress the tumor growth. Furthermore, three compounds were radiolabeled with F-18. Among them, a higher tumor uptake value was observed for [18F]17 (3.73 ± 0.10% ID/g) and [18F]13a (3.66 ± 0.02% ID/g). Compound [18F]18 displayed the highest tumor/blood (35.75) value at 120 min postinjection. In addition, the results from docking studies revealed the binding mechanism of the studied compounds. The findings of this study may provide useful guidance to improve the development of radiotracers and enzyme inhibitors.

Sensing Hypochlorite or pH variations in live cells and zebrafish with a novel dual-functional ratiometric and colorimetric chemosensor.

Both HClO and pH are essential players in multiple biological processes, which thus need to be controlled properly. Dysregulated HClO or pH correlates with many diseases. To meet these challenges, we need to develop highly competent probes for monitoring them. Over the years, despite a rich history of the development of HClO or pH probes, those that can do both jobs are still deficient. Herein, we present a novel dual-functional chemosensor, CMHN, which exhibits a blue and red shift of its fluorescence emission upon reacting with HClO or OH-, respectively. CMHN was successfully harnessed in the imaging detection of HClO or OH- in aqueous solutions, live cells, and zebrafish. Results indicated CMHN can detect HClO with high sensitivity (LOD -132 nM), a quick response time (<70 s), and high selectivity over dozens of interfering species through a colorimetric and ratiometric response. Besides, CMHN can probe pH changes sensitively and reversibly. Its working mechanism was verified by DFT calculations. These superior features make CMHN excel among the HClO or pH probes reported so far. Taken together, CMHN replenishes the deficiency in currently developed HClO or pH probes and paves the way for developing multifunctional HClO or pH probes in the future.

Inactivation of Pseudomonas aeruginosa biofilms by thymoquinone in combination with nisin.

Pseudomonas aeruginosa is one of the most important foodborne pathogens that can persist in leafy green vegetables and subsequently produce biofilms. In this study, the synergistic effect of thymoquinone and nisin in reducing biofilm formation of P. aeruginosa on lettuce was evaluated, and their anti-virulence and anti-biofilm mechanisms were also investigated. At concentrations ranging from 0.5 to 2 mg/ml, thymoquinone inhibited the production of autoinducers and virulence factors, and enhanced the susceptibility of P. aeruginosa biofilms to nisin as evidenced by the scanning electron microscopy and confocal laser scanning microscopy. Integrated transcriptomics, metabolomics, and docking analyses indicated that thymoquinone treatment disrupted the quorum sensing (QS) system, altered cell membrane component, and down-regulated the expressions of genes related to virulence, efflux pump, and antioxidation. The changed membrane component and repressed efflux pump system enhanced membrane permeability and facilitated the entrance of nisin into cells, thus improving the susceptibility of biofilms to nisin. The dysfunctional QS and repressed antioxidant enzymes lead to the enhancement of oxidative stress. The enhanced oxidative stress disrupted energy metabolism and protein metabolism and ultimately attenuated the virulence and pathogenicity of P. aeruginosa PAO1. Our study indicated that thymoquinone has the potential to function as a QS-based agent to defend against foodborne pathogens in combination with nisin.

Design, Synthesis, Biological Evaluation, and Molecular Docking of 2,4-Diaminopyrimidine Derivatives Targeting Focal Adhesion Kinase as Tumor Radiotracers.

There are two important topics in the field of cancer research: one is targeted molecular therapy and the other is tumor molecular imaging. Focal adhesion kinase (FAK) is considered as an attractive target for oncologic diagnosis and therapy. A series of 2,4-diaminopyrimidine derivatives were labeled with 18F to study their biological properties and their potential as positron emission tomography tumor imaging agents. They inhibited the activity of FAK with IC50 values in the wide range of 0.6-2164 nM, among which the IC50 of Q6 was 3.2 nM. For the biodistribution in S180-bearing mice, the corresponding [18F]Q6 was relatively good, with the highest uptake of 3.35 ± 0.32 % ID/g at 30 min postinjection, with a tumor/muscle ratio of 2.08 and a tumor/bone ratio of 2.48. Accordingly, [18F]Q6 was considered as a potential PET imaging agent for tumor diagnosis.

Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential tumour imaging agents.

As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds, with an IC50 range of 5.0-205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [18F]Q-2 is a potential PET tracer for tumour diagnosis.

Synthesis and biological evaluation of 9-fluorenone derivatives for SPECT imaging of α7-nicotinic acetylcholine receptor.

The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for α7-nAChRs. Among the derivatives, the best member of the series 10 (Ki = 2.23 nM) were radiolabeled with 125I for in vitro and in vivo studies. The radiotracer [125I]10 exhibited robust brain uptake and specifically labeled α7-nAChRs with a peak uptake value of 9.49 ±â€¯0.87%ID/g in brain. Blocking studies demonstrated that the tracer was highly specific toward α7-nAChR. Furthermore, ex vivo autoradiography and micro-SPECT/CT dynamic imaging in mice confirmed the excellent imaging properties. In addition, molecular docking was also performed to rationalize the potency of the chosen compounds towards α7-nAChRs. To conclude, compound 10 could serve as a promising radiotracer for the α7-nAChRs.

Design, synthesis and biological evaluation of 1,4-Diazobicylco[3.2.2]nonane derivatives as α7-Nicotinic acetylcholine receptor PET/CT imaging agents and agonists for Alzheimer's disease.

α7-Nicotinic acetylcholine receptor (α7-nAChR) agonists are promising therapeutic drug candidates for treating the cognitive impairment associated with Alzheimer's disease (AD). Thus, a novel class of derivatives of 1,4-diazobicylco[3.2.2]nonane has been synthesized and evaluated as α7-nAChR ligands. Five of them displayed high binding affinity (Ki = 0.001-25 nM). In particular, the Ki of 14 was 0.0069 nM, which is superior to that of the most potent ligand that was previously reported by an order of magnitude. Four of them had high selectivity for α7-nAChRs over α4ß2-nAChRs and no significant hERG (human ether-a-go-go-related gene) inhibition. Their agonist activity was also discussed preliminarily. One of the compounds, 15 (Ki = 2.98 ±â€¯1.41 nM), was further radiolabeled with 18F to afford [18F]15 for PET imaging, which exhibited high initial brain uptake (11.60 ±â€¯0.14%ID/g at 15 min post injection), brain/blood value (9.57 at 30 min post injection), specific labeling of α7-nAChRs and fast clearance from the brain. Blocking studies demonstrated that [18F]15 was α7-nAChR selective. In addition, micro-PET/CT imaging in normal rats further indicated that [18F]15 had obvious accumulation in the brain. Therefore, [18F]15 was proved to be a potential PET radiotracer for α7-nAChR imaging.