Rational design, synthesis, and pharmacological characterisation of dicarbonyl curcuminoid analogues with improved stability against lung cancer via ROS and ER stress mediated cell apoptosis and pyroptosis.

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to ß-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.

Two-Photon Ratiometric Fluorescence Probe with Enhanced Absorption Cross Section for Imaging and Biosensing of Zinc Ions in Hippocampal Tissue and Zebrafish.

Zinc ion (Zn2+) not only plays an important function in the structural, catalytic, transcription, and regulatory of proteins, but is also an essential ionic signal to regulate brain neurotransmitters pass process. In this work, we designed and synthesized an intramolecular charge transfer-based ratiometric two-photon fluorescence probe, P-Zn, for imaging and biosensing of Zn2+ in live cell, hippocampal tissue, and zebrafish. The developed probe demonstrated high two-photon absorption cross section (δ) of 516 ± 77 GM, which increased to 958 ± 144 GM after the probe was coordinated with Zn2+. Furthermore, this P-Zn probe quickly recognized Zn2+ with high selectivity, over other metal ions, amino acids, and reactive oxygen species. More interestingly, the initial emission peak of the present probe at 465 nm decreased with a new peak increased at 550 nm, leading to the ratiometric determination of Zn2+ with high accuracy. Finally, this two-photon fluorescence probe with high temporal resolution and remarkable analytical performance, as well as low-cytotoxicity, was successfully applied in imaging of live cells, hippocampal tissues, and zebrafishes. The present P-Zn probe combined with FLIM provided accurate mapping of Zn2+ distribution at single-cell level. More interestingly, the two-photon spectroscopic results demonstrated that the level of Zn2+ in hippocampal tissue of mouse with AD was higher than that in normal mouse brain.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Two-photon fluorescent Zn2+ probe for ratiometric imaging and biosensing of Zn2+ in living cells and larval zebrafish.

As an essential transition-metal ion in organism, zinc ion (Zn2+) plays a significant role in cellular metabolism, apoptosis and neurotransmission. Herein, we reported a new intramolecular charge transfer-based two-photon probe, (E)-1-(6-(4-(2-(2-(2-methoxyethoxy)ethoxy)eth-oxy)-3,5-dimethylstyryl)quinolin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine (TEO-MPVQ), for ratiometric imaging and biosensing of Zn2+ in living cells and larval zebrafish. The maximum two-photon absorption cross-section values (δmax) of the developed probe increased from 115 ±â€¯16 GM to 188 ±â€¯27 GM, after the probe was chelated with Zn2+. The emission spectrum of TEO-MPVQ probe increased and red-shifted about 60 nm, resulting in the ratiometric determination of Zn2+ with high sensitivity and selectivity. The present fluorescent probe also demonstrated good biocompatibility, high spatial resolution and deep penetration depth for Zn2+ detection. Accordingly, TEO-MPVQ was able to track the endogenous Zn2+ release in neurons and also successfully applied for larval zebrafish imaging. By using of this effective probe, it was found that the endogenous Zn2+ was rapidly released from metallothionein under the stimulation of NO in neurons.

Pharmacokinetic study of rosavin in rat plasma with ultra performance LC-MS/MS after intravenous and gavage administration.

Aim: A sensitive and selective ultra performance LC-MS/MS (UPLC-MS/MS) method was developed to investigate the pharmacokinetics of rosavin as a potential adaptogenic drug isolated from Rhodiola rosa L. in rat plasma with salidroside as an internal standard. Methodology: Chromatographic separation was performed on a UPLC HSS T3 column (1.8 µm, 100 mm × 2.1 mm) with gradient elution. Multiple reaction monitoring was employed for MS analysis. Rosavin and salidroside were determined with multiple reaction monitoring-ion transitions m/z 427.2 → 293.1 and m/z 299.1 → 119.1, respectively. Conclusion: The validated UPLC-MS/MS method showed a satisfied linear range in 5-5000 ng/ml-1 and was successfully applied for the pharmacokinetic study of rosavin in the rat after intravenous and gavage administration.

Determination of fascaplysin in rat plasma with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS): application to a pharmacokinetic study.

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to determine fascaplysin in rat plasma using methylfascaplysin as an internal standard. Both fascaplysin and methylfascaplysin were synthesized in our laboratory. Protein precipitation was applied for the preparation of the plasma sample. Chromatographic separation was performed on a reversed-phase UPLC C18 column (1.8 µm, 100 mm × 2.1 mm) with a flow rate at 0.4 mL min-1. A triple-quadrupole mass spectrometer was employed for multiple reaction monitoring (MRM) in positive ionization mode. The MRM ion transitions m/z 271.0 → 242.1 and m/z 285.1 → 270.1 were selected to determine fascaplysin and methylfascaplysin respectively. The calibration curves for fascaplysin quantification showed excellent linearity in the range of 1-500 ng mL-1 with a limit of lower quantification (LLOQ) of 1 ng mL-1. The within-run and between-run accuracy ranged from 95.1% to 110.0% with precision lower than 7.4% in low, medium and high concentration levels for quality control (QC). The specificity, matrix effect, recovery, and stability were validated in accordance with the FDA bioanalytical method validation guidance. In the end, the proposed UPLC-MS/MS method was successfully applied in a pharmacokinetic study of fascaplysin after intravenous and intragastric administration to rats, which indicates a potential way for the preclinical study of fascaplysin in the future.