VOC-Based Probes, a New Set of Analytical Tools to Monitor Patient Health from Blood Sample. Proof of Concept on Tracking COVID-19 Infection.

Induced volatolomics is an emerging field that holds promise for many biomedical applications including disease detection and prognosis. In this pilot study, we report the first use of a cocktail of volatile organic compounds (VOCs)-based probes to highlight new metabolic markers allowing disease prognosis. In this pilot study, we specifically targeted a set of circulating glycosidases whose activities could be associated with critical COVID-19 illness. Starting from blood sample collection, our approach relies on the incubation of VOC-based probes in plasma samples. Once activated, the probes released a set of VOCs in the sample headspace. The dynamic monitoring of the signals of VOC tracers enabled the identification of three dysregulated glycosidases in the initial phase after infection, for which preliminary machine learning analyses suggested an ability to anticipate critical disease development. This study demonstrates that our VOC-based probes are a new set of analytical tools that can provide access to biological signals until now unavailable to biologists and clinicians and which could be included in biomedical research to properly construct multifactorial therapy algorithms, necessary for personalized medicine.

Induced-volatolomics for the design of tumour activated therapy.

The discovery of tumour-associated markers is of major interest for the development of selective cancer chemotherapy. Within this framework, we introduced the concept of induced-volatolomics enabling to monitor simultaneously the dysregulation of several tumour-associated enzymes in living mice or biopsies. This approach relies on the use of a cocktail of volatile organic compound (VOC)-based probes that are activated enzymatically for releasing the corresponding VOCs. Exogenous VOCs can then be detected in the breath of mice or in the headspace above solid biopsies as specific tracers of enzyme activities. Our induced-volatolomics modality highlighted that the up-regulation of N-acetylglucosaminidase was a hallmark of several solid tumours. Having identified this glycosidase as a potential target for cancer therapy, we designed an enzyme-responsive albumin-binding prodrug of the potent monomethyl auristatin E programmed for the selective release of the drug in the tumour microenvironment. This tumour activated therapy produced a remarkable therapeutic efficacy on orthotopic triple-negative mammary xenografts in mice, leading to the disappearance of tumours in 66% of treated animals. Thus, this study shows the potential of induced-volatolomics for the exploration of biological processes as well as the discovery of novel therapeutic strategies.

Aerodynamic System Machine Learning Modeling with Gray Wolf Optimization Support Vector Regression and Instability Identification Strategy of Wavelet Singular Spectrum.

The prediction of a stall precursor in an axial compressor is the basic guarantee to the stable operation of an aeroengine. How to predict and intelligently identify the instability of the system in advance is of great significance to the safety performance and active control of the aeroengine. In this paper, an aerodynamic system modeling method combination with the wavelet transform and gray wolf algorithm optimized support vector regression (WT-GWO-SVR) is proposed, which breaks through the fusion technology based on the feature correlation of chaotic data. Because of the chaotic characteristic represented by the sequence, the correlation-correlation (C-C) algorithm is adopted to reconstruct the phase space of the spatial modal. On the premise of finding out the local law of the dynamic system variety, the machine learning method is applied to model the reconstructed low-frequency components and high-frequency components, respectively. As the key part, the parameters of the SVR model are optimized by the gray wolf optimization algorithm (GWO) from the biological view inspired by the predatory behavior of gray wolves. In the definition of the hunting behaviors of gray wolves by mathematical equations, it is superior to algorithms such as differential evolution and particle swarm optimization. In order to further improve the prediction accuracy of the model, the multi-resolution and equivalent frequency distribution of the wavelet transform (WT) are used to train support vector regression. It is shown that the proposed WT-GWO-SVR hybrid model has a better prediction accuracy and reliability with the wavelet reconstruction coefficients as the inputs. In order to effectively identify the sign of the instability in the modeling system, a wavelet singular information entropy algorithm is proposed to detect the stall inception. By using the three sigma criteria as the identification strategy, the instability early warning can be given about 102r in advance, which is helpful for the active control.

Acceptor engineering of metallacycles with high phototoxicity indices for safe and effective photodynamic therapy.

Although metallacycle-based photosensitizers have attracted increasing attention in biomedicine, their clinical application has been hindered by their inherent dark toxicity and unsatisfactory phototherapeutic efficiency. Herein, we employ a π-expansion strategy for ruthenium acceptors to develop a series of Ru(ii) metallacycles (Ru1-Ru4), while simultaneously reducing dark toxicity and enhancing phototoxicity, thus obtaining a high phototoxicity index (PI). These metallacycles enable deep-tissue (∼7 mm) fluorescence imaging and reactive oxygen species (ROS) production and exhibit remarkable anti-tumor activity even under hypoxic conditions. Notably, Ru4 has the lowest dark toxicity, highest ROS generation ability and an optimal PI (∼146). Theoretical calculations verify that Ru4 exhibits the largest steric bulk and the lowest singlet-triplet energy gap (ΔE ST, 0.62 eV). In vivo studies confirm that Ru4 allows for effective and safe phototherapy against A549 tumors. This work thus is expected to open a new avenue for the design of high-performance metal-based photosensitizers for potential clinical applications.

Radiation-Responsive Benzothiazolines as Potential Cleavable Fluorogenic Linkers for Drug Delivery.

Radiosensitive compounds can be useful for the detection of radiations and also as prodrugs that can be activated during a radiotherapy. Herein we describe the use of benzothiazolines, which upon treatment with 137 Cs produced γ-irradiation in water give rise to fluorescent benzothiazoles and concomitant release of amines or carboxylic acids. In a proof of concept study, we showed that benzothiazolines may be used as new cleavable linkers that can be triggered upon irradiation.

Long wavelength-emissive Ru(II) metallacycle-based photosensitizer assisting in vivo bacterial diagnosis and antibacterial treatment.

Ruthenium (Ru) complexes are developed as latent emissive photosensitizers for cancer and pathogen photodiagnosis and therapy. Nevertheless, most existing Ru complexes are limited as photosensitizers in terms of short excitation and emission wavelengths. Herein, we present an emissive Ru(II) metallacycle (herein referred to as 1) that is excited by 808-nm laser and emits at a wavelength of ∼1,000 nm via coordination-driven self-assembly. Metallacycle 1 exhibits good optical penetration (∼7 mm) and satisfactory reactive oxygen species production properties. Furthermore, 1 shows broad-spectrum antibacterial activity (including against drug-resistant Escherichia coli) as well as low cytotoxicity to normal mammalian cells. In vivo studies reveal that 1 is employed in precise, second near-infrared biomedical window fluorescent imaging-guided, photo-triggered treatments in Staphylococcus aureus-infected mice models, with negligible side effects. This work thus broads the applications of supramolecular photosensitizers through the strategy of lengthening their wavelengths.

Metal-organic cycle-based multistage assemblies.

It is well known that chemical compositions and structural arrangements of materials have a great influence on their resultant properties. Diverse functional materials have been constructed by using either biomolecules (peptides, DNA, and RNA) in nature or artificially synthesized molecules (polymers and pillararenes). The relationships between traditional building blocks (such as peptides) have been widely investigated, for example how hydrogen bonds work in the peptide multistage assembly process. However, in contrast to traditional covalent bond-based building blocks-based assembly, suprastructures formed by noncovalent bonds are more influenced by specific bond features, but to date only a few results have been reported based on noncovalent bond-based building block multistage assembly. Here, three metal­organic cycles (MOCs) were used to show how coordination bonds influence the bimetallacycle conformation then lead to the topology differences of MOC multilevel ordered materials. It was found that the coordination linker (isophthalate-Pt-pyridine) is an important factor to tune the shape and size of the MOC-derived suprastructures.

Design of a Metallacycle-Based Supramolecular Photosensitizer for In Vivo Image-Guided Photodynamic Inactivation of Bacteria.

Bacterial infection is one of the greatest threats to public health. In vivo real-time monitoring and effective treatment of infected sites through non-invasive techniques, remain a challenge. Herein, we designed a PtII metallacycle-based supramolecular photosensitizer through the host-guest interaction between a pillar[5]arene-modified metallacycle and 1-butyl-4-[4-(diphenylamino)styryl]pyridinium. Leveraging the aggregation-induced emission supramolecular photosensitizer, we improved fluorescence performance and antimicrobial photodynamic inactivation. In vivo studies revealed that it displayed precise fluorescence tracking of S. aureus-infected sites, and in situ performed image-guided efficient PDI of S. aureus without noticeable side effects. These results demonstrated that metallacycle combined with host-guest chemistry could provide a paradigm for the development of powerful photosensitizers for biomedicine.

Anthracene-induced formation of highly twisted metallacycle and its crystal structure and tunable assembly behaviors.

Polycyclic aromatic hydrocarbons (PAHs) continue to attract increasing interest with respect to their applications as luminescent materials. The ordered structure of the metal-organic complex facilitates the selective integration of PAHs that can be tuned to function cooperatively. Here, a unique highly twisted anthracene-based organoplatinum metallacycle was prepared via coordination-driven self-assembly. Single-crystal X-ray diffraction analysis revealed that the metallacycle was twisted through the cooperation of strong π···π stacking interactions and steric hindrance between two anthracene-based ligands. Notably, the intramolecular twist and aggregation behavior introduced restrictions to the conformational change of anthracenes, which resulted in increased emission intensity of the metallacycle in solution. The emission behaviors and suprastructures based on the highly twisted metallacycle can be modulated by the introduction of different solvents. This study demonstrates that this metallacycle with highly twisted structure is a promising candidate for sensing and bioimaging applications.

Resorcinarene Induced Assembly of Carotene and Lutein into Hierarchical Superstructures.

The manipulation of carotenoid-based hierarchical superstructures affords attractive properties that facilitate application in biology and photosynthesis. Here, tubular suprastructures formed from water-soluble amide-modified resorcinarene and ß-carotene were reported, whereas microsheets were formed when ß-carotene was replaced with lutein. These structures were characterized using various measurements, indicating the differences of binding sites between resorcinarene and ß-carotene/lutein. Subsequently, the assembly mechanism was described by calculating the formation energy of the assemblies.

Pillar[5]arene-Containing Metallacycles and Host-Guest Interaction Caused Aggregation-Induced Emission Enhancement Platforms.

Coordination-driven Pt metallacycles have shown potential in controllable modular self-assembly, which has made a vital contribution to biomedicine, catalysis, and multiresponsive materials. Herein, pillar[5]arene units were integrated into one skeleton through coordination-driven self-assembly, resulting in the formation of a hexagonal Pt(II) metallacycle decorated with six pillar[5]arenes. The host-guest interactions of the as-prepared metallacycle (pillar[5]arenes as hosts) and 1-butyl-4-[4-(diphenylamino)styryl]pyridinium (guest) were investigated. The metallacycle was found to facilitate the coaggregation between the guests and pillar[5]arenes through a synergistic effect, thus engendering a sharp increase in fluorescence intensity. The resultant aggregate was investigated by DLS and TEM. Our studies imply that the pillar[5]arene-containing metallacycle can serve as a potential platform for realizing emission enhancement effects.

Self-Assembly of Porphyrin-Based Metallacages into Octahedra.

Despite rapid progress in recent years, it has remained challenging to prepare well-defined metal-organic complex-based suprastructures. As a result, the physicochemical mechanisms leading to their geometrical complexity remain perplexing. Here, a porphyrin-based metallacage was used as a building block to construct octahedra via self-assembly, and the mechanism for the evolution of the metallacages into octahedra was disclosed by both experiments and theoretical simulations.

Fabrication of a Smart Nanofluidic Biosensor through a Reversible Covalent Bond Strategy for High-Efficiency Bisulfite Sensing and Removal.

Bioinspired nanochannel based biosensors have been widely applied for sensing ions, small molecules, and biomolecules. However, the low selectivity and difficulty in recycle sensing still heavily hamper their widespread applications. Herein, we designed and fabricated a nanochannel based biosensor for high-efficiency bisulfite (HSO3-) sensing and removal through forming a reversible covalent bond between HSO3- and 4-aminophenyl-phenyl-methanone (APPM). This nanofluidic biosensor displays a promising HSO3- selectivity with high ion rectification/gating ratio (47 and 5) and excellent reversibility and stability. Of note, the L02 cell line containing excess HSO3- could still maintain high vitality in the presence of such an APPM-functionalized biosensor based membrane. These results will not only help to better understand the biological function of HSO3- in living organisms but also inspire us to develop smart artificial nanochannel based biosensors for biological applications.

[Remediation Effects of Different Composite Materials on Cadmium-Contaminated Farmland Soil].

A pot experiment was conducted to study the application effects of three composite materials, namely SC (lime:organic compound fertilizer=2:3), LS (ferrous sulfate:lime=1:1) and LB (ferrous sulfate:biochar in combinations of 1:1, 1:2, 1:3, 1:4 and 1:5), on soil Cd bioavailability, Cd cumulative distribution in different wheat organs, and wheat yield. The results indicated that:① Addition of composite materials all significantly decreased the soil available Cd content by 50.2%-81.8% (SC), 29.4%-48.1% (LS), and 18.7%-42.2% (LB). Composite materials significantly increased soil pH by 1.37-2.28 (SC), 0.41-0.86 (LS), and 0.14-0.17 (LB) units. ② The Cd cumulative distribution in different wheat organs were in the order of root > leaf > stem > glume > grain. The translocation abilities of Cd in different organs were in the order of root > glume > stem and leaf. ③ Compared with the control, 0.67% SC addition and 0.67% LS addition significantly increased the wheat yields by 56.4% and 51.2%; LB addition significantly increased wheat yield by 39.6% to 51.2%. ④ The correlation analysis showed that soil pH was significantly negatively correlated with soil available Cd and Cd contents in different wheat organs. There were significant positive correlations between soil available Cd and Cd contents in different wheat organs, and the correlation coefficients were 0.711 (grain), 0.817 (glume), 0.593 (stem), 0.630 (leaf) and 0.622 (root). Meanwhile, there is also a significant positive correlation between Cd content in different wheat organs. ⑤ Comprehensively, the addition of 0.93% SC increased soil pH by a maximum of 2.28 units, and the soil available cadmium content was decreased by a maximum of 81.8%. Therefore, adding 0.93% SC was the most suitable treatment for repairing and controlling the Cd pollution in farmland soil.

A FRET probe for the detection of alkylating agents.

Herein, we describe a new strategy for the detection of reactive alkylating agents such as alkyl halides. These toxic compounds react with a FRET-based profluorescent probe, triggering a self-immolative elimination at room temperature, thus leading to a fluorescence signal.

Synthesis and biological evaluation of ferrocene-based cannabinoid receptor 2 ligands.

Ferrocene analogs of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bio-organometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on fatty acid amide hydrolase. None had any fatty acid amide hydrolase activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole-3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM).

Development of novel oxazolo[5,4-d]pyrimidines as competitive CB2 neutral antagonists based on scaffold hopping.

A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB1/CB2 cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB2 ligands with Ki values less than 1 µM. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB2 binding affinity in the nanomolar range and significant selectivity over CB1 receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29.

Versatile on-stage microfluidic system for long term cell culture, micromanipulation and time lapse assays.

We report here a versatile on-stage microfluidic cell culture and assay system which is compatible with different microscopes and sensors, can simultaneously perform steps of long term cell culture, high throughput time lapse cell assays/imaging, and cell micromanipulations. With the system, we cultured a variety of cells for different periods of time and monitored their cell morphology, migration and division. We also performed a series non-invasive real time in situ time lapse assays and micromanipulations on different cells. They include: the first time lapse imaging and measurements on the instantaneous variations of morphology, biomechanical properties and the intracellular protein of human red blood cells in responding to pH fluctuation, drug action and electromagnetic radiation; the first continuous time lapse Raman micro-spectroscopy on a CHO cell in different phases of its entire life cycles; the micro-transfection of GFP into B16 cells and the follow up observation of the cell's morphology and expressed GFP fluorescence varying with incubation time and cell generations. The performance of these experiments not only demonstrated the capability of the system, but also proposed a variety of novel methods for obtaining time- and spatially-resolved information about the cellular and molecular heterogeneity and transformation during development or stimulations.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors.

Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2) or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolaminephospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase 2 (COX-2). Over the past decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their antinociceptive and anti-inflammatory effects, as well as to protect the nervous system.

Hernandezine, a Bisbenzylisoquinoline Alkaloid with Selective Inhibitory Activity against Multidrug-Resistance-Linked ATP-Binding Cassette Drug Transporter ABCB1.

The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients.