Light-Activated Rhenium Complexes with Dual Mode of Action against Bacteria

New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal complexes offer access to alternative modes of action but have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug-resistant S. aureus and E. coli. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.     

Single‐molecule Spectroscopy: Exploring Heterogeneity in Chemical and Biological Systems

Many chemical and biological systems are heterogeneous in the molecular length scale (～ 1 nm). Heterogeneity in many chemical systems and organized assemblies may be monitored using single‐molecule spectroscopy (SMS). In SMS, the size of the focal spot (i.e., the smallest region to be probed) is nearly half of the excitation wavelength (λ/2, i.e., 200–375 nm) for visible light (400–750 nm). We discuss how one can get spatial resolutions better than 200 nm using molecules as nanometric probes. We show that polymer hydrogels, lipid vesicles, room temperature ionic liquids (RTILs), and binary liquid mixtures exhibit such heterogeneity. Another important observation is solute‐dependent friction in RTILs. In an RTIL, diffusion of an ionic solute is slower than that of a neutral solute.     

Altered Membrane Mechanics Provides a Receptor-Independent Pathway for Serotonin Action

Serotonin, an important signaling molecule in humans, has an unexpectedly high lipid membrane affinity. The significance of this finding has evoked considerable speculation. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, providing an activity pathway completely independent of serotonin receptors. Atomic force microscopy shows that serotonin makes artificial lipid bilayers softer, and induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains. Solid-state NMR spectroscopy corroborates this data at the atomic level, revealing a homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, even in the presence of broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the membrane binding and internalization of oligomeric peptides. Our results uncover a mode of serotonin–membrane interaction that can potentiate key cellular processes in a receptor-independent fashion.     

电分析方法测定环境和生物样品中铝含量及其形态分布研究进展

综述了用极普法、吸附伏安法、计时电位法、离子选择性电极法及流动注射分析法测定环境和生物样品中铝含量及其形态分布研究的进展和现状,比较了各种电分析方法的特点及优缺点。引用文献９７篇。     

Cyanine-Flavonol Hybrids for Near-Infrared Light-Activated Delivery of Carbon Monoxide

Carbon monoxide (CO) is an endogenous signaling molecule that controls a number of physiological processes. To circumvent the inherent toxicity of CO, light-activated CO-releasing molecules (photoCORMs) have emerged as an alternative for its administration. However, their wider application requires photoactivation using biologically benign visible and near-infrared (NIR) light. In this work, a strategy to access such photoCORMs by fusing two CO-releasing flavonol moieties with a NIR-absorbing cyanine dye is presented. These hybrids liberate two molecules of CO in high chemical yields upon activation with NIR light up to 820 nm and exhibit excellent uncaging cross-sections, which surpass the state-of-the-art by two orders of magnitude. Furthermore, the biocompatibility and applicability of the system in vitro and in vivo are demonstrated, and a mechanism of CO release is proposed. It is hoped that this strategy will stimulate the discovery of new classes of photoCORMs and accelerate the translation of CO-based phototherapy into practice.     

用于检测生物体系中线粒体活性氧的荧光探针

In addition to being the energy powerhouse of the cell, mitochondria are an important source of reactive oxygen species (ROS) during the process of molecular oxygen metabolism. Mitochondrial ROS are closely associated with normal physiological functions as well as human diseases, and participate in cell signaling, nucleic acid and protein damage, and oxidative stress induction. However, the complicated interplay between mitochondrial ROS and the cellular pathological state has not been fully elucidated. It is expected that research on the mitochondrial ROS undertaking in the molecular pathogenesis of human diseases would benefit from development of efficient tools for the detection of these ROS. In recent years, an increasing number of fluorescent probes for mitochondrial ROS with high sensitivity and selectivity have been developed. Here, we present a review of the recent advances in small molecular fluorescent probes for selective detection of ROS inside the mitochondria. In this review, the design, synthesis, characteristics, and applications of the published fluorescent probes for mitochondrial ROS are discussed in detail.     

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.     

Hofmeister效应对生物和化学体系的影响

Hofmeister效应涉及到的问题范围十分广泛,对很多化学、生物体系都有影响。总的说来,Hofmeister效应会影响到溶液的冰点、沸点、黏度、偏摩尔体积、饱和蒸汽压、传导率、pH、表面张力。文章主要介绍了Hofmeister效应的主要影响因素,以及相关理论的建立与完善,并对不同体系中Hofmeister效应的影响进行了描述。     

Latent and Delayed Action Polymerization Systems

Various approaches to latent polymerization processes are described. In order to highlight recent advances in this field, the discussion is subdivided into chapters dedicated to diverse classes of polymers, namely polyurethanes, polyamides, polyesters, polyacrylates, epoxy resins, and metathesis‐derived polymers. The described latent initiating systems encompass metal‐containing as well as purely organic compounds that are activated by external triggers such as light, heat, or mechanical force. Special emphasis is put on the different chemical venues that can be taken to achieve true latency, which include masked N‐heterocyclic carbenes, latent metathesis catalysts, and photolatent radical initiators, among others. Scientific challenges and the advantageous application of latent polymerization processes are discussed.

     

Exploring Microfluidic Routes to Microgels of Biological Polymers

Polymer microgels in the size range from several micrometers to hundreds of micrometers are used in the pharmaceutical, cosmetics, nutrition, pesticide, and food industries, as well as in the encapsulation of cells. To date, a broad range of strategies for the generation of polymer microgels exist, however, these methods involve multistage processes, do not utilize biocompatible components or do not allow precise control of the dimensions and internal structure of the microgels. Recently, microfluidic strategies for the production of polymer particles have offered precise control over the shapes, morphologies, and size distributions of polymer colloids. This paper discusses the most recent results obtained by the authors in the area of the microfluidic production of biopolymer microgels. It provides a brief review of the microfluidic methods for the continuous synthesis and fabrication of microgels, sets the criteria for the successful microfluidic generation of biomicrogels, and describes two methods for the preparation of microgels by microfluidic means. The article concludes with a summary and an outlook.

     

化学及生物体系中的分别识别*

分子识别的目标是研究分子间专一性地相互作用, 这在化学及生命过程中起着非常重要的作用。本文综述了分子识别的机制及其在化学、生命科学、材料、信息等有关学科中的应用。     

Recent Progress of Small-Molecule Ratiometric Fluorescent Probes for Peroxynitrite in Biological Systems

Peroxynitrite (ONOO⁻) as a major reactive oxygen species plays important roles in cellular signal transduction and homeostatic regulation. Precise detection of ONOO⁻ in biological systems is vital for exploring its physiological and pathological function. Among numerous detection methods, fluorescence imaging technology using fluorescent probes offers some advantages, including simple operation, high sensitivity and selectivity, as well as real-time and nondestructive detection. In particular, ratiometric fluorescent probes, in which the built-in calibration of the two emission bands prevents interference from the biological environment, have been extensively employed to monitor the fluctuation of bioactive species. In this review, we will discuss small-molecule ratiometric fluorescent probes for ONOO⁻ in live cells or in vivo, which involves chemical structures, response mechanisms, and biological applications. Moreover, the challenges and future prospects of ONOO⁻-responsive ratiometric fluorescent probe are also proposed.     

Further Exploring Linear Concentration Addition and Independent Action for Predicting Non-interactive Mixture Toxicity

Since it is unrealistic to do an experimental mixture assessment on every possible combination, mathematical model plays an important role in predicting the mixture toxicity. The present study is devoted to the further application of linear concentration addition(CA)-based model(LCA) and independent action(IA)-based model(LIA) to predict the non-interactive mixture toxicity. The 26 mixtures including 312 data points were used to evaluate the predictive powers of LCA and LIA models. The models were internally validated using the leave-one-out cross-validation and y-randomization test, and the external validations were evaluated by the test tests. Both LCA and LIA models agree well with the experimental values for all mixture toxicity, and present high internally(R~2 and Q~2 0.98) and externally(Q~2_(F1), Q~2_(F2), and Q~2_(F3) 0.99) predictive power. The use of LCA and LIA led to improved predictions compared to the estimates based on the CA and IA models. Both LCA and LIA were found to be appropriate methods for modeling toxicity of non-interactive chemical mixtures.     

Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer

Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy.     

A Light-Responsive Injectable Hydrogel with Remodeling Tumor Microenvironment for Light-Activated Chemodynamic Therapy

Chemodynamic therapy (CDT) based on Fenton-like reaction is often limited by the tumor microenvironment (TME), which has insufficient hydrogen peroxide, and single CDT treatment is often less efficacious. To overcome these limitations, a hydrogel-based system is designed to enhance the redox stress (EOH) by loading the composite nanomaterial Cu-Hemin-Au, into the agarose hydrogels. The hydrogels can reach the tumor site upon intratumoral injection, and then coagulate and stay for extended period. Once irradiated with near-infrared light, the Cu-Hemin-Au act as a photothermal agent to convert the light energy into heat, and the EOH gradually heated up and softened, releasing the Cu-Hemin-Au residing in it to achieve photothermal therapy (PTT). Benefiting from the glucose oxidase (GOx)-like activity of the Au nanoparticles, glucose in the tumor cells is largely consumed, and hydrogen peroxide (H₂O₂) is generated in situ, and then Cu-Hemin-Au react with sufficient H₂O₂ to generate a large amount of reactive oxygen species, which promote the complete inhibition of tumor growth in mice during the treatment cycle. The hydrogel system for the synergistic enhancement of oxidative stress achieves good PTT/CDT synergy, providing a novel inspiration for the next generation of hydrogels for application in antitumor therapy.