Sulfotransferases: structure, mechanism, biological activity, inhibition, and synthetic utility

The sulfonation (also known as sulfurylation) of biomolecules has long been known to take place in a variety of organisms, from prokaryotes to multicellular species, and new biological functions continue to be uncovered in connection with this important transformation. Early studies of sulfotransferases (STs), the enzymes that catalyze sulfonation, focused primarily on the cytosolic STs, which are involved in detoxification, hormone regulation, and drug metabolism. Although known to exist, the membrane-associated STs were not studied as extensively until more recently. Involved in the sulfonation of complex carbohydrates and proteins, they have emerged as central players in a number of molecular-recognition events and biochemical signaling pathways. STs have also been implicated in many pathophysiological processes. As a result, much interest in the complex roles of STs and in their targeting for therapeutic intervention has been generated. Progress in the elucidation of the structures and mechanisms of sulfotransferases, as well as their biological activity, inhibition, and synthetic utility, are discussed in this Review.     

Targeted therapy of the insulin-like growth factor-1 receptor in cancer

Recently, significant progress has been made towards understanding the pathogenesis of cancer from the molecular standpoint. To this end, a growing number of approaches are being exploited for the identification and validation of new therapeutic targets suitable for potent and specific intervention. The type 1 insulin-like growth factor receptor (IGF-1R) system has recently become the focus of major attention in the arena of cancer research. The involvement of the receptor and its downstream signaling cascades in the carcinogenesis process makes this system an excellent target for potential cancer therapy. Indeed, advances in the understanding of the molecular mechanisms behind IGF-1R activation have led to the discovery of agents designed selectively for targeting IGF-1R. The potential application of these inhibitors is currently under intense clinical investigation. This review describes the biology of IGF-1R particularly from a cancer perspective. The attempts to develop effective IGF-1R antagonists are discussed comprehensively with special emphasis on antibodies and small tyrosine kinase inhibitors.     

New techniques and strategies in drug discovery

Great success has been witnessed in last decades, some new techniques and strategies have been widely used in drug discovery. In this roadmap, several representative techniques and strategies are highlighted to show recent advances in this filed. (A) A DOX protocol has been developed for accurate protein-ligand binding structure prediction, in which first principle method was used to rank the binding poses. Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%, indicating significant improvement over molecular docking method. (B) Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen, which has been used in hit/lead identification, drug repositioning, and mechanism-of-action studies. Current and emerging methods for virtual target profiling are briefly summarized herein. (C) Research on targeted autophagy to treat diseases has received encouraging progress. However, due to the complexity of autophagy and disease, experimental and in silico methods should be performed synergistically for the entire process. This part focuses on in silico methods in autophagy research to promote their use in medicinal research. (D) Histone deacetylases (HDACs) play important roles in various biological functions through the deacetylation of lysine residues. Recent studies demonstrated that HDACs, which possess low deacetylase activities, exhibited more efficient defatty-acylase activities. Here, we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor. (E) The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area. (F) Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance. (G) Since nitric oxide (NO) exerts anticancer activity depending on its concentration, optimal levels of NO in cancer cells is desirable. In this minireview, we briefly describe recent advances in the research of NO-based anticancer agents by our group and present some opinions on the future development of these agents. (H) The field of photoactivation strategies have been extensively developed for controlling chemical and biological processes with light. This review will summarize and provide insight into recent research advances in the understanding of photoactivatable molecules including photoactivatable caged prodrugs and photoswitchable molecules.     

Unraveling molecular transformations on surfaces: a critical comparison of oxidation reactions on coinage metals

The coinage metals, copper, silver, and gold, have unique characteristics for selective oxidation catalysis, particularly for partial oxidation of alcohols and olefins. A basic understanding of surface chemistry at the molecular level can help facilitate the improvement of current catalytic processes and the designing of new catalytic systems. In this critical review, the current state of knowledge of these reactions is reviewed. First, both the experimental and theoretical methods necessary for understanding surface reactivity are discussed with a specific set of examples directly related to these reactions. Next the state of understanding of the surface chemistry of the oxidation reactions of alcohols and olefins on these three coinage metals is reviewed and the reaction pathways are compared. Clear relationships between the low pressure surface science studies and more practical catalytic conditions are illustrated. Finally, recent theoretical advances in this area are discussed as well as possible future directions in this field (132 references).     

On-chip screening method for cell migration genes based on a transfection microarray

Cell migration plays a major role in a variety of biological processes and a detailed understanding of associated mechanisms should lead to advances in the medical sciences, for example, in drug discovery for cancer therapy. However, the traditional methods used for analysis of cell migration cannot easily be scaled up for high-throughput screening. In this study, we have attempted to develop a novel simple method for high-throughput phenotypic screening for the identification of genes that are required for cell migration. As the appropriate cell line for the method, we found NBT-L2b cells that would be suitable for screening of migration-related genes in our method without influence by other cellular processes. Moreover, the idea for printing both the labeled fibronectin, for identification of the starting region of a cell, and the green fluorescent protein (GFP) expression vector, for identification of cells that had been transfected with siRNA and of the end point of migration, brings a rapid and efficient high-throughput screening procedure. Our new method will lead to an enhanced understanding of cell migration.     

Magnetic hyperthermia: Potentials and limitations

Despite the fact that the magnetic hyperthermia (MH) has been known for more than 75 years, it is still debated in its clinical applications. The generation of a higher temperature at a tumor is called hyperthermia. There is a different of temperature ranges going from 39 to 40 ?°C up to such high temperatures as 80–90 ?°C. However, due to its high potential, MH is used along with nanoparticles as heat intermediaries in the treatment of cancer. Many Magnetic Nanoparticles (MNPs) with several properties and morphological metallic structures have been useful to magnetics hyperthermia therapy. These MNPs are categorized into two groups; magnetic alloy nanoparticles (MANPs) and magnetic metal oxide nanoparticles (MMONPs). The principal challenges of this method are the control of local tumoral temperature and the increase in nanoparticles heating power. The hyperthermia agents derived from magnetic nanoparticles along with magnetic field. In the recent study, hyperthermia thought, dissimilar types of magnetic nanoparticles for hyperthermia, efficacy for cancer therapy, advances, challenges, and future chances have been examined.     

Frustrated Lewis Pairs in Heterogeneous Catalysis: Theoretical Insights

Frustrated Lewis pair (FLP) catalysts have attracted much recent interest because of their exceptional ability to activate small molecules in homogeneous catalysis. In the past ten years, this unique catalysis concept has been extended to heterogeneous catalysis, with much success. Herein, we review the recent theoretical advances in understanding FLP-based heterogeneous catalysis in several applications, including metal oxides, functionalized surfaces, and two-dimensional materials. A better understanding of the details of the catalytic mechanism can help in the experimental design of novel heterogeneous FLP catalysts.     

Genome-wide identification of antioxidant component biosynthetic enzymes: comprehensive analysis of ascorbic acid and tocochromanols biosynthetic genes in rice

During the last two decades, several exciting reports have provided many advances in the role and biosynthesis of l-ascorbic acid (AsA) and tocochromanols, including tocopherols and tocotrienols, in higher plants. There are increasing bodies of experimental evidence that demonstrate that AsA and tocochromanols (especially tocopherols) play an important role as antioxidants and nutrients in mammals and photosynthetic organisms and are also involved in plant responses to stimuli. Although AsA and tocochromanol biosynthesis pathways have been well characterized using Arabidopsis, these pathways are still poorly understood in rice, which is an economically important monocot cereal crop. In this study using computational analysis of sequenced rice genome, we identified eight and seven potential non-redundant members involved in AsA and tocochromanol biosynthetic pathways, respectively. The results reveal that the common feature of these gene promoters is the combination of light-responsive, hormone-responsive, and stress-responsive elements. These findings, together with expression analysis in the MPSS database, indicate that AsA and tocochromanols might be co-related with the complex signaling pathways involved in plant responses.     

Construction and Properties of Sierpiński Triangular Fractals on Surfaces

Fractal structures are of fundamental importance in science, engineering, mathematics, and aesthetics. Construction of molecular fractals on surfaces can help to understand the formation mechanism of fractals and a series of achievements have been acquired in the preparation of molecular fractals. This review focuses on Sierpiński triangles (STs), representatives of various prototypical fractals, on surfaces. They are investigated by Monte Carlo simulations and ultra-high vacuum scanning tunneling microscopy. STs are bonded through halogen bonds, hydrogen bonds, metal-organic coordination bonds and covalent bonds. The coexistence of and competition between fractals and crystals are realized for a hydrogen-bonded system. Electronic properties of two types of STs are summarized.     

Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.     

Silicone rod and silicone tube sorptive extraction

This review focuses on the applications of silicone in the form of tubes or rods for sorptive extraction of organic compounds as sample preparation method in combination with various chromatographic techniques. Silicone rods (SRs) and silicone tubes (STs) have the advantage of being inexpensive, flexible and robust. SRs and STs with different sizes and volumes of silicone (8–635 μL) have so far been applied for the extraction/preconcentration of a large variety of organic micropollutants from different matrices. The theoretical principle of SR and ST extraction in comparison with similar microextraction techniques is presented as well as a summary of the published applications of SR and ST extraction in combination with gas chromatography (GC) or liquid chromatography (LC). Furthermore, the use of SRs and STs for time-integrated (passive) sampling is reported.     

Hydrophobins: Proteins that self assemble at interfaces

Hydrophobins are surface active proteins that are produced by filamentous fungi. They are interesting from a Surf Sci point of view because some of their properties as surface active proteins are quite spectacular. In this review, recent advances in understanding these properties will be surveyed. We will attempt to define what the properties are that make them unique. As an understanding of both structure and function of hydrophobins is emerging we see that this is paving the way for industrial applications as well as an understanding of their biological functions.

Major recent advances

Recently there has been a clear increase in attempts to use hydrophobins in applications. We are starting to understand their unique properties as surfactants and especially applications related to the stability and development of foams and various surface treatments are emerging. There are several new reports on molecular structures as well on mechanisms of self-assembly. Hydrophobins have functions in biology that are far from understood, but also here techniques are developing and a broader understanding is emerging.     

The genesis of molecular electronics

Molecular electronics is, relatively speaking, a young field. Even so, there have been many significant advances and a much greater understanding of the types of materials that will be useful in molecular electronics, and their properties. The purpose of this review is to provide a broad basis for understanding the areas where new advances might arise, and to provide introduction to the subdisciplines of molecular electronics. This review is divided into two major parts; an historical examination of the development of conventional electronics, which should provide some understanding of the push towards molecular electronics. The problems associated with continuing to shrink conventional systems are presented, along with references to some of the efforts to solve them. This section is followed by an in-depth look at the most important research into the types of behaviors that molecular systems have been found to display.     

Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling

Despite the immense therapeutic advances in the field of health sciences, cancer is still to be found among the global leading causes of morbidity and mortality. Ethnomedicinally, natural bioactive compounds isolated from various plant sources have been used for the treatment of several cancer types and have gained notable attention. Ferulic acid, a natural compound derived from various seeds, nuts, leaves, and fruits, exhibits a variety of pharmacological effects in cancer, including its proapoptotic, cell-cycle-arresting, anti-metastatic, and anti-inflammatory activities. This review study presents a thorough overview of the molecular targets and cellular signaling pathways modulated by ferulic acid in diverse malignancies, showing high potential for this phenolic acid to be developed as a candidate agent for novel anticancer therapeutics. In addition, current investigations to develop promising synergistic formulations are also discussed.     

基于长波长光激发的光敏剂和载体在肿瘤光动力治疗中的应用

光动力疗法是近年来兴起的一种新型的微创性治疗肿瘤的方法,目前已经成功地应用于临床上多种恶性肿瘤治疗中,并取得了良好的效果。然而,由于生物组织对可见光的吸收和散射,使得光线无法穿透组织到达身体内的目标区域,所以该疗法更适用于浅表肿瘤的治疗。长波长光尤其是近红外光具有良好的组织穿透深度,其在治疗组织深处的肿瘤方面具有显著的优势。基于长波长光激发的光敏剂及载体在实体肿瘤的治疗领域已经取得了丰硕的研究成果。本文将从光敏剂的研发、双光子激光的使用、上转换纳米粒子的引入等方面简要概述近十年来用于光动力治疗中的组装体系,以及长波长激发光在光动力治疗方面的发展趋势。     

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.     

Engineering the properties of D-amino acid oxidases by a rational and a directed evolution approach

D-amino acid oxidase (DAAO) is a FAD-containing flavoprotein that dehydrogenates the D-isomer of amino acids to the corresponding imino acids, coupled with the reduction of FAD. The cofactor then reoxidizes on molecular oxygen and the imino acid hydrolyzes spontaneously to the alpha-keto acid and ammonia. In vitro DAAO displays broad substrate specificity, acting on several neutral and basic D-amino acids: the most efficient substrates are amino acids with hydrophobic side chains. D-aspartic acid and D-glutamic acid are not substrates for DAAO. Through the years, it has been the subject of a number of structural, functional and kinetic investigations. The most recent advances are represented by site-directed mutagenesis studies and resolution of the 3D-structure of the enzymes from pig, human and yeast. The two approaches have given us a deeper understanding of the structure-function relationships and promoted a number of investigations aimed at the modulating the protein properties. By a rational and/or a directed evolution approach, DAAO variants with altered substrate specificity (e.g., active on acidic or on all D-amino acids), increased stability (e.g., stable up to 60 degrees C), modified interaction with the flavin cofactor, and altered oligomeric state were produced. The aim of this paper is to provide an overview of the most recent research on the engineering of DAAOs to illustrate their new intriguing properties, which also have enabled us to pursue new biotechnological applications.