Antimutagenic compounds and their possible mechanisms of action

Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems. Antimutagenic agents are able to counteract the effects of mutagens. This group of agents includes both natural and synthetic compounds. Based on their mechanism of action among antimutagens, several classes of compounds may be distinguished. These are compounds with antioxidant activity; compounds that inhibit the activation of mutagens; blocking agents; as well as compounds characterized with several modes of action. It was reported previously that several antitumor compounds act through the antimutagenic mechanism. Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research. It may be observed that, in recent years, many publications were focused on the screening of both natural and synthetic compounds for their beneficial muta/antimutagenicity profile. Thus, the present review attempts to give a brief outline on substances presenting antimutagenic potency and their possible mechanism of action. Additionally, in the present paper, a screening strategy for mutagenicity testing was presented and the characteristics of the most widely used antimutagenicity assays were described.     

Diversity of antimicrobial peptides and their mechanisms of action

Antimicrobial peptides encompass a wide variety of structural motifs. Many peptides have alpha-helical structures. The majority of these peptides are cationic and amphipathic but there are also hydrophobic alpha-helical peptides which possess antimicrobial activity. In addition, some beta-sheet peptides have antimicrobial activity and even antimicrobial alpha-helical peptides which have been modified to possess a beta-structure retain part of their antimicrobial activity. There are also antimicrobial peptides which are rich in a certain specific amino acid such as Trp or His. In addition, antimicrobial peptides exist with thio-ether rings, which are lipopeptides or which have macrocyclic Cys knots. In spite of the structural diversity, a common feature of the cationic antimicrobial peptides is that they all have an amphipathic structure which allows them to bind to the membrane interface. Indeed, most antimicrobial peptides interact with membranes and may be cytotoxic as a result of disturbance of the bacterial inner or outer membranes. Alternatively, a necessary but not sufficient property of these peptides may be to be able to pass through the membrane to reach a target inside the cell. The interaction of these peptides with biological membranes is not just a function of the peptide but is also modulated by the lipid components of the membrane. It is not likely that this diverse group of peptides has a single mechanism of action, but interaction of the peptides with membranes is an important requirement for most, if not all, antimicrobial peptides.     

Yeast killer toxins,molecular mechanisms of their action and their applications

Killer toxins secreted by some yeast strains are the proteins that kill sensitive cells of the same or related yeast genera. In recent years, many new yeast species have been found to be able to produce killer toxins against the pathogenic yeasts, especially Candida albicans. Some of the killer toxins have been purified and characterized, and the genes encoding the killer toxins have been cloned and characterized. Many new targets including different components of cell wall, plasma membrane, tRNA, DNA and others in the sensitive cells for the killer toxin action have been identified so that the new molecular mechanisms of action have been elucidated. However, it is still unknown how some of the newly discovered killer toxins kill the sensitive cells. Studies on the killer phenomenon in yeasts have provided valuable insights into a number of fundamental aspects of eukaryotic cell biology and interactions of different eukaryotic cells. Elucidation of the molecular mechanisms of their action will be helpful to develop the strategies to fight more and more harmful yeasts.     

Deciphering bioactive peptides and their action mechanisms through proteomics

Introduction: Bioactive peptides such as antimicrobial peptides (AMPs), ribosomally synthesized and post translationally modified peptides (RiPPs) and the non-ribosomal peptides (NRPs) have emerged with promising applications in medicine, agriculture and industry. However, their development has been limited by several difficulties making it necessary to search for novel discovery methods. In this context, proteomics has been considered a reliable tool.

Areas covered: This review highlights recent developments in proteomic tools that facilitate the discovery of AMPs, RiPPs and NRPs as well as the elucidation of action mechanisms of AMPs and resistance mechanisms of pathogens to them.

Expert commentary: Proteomic approaches have emerged as useful tools for the study of bioactive peptides, especially mass spectrometry-based peptidomics profiling, a promising strategy for AMP discovery. Furthermore, the rapidly expanding fields of genome mining and genome sequencing techniques, as well as mass spectrometry, have revolutionized the discovery of novel RiPPs and NRPs from complex biological samples.     

Liver stem/progenitor cells: their characteristics and regulatory mechanisms

Liver stem cells give rise to both hepatocytes and bile duct epithelial cells also known as cholangiocytes. During liver development hepatoblasts emerge from the foregut endoderm and give rise to both cell types. Colony-forming cells are present in the liver primordium and clonally expanded cells differentiate into either hepatocytes or cholangiocytes depending on culture conditions, showing stem cell characteristics. The growth and differentiation of hepatoblasts are regulated by various extrinsic signals. For example, periportal mesenchymal cells provide a cue for bipotential hepatoblasts to become cholangiocytes, and mesothelial cells covering the parenchyma support the expansion of foetal hepatocytes by producing growth factors. The adult liver has an extraordinary capacity to regenerate, and after 70% hepatectomy the liver recovers its original mass by replication of the remaining hepatocytes without the activation of liver stem cells. However, in certain types of liver injury models, liver stem/progenitor-like cells, known as oval cells in rodents, proliferate around the portal vein, while the roles of such cells in liver regeneration remain a matter of debate. Clonogenic and bipotential cells are also present in the normal adult liver. In this minireview we describe recent studies on liver stem/progenitor cells by focusing on extracellular signals.     

The importance of regulatory ubiquitination in cancer and metastasis

Ubiquitination serves as a degradation mechanism of proteins, but is involved in additional cellular processes such as activation of NFκB inflammatory response and DNA damage repair. We highlight the E2 ubiquitin conjugating enzymes, E3 ubiquitin ligases and Deubiquitinases that support the metastasis of a plethora of cancers. E3 ubiquitin ligases also modulate pluripotent cancer stem cells attributed to chemotherapy resistance. We further describe mutations in E3 ubiquitin ligases that support tumor proliferation and adaptation to hypoxia. Thus, this review describes how tumors exploit members of the vast ubiquitin signaling pathways to support aberrant oncogenic signaling for survival and metastasis.     

Telomeres and telomerase: their mechanisms of action and the effects of altering their functions

The molecular features of telomeres and telomerase are conserved among most eukaryotes. How telomerase and telomeres function and how they interact to promote the chromosome-stabilizing properties of telomeres are discussed here.     

调节性B细胞的发现和研究进展

B细胞主要通过呈递抗原和产生抗体发挥免疫调节作用.新近研究表明,一种全新的B细胞亚群--调节性B细胞(regulatory B cell,Bregs),可通过产生白细胞介素10(IL-10)或转化生长因子β1(TGF-β1)等抑制性细胞因子介导免疫耐受,抑制过度炎症反应.Bregs在一些慢性炎性疾病包括肠炎、类风湿性关节炎、实验性自身免疫脑脊髓炎、多发性硬化症、感染和肿瘤等发生、发展和转归过程起重要调节作用.Bregs的发现和作用机制的阐明,将为全面、深入了解免疫耐受的机制,寻找和开发更合理治疗慢性炎性疾病的策略提供理论依据.本文综述了Bregs的发现、生物学特征、发育调节及其参与炎性疾病发病的作用和机制.     

Patterning mechanisms and morphological diversity of spider appendages and their importance for spider evolution

The prosoma of spiders bears different gnathal (labrum, chelicerae, pedipalps) and locomotory appendages (legs). In most species these appendages are also used for additional functions, e.g. sensing, mating, and courtship. The opisthosoma is equipped with four pairs of highly specialized appendages. Two pairs of spinnerets are used for silk production and manipulation. The other two pairs of appendages are internalized during development and give rise to a complex respiratory system of book lungs and tracheae. Thus spiders have a number of different appendage types with radically different adult morphologies. Furthermore, all these appendage types display significant additional species specific diversity correlating with a large spectrum of functions of the appendages. Despite this importance of appendage diversity for the evolution of the spiders we know relatively little about the genetic patterning mechanisms producing this diversity of morphology. We review recent advances concerning the developmental genetics of spider appendage diversification, mainly concentrating on open questions and future directions of research. We conclude that the deeper understanding of appendage development and diversity in spiders can contribute significantly not only to evolutionary developmental biology, but also to behavioral biology, speciation research and population genetics, and the study of sexually dimorphic traits.     

Modeling and identification of endocrine-metabolic systems. theoretical aspects and their importance in practice

Some guidelines for modeling, identification, and validation in endocrinology and metabolism are presented. Fundamentals based on recent theoretical developments are given, and their essential role for solving physiological and clinical problems is shown. Concepts and issues discussed include a priori and a posteriori identifiability; optimal experiment design; assessment of model validity; simple and complex models; compartmental and noncompartmental models. Recent studies on the glucose-insulin system and on ketone body metabolism are used to illustrate the methodological line of thought discussed in the paper.     

哺乳动物季节性繁殖的神经内分泌调节机制

动物的季节性繁殖,是指其繁殖活动从静止到复苏的一个年周期性循环。研究显示,kisspeptin和RFRP对繁殖的季节性变化具有重要作用。非繁殖期最显著的特点是雌激素对GnRH分泌的负反馈效应的增加,而雌激素的这种效应是由kisspeptin神经元传导的。因此,kisspeptin是影响繁殖活动的一个重要因子。RFRP的表达依赖于褪黑激素的分泌并呈现出季节性变化,在非繁殖期对繁殖活动的抑制作用非常明显。此外,甲状腺激素在繁殖期的终止上发挥着至关重要的作用,而多巴胺能神经元A14/A15也促进了雌激素负反馈效应的季节性变化。这些神经元系统通过协同作用一起调节了生殖功能随光周期的季节性转变。文章对繁殖的季节性和这4个神经内分泌系统之间的关系进行了系统的阐述。     

Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms

An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity. Among the potential analogs we synthesized, (E)-6-(4-Ethylstyryl)-4-methoxy-2H-pyran-2-one (14) and (E)-6-(4-Butylstyryl)-4-methoxy-2H-pyran-2-one (21) both significantly up-regulated Runx2 and Osterix mRNA expression at 10 µM. These osteogenic activities could be mediated by bone morphogenetic protein (BMP) and activation of p38 MAPK signaling pathways. Compounds 14 and 21 also inhibited RANKL-induced osteoclast differentiation of RAW264 cells. These results indicated that novel 5,6-dehydrokawain analogs not only increase osteogenic activity but also inhibit osteoclast differentiation, and could be potential lead compounds for the development of anti-osteoporosis agents.