REVIEW OF RESEARCH ON THE RELATIONSHIP BETWEEN CIRCADIAN RHYTHMS AND CARCINOGENESIS USING ANIMAL MODELS

Purpose of the study: to review in vivo studies on the relationship and role of various molecular genetic components of the circadian rhythm system in the initiation and development of malignant neoplasms. in contrast to clinical and epidemiological studies, animal models, including transgenic animal models, can model various changes and disturbances in the activity of clock genes and track the results of these changes.Material and Methods. the review includes data from studies carried out over the past 10 years in animal models, studying the mechanisms and effects of disturbances in the system of circadian rhythms related to the formation and development of tumors. the data sources for the review were the Medline, embase and scopus databases.Results. analysis of the literature has shown that interference with the work of the «biological clock» by changing the light cycle, disrupting the expression of clock genes and other manipulations is a factor predisposing to the development of tumors. in tumors of various types, the expression of clock genes is often mismatched, and it is unclear at what stage of their formation this occurs. in addition, the development of tumors disrupts the circadian homeostasis of the body. there are three key areas of research aimed at studying the role of circadian rhythms in tumor development: disturbance of circadian rhythms as a carcinogenic factor, disturbances in the clock gene system in a tumor, disturbances in the clock gene system of the whole organism, provoked by tumor development.Conclusion. the results of studies on animal models demonstrate that the relationship between the disturbance of circadian rhythms and the tumor process is complex since the causal relationship has not yet been studied. in this regard, the prospect of targeted pharmacological correction of circadian rhythms in clinical practice in cancer patients does not seem to be the nearest one.

Scaling dictates the decoder structure

Despite variability in embryo size, the tissue, organ and body plan developin proportionwith embryo size, known as the scaling phenomenon. Scale-invariant patterning of gene expression is a common feature in development and regeneration, and can be generated by mechanisms such as scaling morphogen gradient and dynamic oscillation. However, whether and how static non-scaling morphogens (input) can induce a scaling gene expression (output) across the entire embryo is not clear. Here we show that scaling requirement sets severe constraints on the geometric structure of the input-output relation (the decoder), from which information about the regulation and mutants’ behavior can be deduced without going into any molecular details. We demonstrate that theDrosophilagap gene system achieves scaling in the way that is entirely consistent with our theory. Remarkably, following the geometry dictated by scaling, a parameter-free decoder correctly and quantitatively accounts for the gap gene expression patterns in nearly all morphogen mutants. Furthermore, the regulation logic and the coding/decoding strategy of the gap gene system can also be revealed from the decoder geometry. Our work provides a general theoretical framework on a large class of problems where scaling output is induced by non-scaling input, as well as a unified understanding of scaling, mutants’ behavior and regulation in theDrosophilagap gene and related systems.Significance StatementWithin a given species, fluctuation in egg or embryo size is unavoidable. Despite this, the gene expression pattern and hence the embryonic structure often scale in proportion with the body length. Thisscalingphenomenon is very common in development and regeneration, and has long fascinated scientists. In this paper, the authors address the question of whether and how a scaling gene expression pattern can originate from non-scaling signals (morphogens). They found that scaling has profound implications in the developmental programming -- properties and behaviors of the underlying gene network can be deduced from the scaling requirement. They demonstrated that the scaling in fruit fly embryogenesis indeed works in this way. Thus, although biological regulatory systems are very complex in general, it can be forced to exhibit simple macroscopic behaviors due to selection pressure, as demonstrated in this study.

Differential Effects of Components in Artemisia annua Extract on the Induction of Drug-Metabolizing Enzyme Expression Mediated by Nuclear Receptors

Artemisia annua tea is a popular dosage form used to treat and prevent malaria in some developing countries. However, repeated drinking leads to an obviously decreased efficacy, which may be related to the induction of metabolizing enzymes by artemisinin. In the present study, the ability of different components in A. annua to activate the pregnane X receptor and constitutive androstane receptor was evaluated by the dual luciferase reporter gene system. The changes in mRNA and protein expression of CYP3A4 and CYP2B6 were determined by quantitative real-time PCR and Western blotting. Results showed that in the pregnane X receptor-mediated CYP3A4 reporter gene system, chrysosplenetin and arteannuin B exhibited a weak induction effect on pregnane X receptor wt, while arteannuin A had a strong induction effect on pregnane X receptor wt and pregnane X receptor 370 and a weak induction effect on pregnane X receptor 163. In the pregnane X receptor-mediated CYP2B6 reporter gene system, arteannuin A had a moderate induction effect on pregnane X receptor wt and pregnane X receptor 379, and a weak induction effect on pregnane X receptor 403, while arteannuin B had a weak induction effect on pregnane X receptor wt and pregnane X receptor 379. Arteannuin A had a strong induction effect on constitutive androstane receptor 3 in constitutive androstane receptor-mediated CYP3A4/2B6 reporter gene systems, while arteannuin B showed a weak induction effect on constitutive androstane receptor 3 in the constitutive androstane receptor-mediated CYP2B6 reporter gene system. The mRNA and protein expressions of CYP3A4 and CYP2B6 were increased when the pregnane X receptor or constitutive androstane receptor was activated. Various components present in A. annua differentially affect the activities of pregnane X receptor isoforms and the constitutive androstane receptor, which indicates the possibility of a drug-drug interaction. This partly explains the decline in efficacy after repeated drinking of A. annua tea.

Effect of SnTOX effectors on the virulence degree of Stagonospora nodorum isolates

Stagonospora nodorum Berk. is the causal agent of Septoria nodorum blotch (SNB) of wheat (Triticum aestivum L.). It synthesizes host-specific necrotrophic effectors (NEs), which facilitate infection process and ensure virulence of pathogen on host plant with a dominant susceptibility gene. The interaction of virulence genes products of the NEs pathogen (SnTox) with susceptibility genes products of the host plant (Snn) in the S. nodorum - wheat pathosystem is carried out in inverted gene-for-gene system and causes the development of disease. In this study, we tested three main NEs SnToxA, SnTox1, SnTox3, which have already been identified in S. nodorum at the gene level. The NEs role in the development of SNB has already been proven; however, the overall host response to SNB does not always strictly follow the inverted gene-for-gene system, as multiple SnTox-Snn interactions can be additive or epistatic. In this regard, the aim of the work was to identify the NE genes in three S. nodorum isolates and to study effect of NEs genes transcriptional activity on the isolate virulence. We have shown that all three NEs SnToxA, SnTox3 and SnTox1 played an important role in the development of the disease in compatible interactions. Effectors SnTox3 and SnTox1 exhibited epistatic interaction that was removed by a triple compatible interaction (SnTox3-Snn3, SnToxA-Tsn1 and SnTox1-Snn1). This effect was shown by us for the first time. The mechanisms of epistatic and additive interactions, as well as the virulence of the isolate were associated with the regulation of the NEs genes transcriptional activity. The avirulent isolate Sn4VD lacked transcription of all three NEs genes, and the virulent isolate Sn9MH was characterized by a high level of mRNA accumulation of all three NEs genes during infection on susceptible cultivar. We also showed that SnTox expression depended both on the host genotype in SnToxA and SnTox3 and on the number of compatible interactions exhibiting additive or epistatic interactions in SnTox1 and SnTox3. Finally, the virulence of the S. nodorum isolate depended on the qualitative and quantitative composition of NEs.