Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.     

The interplay between endoplasmic reticulum stress and inflammation

Endoplasmic reticulum (ER) stress may be both a trigger and consequence of chronic inflammation. Chronic inflammation is often associated with diseases that arise because of primary misfolding mutations and ER stress. Similarly, ER stress and activation of the unfolded protein response (UPR) is a feature of many chronic inflammatory and autoimmune diseases. In this review, we describe how protein misfolding and the UPR trigger inflammation, how environmental ER stressors affect antigen presenting cells and immune effector cells, and present evidence that inflammatory factors exacerbate protein misfolding and ER stress. Examples from both animal models of disease and human diseases are used to illustrate the complex interactions between ER stress and inflammation, and opportunities for therapeutic targeting are discussed. Finally, recommendations are made for future research with respect to the interaction of ER stress and inflammation.     

The interplay between inflammation and oxidative stress in carcinogenesis

Emerging data suggest that primary dysfunction in the tumor microenvironment is crucial for carcinogenesis. These recent findings make a compelling case for targeting the milieu for cancer chemoprevention as well as therapy. The stroma is an integral part of its physiology, and functionally, one cannot totally dissociate the tumor surrounding from the tumor cells. A thorough understanding of the tumor and stroma will aid us in developing new treatment targets. In this review, we shed light at the key aspects of the carcinogenic process and how oxidative stress and inflammation contribute to this process. We dissect the connection between metastasis and oxidative stress and focus on the key players in the tumor microenvironment that leads to inflammation, oxidative stress and DNA damage. Moreover, we consider the role of inflammation in disease, specifically cancer and metastasis. Finally, we discuss the potential applications in prognosis and cancer treatment.     

Cytokines as modulators of the hypothalamus-pituitary-adrenal axis

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.     

Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm

Hepatic encephalopathy (HE) defines a primary gliopathy associated with acute and chronic liver disease. Astrocyte swelling triggered by ammonia in synergism with different precipitating factors, including hyponatremia, tumor necrosis factor (TNF)-alpha, glutamate and ligands of the peripheral benzodiazepine receptor (PBR), is an early pathogenetic event in HE. On the other hand, reactive nitrogen and oxygen species (RNOS) including nitric oxide are considered to play a major role in HE. There is growing evidence that osmotic and oxidative stresses are closely interrelated. Astrocyte swelling produces RNOS and vice versa. Based on recent investigations, this review proposes a working model that integrates the pathogenetic action of osmotic and oxidative stresses in HE. Under participation of the N-methyl-D-aspartate (NMDA) receptor, Ca(2+), the PBR and organic osmolyte depletion, astrocyte swelling and RNOS production may constitute an autoamplificatory signaling loop that integrates at least some of the signals released by HE-precipitating factors.     

Organizer and axes formation as a self-organizing process

It is a widely held view that axis formation is based essentially on pre-localized determinants. However, the robustness of early development, the pattern regulation observed after experimental interferences and the existence of systems that don't require maternal determinants suggest that self-regulating pattern forming systems are also involved. A model is proposed that allows axes formation by a chain of reactions based on local self-enhancement and long-range inhibition. Their appropriate linkage ensures that the intermediary patterns emerge in the correct sequence and have the correct spatial relation to each other. Specifically, the model comprises the following events: the generation of a pole by a pattern-forming process, the formation of a second organizer eccentric to the pole (e.g. the Nieuwkoop center), the ecto-meso-endo subdivision, the generation of the Spemann-Mangold organizer with its anterior-posterior subdivision under the influence of the Nieuwkoop center, the conversion of the Spemann-Mangold organizer (a hot spot) into the notochord (a hot stripe), and the marking of the left side of the organism by a patterning reaction influenced by the midline. The pattern forming reactions do not depend on but can make use of maternally pre-localized determinants or asymmetries. Comparison with known genes and molecules reveals that many of the expected ingredients are present. Computer simulations show that the model accounts for many regulatory features reported in the literature. The computer simulations are available in an animated form at.     

TG2 transamidating activity acts as a reostat controlling the interplay between apoptosis and autophagy

Tissue transglutaminase (TG2) activity has been implicated in inflammatory disease processes such as Celiac disease, infectious diseases, cancer, and neurodegenerative diseases, such as Huntington’s disease. Furthermore, four distinct biochemical activities have been described for TG2 including protein crosslinking via transamidation, GTPase, kinase and protein disulfide isomerase activities. Although the enzyme plays a complex role in the regulation of cell death and autophagy, the molecular mechanisms and the putative biochemical activity involved in each is unclear. Therefore, the goal of the present study was to determine how TG2 modulates autophagy and/or apoptosis and which of its biochemical activities is involved in those processes. To address this question, immortalized embryonic fibroblasts obtained from TG2 knock-out mice were reconstituted with either wild-type TG2 or TG2 lacking its transamidating activity and these were subjected to different treatments to induce autophagy or apoptosis. We found that knock out of the endogenous TG2 resulted in a significant exacerbation of caspase 3 activity and PARP cleavage in MEF cells subjected to apoptotic stimuli. Interestingly, the same cells showed the accumulation of LC3 II isoform following autophagy induction. These findings strongly suggest that TG2 transamidating activity plays a protective role in the response of MEF cells to death stimuli, because the expression of the wild-type TG2, but not its transamidation inactive C277S mutant, resulted in a suppression of caspase 3 as well as PARP cleavage upon apoptosis induction. Additionally, the same mutant was unable to catalyze the final steps in autophagosome formation during autophagy. Our findings clearly indicate that the TG2 transamidating activity is the primary biochemical function involved in the physiological regulation of both apoptosis and autophagy. These data also indicate that TG2 is a key regulator of cross-talk between autophagy and apoptosis.     

Lupine embryo axes under salinity stress. I. Ultrastructural response

Embryonic root is the primary site of salinity perception in germinating seeds. To understand better the NaCl stress response of lupine embryo axes, ultrastructural approach combined with analysis of DNA degradation was used. In this study lupine embryo axes were cultured in vitro on the medium supplemented with two salt concentrations 250 and 500 mM to differ the reaction. To assess the rate of DNA damage, alkaline electrophoresis of isolated nuclei and DNA fragmentation analysis were performed. Results of these studies suggest programmed cell death induction under salinity stress. Moreover, ultrastructure observations revealed other characteristic features of programmed cell death like endoplasmic reticulum reorganization, increased level of vacuolization, chromatin condensation and starch grains degradation. Our comparative analysis of ultrastructure changes and DNA fragmentation speak in favour of programmed cell death in lupine (Lupinus luteus L. ‘Mister’) embryo axes treated for 12 h with 250 and 500 mM NaCl.     

Exercise training and oxidative stress in the elderly as measured by antipyrine hydroxylation products.

Effects of 12 wk exercise training on oxidative stress were examined in elderly humans. We measured oxidative stress during a 45 min cycling test by using antipyrine hydroxylation products. Antipyrine breakdown is independent of blood flow to the liver, which is important during exercise. Furthermore, antipyrine reacts quickly with hydroxyl radicals to form para- and ortho-hydroxyantipyrine. Ortho-hydroxyantipyrine is not formed in man through the mono-oxygenase pathway of cytochrome P450. Twenty subjects (9 women; 60 +/- 3 y) participated in the training program. Thirteen subjects (5 women; 64 +/- 7 y) served as inactive controls. Subjects trained, twice a week for 1 h, at a fitness center. After 12 wk, maximal oxygen uptake (p < .005) and workload capacity (p < .001) were only significantly elevated in the training group. After 12 wk, both groups observed no change in the ratios of antipyrine hydroxylates, para- and ortho-hydroxyantipyrine, to native antipyrine. Furthermore, no differences were observed within or between groups in the exercise-induced increase in the plasma level of thiobarbituric acid reactive species. In conclusion, 12-wk training had no effect on exercise-induced oxidative stress in elderly humans as measured by free radical reaction products of antipyrine. Despite the fact that training in elderly humans improves functional capacity, it appears not to compromise antioxidant defense mechanisms.     

Establishment and expression of embryonic axes: comparisons between different model organisms

In an accompanying article (C. Sardet et al. m/s 2004; 20 : 414-423) we reviewed determinants of polarity in early development and the mechanisms which regulate their localization and expression. Such determinants have for the moment been identified in only a few species: the insect Drosophila melanogaster, the worm Caenorhabditis elegans, the frog Xenopus laevis and the ascidians Ciona intestinalis and Holocynthia roretzi. Although oogenesis, fertilization, and cell divisions in these embryos differ considerably, with respect to early polarities certain common themes emerge, such as the importance of cortical mRNAs, the PAR polarity proteins, and reorganizations mediated by the cytoskeleton. Here we highlight similarities and differences in axis establishment between these species, describing them in a chronological order from oocyte to gastrula, and add two more classical model organisms, sea urchin and mouse, to complete the comparisons depicted in the form of a Poster which can be downloaded from the site http://biodev.obs-vlfr.fr/biomarcell.     

Assessing the interplay between dengue incidence and weather in Jakarta via a clustering integrated multiple regression model

Dengue incidence has been increasing dramatically in last few years with nearly four hundred million annual cases worldwide. It has been postulated that the wide-spread of dengue be due to climate change and increased exposure following the increasing human population in the affected regions. Climate change impacts on ecosystem have also set a critical role in the unpredictability of vector breeding behavior. A compelling strategy in the modeling of dengue outbreak must therefore integrate climate factors inasmuch as they determinedly govern incidence patterns. The aim of this paper is to construct a clustering integrated multiple regression model for predicting dengue incidence rate based on incidence, rainfall, and humidity data, which renders early warning information. The data used were dengue incidence data in Jakarta obtained from Jakarta Health Office and meteorological data from Indonesian Agency for Meteorology, Climatology and Geophysics (BMKG) in the period 2008–2016, defined on weekly basis. Cross-correlation was used to determine the interrelationship between dengue, rainfall, and relative humidity in Jakarta. Further improvement of the model was done by instrumenting the accumulated preceding one-month dengue incidence as an additional correction term in the model. The best fittings in terms of outbreak catchment and minimal mean squared error were obtained from the model variants involving the accumulated original and logarithm of the incidence rates respectively. Both the historical incidence rate locale and centroids of the meteorological data related to the clustering as well as the accumulated incidence rate serve as the key determinant for the upcoming incidence rate. An optimal clustering was determined in a way that the mean squared error achieves its foremost minimum, which almost coincides with the division into tertiles. These clustering strategies can be utilized to provide a more accurate forecast of the ominous dengue incidence for a few weeks’ lead-time.     

Understanding the interplay between density dependent birth function and maturation time delay using a reaction-diffusion population model

The present work employs a nonlocal delay reaction-diffusion model to study the impacts of the density dependent birth function, maturation time delay and population dispersal on single species dynamics (i.e., extinction, survival, extinction-survival). It is shown that the maturation time and the birth function are two major factors determining the fate of single species. Whereas the dispersal acts as a subsidiary factor that only affects the spatial patterns of population densities. When the birth function has a compensating density dependence, maturation time delay cannot destabilize the population survival at the positive equilibrium. Nevertheless, when the birth function has an over-compensating density dependence, the population densities of single species fluctuate in the spatial domain due to the increased maturation time delay. With the Allee effect and over-compensating density dependence, the increases in the maturation time may cause extinction of the single species in the entire spatial domain. The numerical simulations suggest that the solutions of the general model may temporarily remain nearby a stationary wave pulse or a stationary wavefront of the reduced model. The former indicates the survival of single species in a narrow region of the spatial domain. Whereas the latter represents the survival in the entire left-half or right-half of the spatial domain.     

A review on interplay between small RNAs and oxidative stress in cancer progression

Molecular and Cellular Biochemistry - Oxidative stress has been known to be the underlying cause in many instances of cancer development. The new aspect of cancer genesis that has caught the...     

Lupine embryo axes under salinity stress. II. Mitochondrial proteome response

Germination is the first step of plant growth in plant life cycle. An embryonic radicle protruding the seed coat is the first part of plant which has direct contact with external environment including salt-affected soil. In embryo axes, mitochondria are the main energy producer. To understand better salinity impact on mitochondria functioning, this study was focused on the effect of NaCl stress onto mitochondria proteome. Mitochondria were isolated from yellow lupine (Lupine luteus L. ‘Mister’) embryo axes cultured in vitro for 12 h with 250 and 500 mM NaCl. Two-dimensional gel electrophoresis of mitochondrial proteins isolated from NaCl-treated axes demonstrated significant changes in proteins abundances as a response to salinity treatment. Twenty-one spots showing significant changes in protein expression profiles both under 250 and 500 mM NaCl treatment were selected for tandem mass spectrometry identification. This approach revealed proteins associated with different metabolic processes that represent enzymes of tricarboxylic acid cycle, mitochondrial electron transport chain, enzymes and proteins involved in mitochondria biogenesis and stresses response. Among proteins involved in mitochondria biogenesis, mitochondrial import inner membrane translocase, subunit Tim17/22, mitochondrial-processing peptidase subunit alpha-1, mitochondrial elongation factor Tu and chaperonins CPN60 were revealed. Finally, formate dehydrogenase 1 was found to accumulate in lupine embryo axes mitochondria under salinity. The functions of identified proteins are discussed in relation to salinity stress response, including salinity-induced PCD.     

The interplay between inflorescence development and function as the crucible of architectural diversity

Background

Most angiosperms present flowers in inflorescences, which play roles in reproduction, primarily related to pollination, beyond those served by individual flowers alone. An inflorescence''s overall reproductive contribution depends primarily on the three-dimensional arrangement of the floral canopy and its dynamics during its flowering period. These features depend in turn on characteristics of the underlying branching structure (scaffold) that supports and supplies water and nutrients to the floral canopy. This scaffold is produced by developmental algorithms that are genetically specified and hormonally mediated. Thus, the extensive inflorescence diversity evident among angiosperms evolves through changes in the developmental programmes that specify scaffold characteristics, which in turn modify canopy features that promote reproductive performance in a particular pollination and mating environment. Nevertheless, developmental and ecological aspects of inflorescences have typically been studied independently, limiting comprehensive understanding of the relations between inflorescence form, reproductive function, and evolution.

Scope

This review fosters an integrated perspective on inflorescences by summarizing aspects of their development and pollination function that enable and guide inflorescence evolution and diversification.

Conclusions

The architecture of flowering inflorescences comprises three related components: topology (branching patterns, flower number), geometry (phyllotaxis, internode and pedicel lengths, three-dimensional flower arrangement) and phenology (flower opening rate and longevity, dichogamy). Genetic and developmental evidence reveals that these components are largely subject to quantitative control. Consequently, inflorescence evolution proceeds along a multidimensional continuum. Nevertheless, some combinations of topology, geometry and phenology are represented more commonly than others, because they serve reproductive function particularly effectively. For wind-pollinated species, these combinations often represent compromise solutions to the conflicting physical influences on pollen removal, transport and deposition. For animal-pollinated species, dominant selective influences include the conflicting benefits of large displays for attracting pollinators and of small displays for limiting among-flower self-pollination. The variety of architectural components that comprise inflorescences enable diverse resolutions of these conflicts.     

Errors in the orientation of the principal stress axes if bone tissue is modeled as isotropic

The error in the prediction of the orientation of the principal axes of stress in bone tissue is determined in the case when the tissue is modeled as elastically isotropic rather than as orthotropic, the probable symmetry of bone tissue. Results are two-dimensional and assume the same underlying strain state for both the orthotropic and isotropic cases. The maximum error is 45 degrees, and the typical error is generally significant.     

The interplay between autophagy and tumorigenesis: exploiting autophagy as a means of anticancer therapy

In wild‐type cells, autophagy represents a tumour‐suppressor mechanism, and dysfunction of the autophagy machinery increases genomic instability, DNA damage, oxidative stress and stem/progenitor expansion, which are events associated with cancer onset. Autophagy occurs at a basal level in all cells depending on cell type and cellular microenvironment. However, the role of autophagy in cancer is diverse and can promote different outcomes even in a single tumour. For example, in hypoxic tumour regions, autophagy emerges as a protective mechanism and allows cancer cell survival. By contrast, in cancer cells surrounding the tumour mass, the induction of autophagy by radio‐ or chemotherapy promotes cell death and significantly reduces the tumour mass. Importantly, inhibition of autophagy compromises tumorigenesis by mechanisms that are not entirely understood. The aim of this review is to explain the apparently contradictory role of autophagy as a mechanism that both promotes and inhibits tumorigenesis using different models. The induction/inhibition of autophagy as a mechanism for cancer treatment is also discussed.