The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach.

As a potent endogenous regulator of homeostasis, the circadian time-keeping system synchronizes internal physiology to periodic changes in the external environment to enhance survival. Adapting endogenous rhythms to the external time is accomplished hierarchically with the central pacemaker located in the suprachiasmatic nucleus (SCN) signaling the hypothalamus-pituitary-adrenal (HPA) axis to release hormones, notably cortisol, which help maintain the body's circadian rhythm. Given the essential role of HPA-releasing hormones in regulating physiological functions, including immune response, cell cycle, and energy metabolism, their daily variation is critical for the proper function of the circadian timing system. In this review, we focus on cortisol and key fundamental properties of the HPA axis and highlight their importance in controlling circadian dynamics. We demonstrate how systems-driven, mathematical modeling of the HPA axis complements experimental findings, enhances our understanding of complex physiological systems, helps predict potential mechanisms of action, and elucidates the consequences of circadian disruption. Finally, we outline the implications of circadian regulation in the context of personalized chronotherapy. Focusing on the chrono-pharmacology of synthetic glucocorticoids, we review the challenges and opportunities associated with moving toward personalized therapies that capitalize on circadian rhythms.

The interplay of spatial organization and biochemistry in building blocks of cellular signalling pathways.

Biochemical pathways and networks are central to cellular information processing. While a broad range of studies have dissected multiple aspects of information processing in biochemical pathways, the effect of spatial organization remains much less understood. It is clear that space is central to intracellular organization, plays important roles in cellular information processing and has been exploited in evolution; additionally, it is being increasingly exploited in synthetic biology through the development of artificial compartments, in a variety of ways. In this paper, we dissect different aspects of the interplay between spatial organization and biochemical pathways, by focusing on basic building blocks of these pathways: covalent modification cycles and two-component systems, with enzymes which may be monofunctional or bifunctional. Our analysis of spatial organization is performed by examining a range of 'spatial designs': patterns of localization or non-localization of enzymes/substrates, theoretically and computationally. Using these well-characterized in silico systems, we analyse the following. (i) The effect of different types of spatial organization on the overall kinetics of modification, and the role of distinct modification mechanisms therein. (ii) How different information processing characteristics seen experimentally and studied from the viewpoint of kinetics are perturbed, or generated. (iii) How the activity of enzymes (bifunctional enzymes in particular) may be spatially manipulated, and the relationship between localization and activity. (iv) How transitions in spatial organization (encountered either through evolution or through the lifetime of cells, as seen in multiple model organisms) impacts the kinetic module (and pathway) behaviour, and how transitions in chemistry may be impacted by prior spatial organization. The basic insights which emerge are central to understanding the role of spatial organization in biochemical pathways in both bacteria and eukaryotes, and are of direct relevance to engineering spatial organization of pathways in bottom-up synthetic biology in cellular and cell-free systems.

Dichlorido(4'-phenyl-2,2':6',2''-ter-pyridyl)zinc.

The title compound, [ZnCl(2)(C(21)H(15)N(3))], was obtained from the reaction of ZnCl(2)·4H(2)O with 4'-phenyl-terpyridine (L) and disodium 2,6-dipicolinate. The Zn(2+) cation is ligated by the N atoms of the tridentate L ligand and two chloride anions, forming a ZnN(3)Cl(2) polyhedron with a distorted trigonal-bipyramidal coordination geometry. In the crystal, nonclassical C-H⋯Cl hydrogen bonds are observed.

[Effect of 5-fluorouracil on modulation of immunity-associated cytokine during severe sepsis in rat].

OBJECTIVE: To observe the effect of 5-fluorouracil (5-FU) on modulation of the disorders of proinflammatory and anti-inflammatory cytokines in the severe sepsis as a result of intra-abdominal infection in rat, and to investigate the mechanism of efficacy of 5-FU in the treatment of severe sepsis. METHODS: Thirty female Wistar rats were randomly divided into three groups: control group, severe sepsis group and 5-FU group. Healthy rats served as control (n=10). Severe sepsis was induced by peritoneal injection of 1.8x10(12) cfu/L E. coli with the volume of 10 ml/kg body weight. In the 5-FU group, 50 mg/kg of 5-FU was injected intraperitoneally 40 minutes after severe sepsis was induced. All rats were sacrificed 6 hours after operation. The mortality and the ascites rate were assessed 6 hours after sepsis. At the same time the wet weight of the lung was measured and venous blood was collected for determination of concentrations of interleukin-6 (IL-6) and IL-10. RESULTS: Compared with those of severe sepsis group, the mortality and the ascites rate at 6 hours were decreased significantly in 5-FU group (P<0.05 and P<0.01). The wet weight of lung in severe sepsis group was higher significantly than that in control group (P<0.01). The lung tissue wet weight in 5-FU group was lower than that of severe sepsis group (P<0.05), but it showed no difference when compared with that of control group. The levels of IL-6 and IL-10 in severe sepsis group were higher significantly than those in control group (both P<0.01). The level of IL-6 in 5-FU group was lower than that in severe sepsis group, but with no difference compared with that of control group. The level of IL-10 in 5-FU group was also lower than that in severe sepsis group, but higher than that in control group (both P<0.01). CONCLUSION: 5-FU may lower simultaneously the level of proinflammatory IL-6 and anti-inflammatory IL-10, alleviate lung edema and inflammation. 5-FU has the protective effect against severe sepsis in rat.

[Effects of rhubarb on the immune substances secreted from intestine in mice].

OBJECTIVE: To investigate the therapeutic mechanism of rhubarb in protecting the intestinal muco-membranous barrier in the mice. METHOD: Bal b/c mice were divided into 2 groups, gavaged with normal saline and 10% rhubarb decoction, respectively. The animals were killed after 24 hours after the treatments. The intestinal juice was collected after intestinal lavage and centrifuged for determination of IgA, total protein, C3, high density lipoprotein, type II PLA2 activity, and content of lysozyme. At the same time, 40 mg of small intestine were incised in each mouse. Reverse transcription polymerase chain reaction (RT-PCR) and gel image analysis were performed to detect the content of the cryptdin gene expression. RESULT: The content of IgA, total protein, the C3, lysozyme, and the type II PLA2 activity in intestinal lavaged juice exhibited the statistical differences between the two groups (P < 0.05). There were no significant difference in the ontents of HDL, cryptdin-1 and cryptdin-4 gene expression between the two groups (P > 0.05). CONCLUSION: Rhubarb could increase secretion of several immune associated substances of the mucous membrane in normal intestine, indicating a possibility to abate the injury of intestine mucus resulted from severe stress induced by trauma, burn and shock. Through above mechanisms Rhubarb may also reduce the incidence of bacterial translocation and systemic inflammatory reaction syndrome (SIRS).