A hybrid bioregulatory model of angiogenesis during bone fracture healing

Bone fracture healing is a complex process in which angiogenesis or the development of a blood vessel network plays a crucial role. In this paper, a mathematical model is presented that simulates the biological aspects of fracture healing including the formation of individual blood vessels. The model consists of partial differential equations, several of which describe the evolution in density of the most important cell types, growth factors, tissues and nutrients. The other equations determine the growth of blood vessels as a result of the movement of leading endothelial (tip) cells. Branching and anastomoses are accounted for in the model. The model is applied to a normal fracture healing case and subjected to a sensitivity analysis. The spatiotemporal evolution of soft tissues and bone, as well as the development of a blood vessel network are corroborated by comparison with experimental data. Moreover, this study shows that the proposed mathematical framework can be a useful tool in the research of impaired healing and the design of treatment strategies.     

Molecular interaction maps of bioregulatory networks: a general rubric for systems biology

A standard for bioregulatory network diagrams is urgently needed in the same way that circuit diagrams are needed in electronics. Several graphical notations have been proposed, but none has become standard. We have prepared many detailed bioregulatory network diagrams using the molecular interaction map (MIM) notation, and we now feel confident that it is suitable as a standard. Here, we describe the MIM notation formally and discuss its merits relative to alternative proposals. We show by simple examples how to denote all of the molecular interactions commonly found in bioregulatory networks. There are two forms of MIM diagrams. "Heuristic" MIMs present the repertoire of interactions possible for molecules that are colocalized in time and place. "Explicit" MIMs define particular models (derived from heuristic MIMs) for computer simulation. We show also how pathways or processes can be highlighted on a canonical heuristic MIM. Drawing a MIM diagram, adhering to the rules of notation, imposes a logical discipline that sharpens one's understanding of the structure and function of a network.     

Corticotropin releasing hormone and related peptides can act as bioregulatory factors in human keratinocytes

Summary Following previous findings in human skin of the functional expression of genes for the corticotropin releasing hormone (CHR) receptor type 1 (CRH-R1) and CRH itself, we searched for local phenotypic effects for peptides related to CRH. We now report that CRH, sauvagine, and urocortin inhibit proliferation of human HaCaT keratinocytes in a dose-dependent manner. The peptides produced variable cyclic adenosine 3′∶5′-monophosphate stimulation with CRH having the highest potency. Binding of iodine 125 CRH to intact keratinocytes was inhibited by increasing doses of CRH, sauvagine, or urocortin, all showing equal inhibitory potency. Immunocytochemistry identified CRH-R1 immunoreactivity in HaCaT keratinocytes. In conclusion, CRH (exogenous or produced locally) and the related urocortin and sauvagine peptides can modify human keratinocyte phenotype through a receptor-mediated pathway.     

Preventing sexual transmission of HIV: anti-HIV bioregulatory and homeostatic components of commercial sexual lubricants

Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes. Activity against HIV and HIV-infected cells by glycerin was stable through 24 hours at 37 degrees C. Glycerin and polyquaternium-32 were active at minimum concentrations of approximately 2% and 0.01%, respectively--well within the highest FDA safety guidelines. Both active components disrupted infected leukocytes within 5 minutes which resulted in inhibition of infectious HIV production by infected leukocytes of greater than 25 to 100-fold. These components do not disrupt vaginal epithelial cells in vivo.These components also rapidly inactivate cell-free HIV by 10- to 30-fold. Thus, we may conclude that the active components of the OTC lubricants are glycerin and polyquaternium-32. Using these components, OTC sexual lubricants could be reformulated to optimize their anti-HIV activity. Furthermore, clinical trials of these lubricants and components seem to be indicated because of their FDA safety level, wide availability, and low cost.     

De-differentiation-derived mesenchymal stem cells demonstrate selective repression in H19 bioregulatory RNA gene expression

Cellular de-differentiation can induce anticancer activity that makes cells resistant to carcinogenesis, but the molecular mechanism of this phenomenon has not been defined. To determine whether stable molecular changes develop in association with the process of de-differentiation, DNA microarray analyses were performed. These analyses compared control undifferentiated cells with three carcinogenesis-resistant clones of de-differentiated cells that were derived from mature adipocytes. The results of analysis of 6,000 genes and 6,000 ESTs establish that relative to control cells, all three de-differentiation-derived cell clones demonstrate that only one gene shows a consistent difference in expression. The expression of the H19 bioregulatory RNA is repressed an average of >fourfold in all de-differentiated cell clones. Real-time PCR analyses confirm these findings. This suggests that decreased H19 expression may account, at least in part, for the anticancer activity observed in de-differentiated cell clones.     

Assessment of the bioregulatory activity of the leaf juices of higher plants in Al-Taif,Saudi Arabia against Fusarium solani,Phytophthora spp. and Rhizoctonia solani

Resistance to conventional fungicides causes poor disease control in agriculture. Natural products from plants have great potential as novel fungicide sources for controlling pathogenic fungi. In this study the antipathogenic activity of the leaf juices of 11 plant species (Chenopodium ambrosioides, Pulicaria vulgaris, Lavandula pubescens, Lavandula dentata, Ageratum conyzoides, Ficus retusa, Zizyphus nummularia, Acacia tortilis, Phragmanthera sp. Aff. Rufescens, Lawsonia alba and Olea europaea) were evaluated in vitro against three plant pathogenic fungi (Fusarium solani, Phytophthora spp. and Rhizoctonia solani). Plate assays showed that the leaf aqueous juices have antifungal activity against these fungi. The aqueous extracts of Pulicaria vulgaris, Lavandula dentata, Ageratum conyzoides, Ficus retusa, Zizyphus nummularia, Acacia tortilis, Phragmanthera sp. Aff. Rufescens (when associated with Acacia tortilis), Lawsonia alba and Olea europaea exhibited antifungal properties against Fusarium solani, Phytophthora spp. and Rhizoctonia solani with variable degrees. On the other hand, Chenopodium ambrosioides, Lavandula pubescens and Phragmanthera sp. Aff. Rufescens (when associated with Zizyphus nummularia) did not exhibit any fungitoxicity. All these observations suggest the possible exploitation of Chenopodium oil as a potential botanical fungitoxicant in ecofriendly control of post-harvest biodeterioration of food commodities from storage fungi.     

神经系统与内分泌系统的相互影响与协同作用

在人体内,神经系统和内分泌系统紧密联系,协调配合,相互作用。它们的基本功能都是信息传递,在此功能之上,两大系统几乎调控着机体全部的代谢活动。将以综述的形式,介绍神经内分泌系统的结构基础,神经系统与内分泌系统的相互作用,以及两大系统共同发挥作用的主要领域。     

Erythropoietin processing in erythropoietic system and central nervous system

We describe possible functions of carbohydrates attached to growth factors and strategies to examine the functions, concentrating on erythropoietin, a major regulator of erythropoiesis. Erythropoietin in erythropoiesis functions as an endocrine hormone; it is produced by kidney cells and transferred into the circulation to hemopoietic sites. In the brain, erythropoietin acts on neurons in a paracrine fashion. Comparison of glycosylation has been made between kidney and brain erythropoietins.Abbreviations BHK Baby Hamster Kidney - Epo Erythropoietin - Epo-R erythropoietin receptor     

The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.     

Calcitonin and prostaglandin system

It has been repeatedly reported that calcitonin treatment in various diseases with high levels of bone resorption is associated with an antalgic effect, the mechanism of which is far from been clarified. The involvment of prostaglandins and thromboxane in hyperalgesia prompted us to consider the possibility that calcitonin induces its antalgic effect through on interference with prostaglandin and thromboxane synthesis. Guinea pig lung which, perfused with arachidonic acid releases in the perfusate a mixture of thromboxane and prostaglandins, each measurable on a separate smooth muscle tissue (rabbit aorta and rat stomach strip), was used as a test system. Calcitonin added to the perfusion fluid was shown to inhibit the synthesis both of prostaglandins and thromboxane. The concentration of calcitonin (salmon) which decreased the activity of arachidonic acid by 50% (KB) was 0.27 and 0.40 nmoles for prostaglandins and thromboxane respectively. In the experiments carried out using Ca⁺⁺ concentration in the perfusion fluid 50% higher than normal (0.28 g/l), calcitonin inhibition of prostaglandins and thromboxane was unchanged (KB = 0.23 and 0.36 nmoles respectively). The reported results by indicating that calcitonin has an influence on cyclooxygenase as indomethacin (used as reference standard) whose it is well known the activity at this level, support the interesting possibility that the antalgic effect consequent to the treatment with the hormone is due, at least in part, to a mechanism involving the prostaglandin synthetase system.     

Renin-angiotensin system and sympathetic nervous system in cardiac pressure-overload hypertrophy

Angiotensin II and norepinephrine (NE) have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. The purpose of this study was to determine the temporal sequence for activation of the renin-angiotensin and sympathetic nervous systems in the rat after 3-60 days of pressure overload induced by aortic constriction. Initially on pressure overload, there was transient activation of the systemic renin-angiotensin system coinciding with the appearance of left ventricular hypertrophy (day 3). At day 10, there was a marked increase in AT(1) receptor density in the left ventricle, increased plasma NE concentration, and elevated cardiac epinephrine content. Moreover, the inotropic response to isoproterenol was reduced in the isolated, perfused heart at 10 days of pressure overload. The affinity of the beta(2)-adrenergic receptor in the left ventricle was decreased at 60 days. Despite these alterations, there was no decline in resting left ventricular function, beta-adrenergic receptor density, or the relative distribution of beta(1)- and beta(2)-receptor sites in the left ventricle over 60 days of pressure overload. Thus activation of the renin-angiotensin system is an early response to pressure overload and may contribute to the initial development of cardiac hypertrophy and sympathetic activation in the compensated heart.     

眼镜蛇毒注射液对动物心血管系统神经系统及呼吸系统影响的研究

本文报告眼镜蛇毒注射液对动物的神经系统无不良影响;不影响猫、大鼠的血压;注射三种剂量后对家兔、猫、大鼠三种动物的心电图波形不产生影响,可使心律稍有降低,但在２．５小时后恢复正常;眼镜蛇毒注射液低剂量组对动物呼吸频率无不良影响,中高剂量组槿使呼吸频率销有下降,但在２．５小时后恢复正常。