Various saponins, plant glycosides with favorable anti-tumorigenic properties, have been used to inhibit tumor cell growth by cell cycle arrest and apoptosis with IC50 values of up to 0.2 μM. We describe several groups of saponins (dioscins, saikosaponins, julibrosides, soy saponins, ginseng saponins and avicins) currently investigated for their use in tumor therapy. We focus on cellular and systemic mechanisms of tumor cell growth inhibition both in vitro and in vivo, combinational approaches with saponins and conventional tumor treatment strategies, and successful syntheses of saponins. The increasing interest in saponins for tumor therapy is very promising for the future development of sophisticated anti-cancer drugs.

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Saponins are plant glycosides that consist of a steroid, steroid alkaloid or triterpenoid aglycone and one or more sugar chains that are covalently linked by glycosidic binding to the aglycone. Glucose, galactose, glucuronic acid, xylose and rhamnose are commonly bound monosaccharides. Saponins are found in all organs of a variety of higher plants. Due to the great variability of their structures, diverse functions have been described for distinct saponins; including foaming and pore forming properties as well as selective removal of protozoa from the rumen. The most interesting properties are, however, favorable anti-tumorigenic effects. Several saponins inhibit tumor cell growth by cell cycle arrest and apoptosis with half maximal inhibitory concentrations of down to 0.2 microM. A drawback of saponins in tumor therapy is the non-targeted spreading throughout the whole body. Surprisingly, certain saponins were identified that drastically enhance the efficacy of targeted chimeric toxins bearing the ribosome-inactivating protein saporin as cell-killing moiety. It was demonstrated that this effect is substantially more pronounced on target cells than on non-target cells, thus not only preserving the target specificity of the chimeric toxin but also broadening the therapeutic window with simultaneous dose lowering. This review describes the role of saponins as drug in general, their use as single drug treatment in tumor therapy, their combination with conventional tumor treatment strategies and the synergistic effects with particular targeted tumor therapies that are based on recombinant proteins.

Effective management of digital assets as well as increasing research exposure and impact are particular challenges faced by smaller institutions with limited infrastructure and resources. The paper explores the significant factors involved in considering, planning and establishing an institutional repository for Bond University, one of the smaller higher education providers in Australia. The salient benefits and advantages as well as the disadvantages of implementing an off-the-shelf product as opposed to an open source solution for an institutional repository are compared. The rationale for choosing a proprietary product over an open source solution is discussed, as well as the process for obtaining funding and the support of key stakeholders within the University. The paper describes the strategies employed to populate the repository retrospectively and to train academic staff and researchers in self-archiving. The development of policy governing the repository and intellectual property and copyright implications are also covered.

This article describes a method for creating an improved emergence profile with single-tooth, implant-supported restorations. An easily trimmed silicone gingival substitute is used to allow polymerization of acrylic resin provisional restorations to achieve control of the emergence profile. Gingival trauma is minimized by eliminating intraoral use of monomer and minimizing surgical procedures. Provisional restorations can be assessed to ensure the contour is acceptable and the trimmed gingival substitute can be used to fabricate a similar profile in the definitive prosthesis. The provisional restorations may be used instead of standard prefabricated healing abutments to guide the healing contours of the peri-implant gingival tissue.

The aim of the present study was to evaluate the possible mechanisms of testicular toxicity of GR40370X, a follow-up 5-hydroxytryptamine (5-HT) receptor agonist. Administration to adult male rats of a single (toxic) dose of 750 mg/kg GR40370X induced marked distension of seminiferous tubules and an associated increase in testis weight at 12-24 h with a gradual recovery to normal by 96 h. Seminiferous tubule distension was due to expansion of the lumen, which occurred at all stages of the spermatogenic cycle and was accompanied by vacuolation of the cytoplasm of elongating spermatids. Seminiferous tubule distension was preceded/accompanied by distension of the efferent ducts and rete testis with maximal changes evident at 24-48 h. These changes could not be explained by increases in seminiferous tubule fluid or interstitial fluid production, as both were reduced (15-20%), rather than increased, by treatment. Examination of the vasculature after treatment with 750 mg/kg GR40370X revealed significant changes that were maximal at 4 h and thus preceded rete/testicular changes. Veins of the mediastinal venous plexus, which overlies the rete, were constricted and arteriovenous anastomoses in the spermatic cord were shut/constricted, as determined (indirectly) by measurement of the dilution of outflowing testicular venous blood by incoming arterial blood. The latter effect of GR40370X could be blocked by co-administration of minoxidil, a vasodilator. Vascular effects of GR40370X had normalised by 24-48 h. It was also noted that administration of a toxic dose of GR40370X significantly lowered blood levels of LH and testosterone, though these changes were considered to be incidental and not involved in the other changes described above. None of the above changes were induced by a pharmacologically active dose (1 mg/kg) of GR40370X. It is concluded that the mechanism of testicular toxicity induced by 750 mg/kg GR40370X results from primary effects on the vasculature of the testis/neighbouring region, which in turn lead to impaired fluid resorption from the efferent ducts and rete and thence to accumulation of seminiferous tubule fluid in the rete and testis.

The 12-lipoxygenase pathway of arachidonic acid metabolism in platelets and other cells is bifurcated into a reduction route yielding 12-hydroxyeicosatetraenoic acid (12-HETE) and an isomerization route forming hepoxilins. Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets. The ratio of the activity of PHGPx to that of cytosolic glutathione peroxidase (GPx-1) was consistently found to be approx. 1:60 in platelets and UT7 megakaryoblasts. Moreover, short-lived PHGPx mRNA was detected in megakaryocytes but not in platelets. Carboxymethylation of selenium-containing glutathione peroxidases by iodoacetate, which results in the inactivation of PHGPx and GPx-1 without inhibition of 12-lipoxygenase, markedly altered the pattern of arachidonic acid metabolism in human platelets. Whereas the formation of 12-HETE was inhibited by 80%, a concomitant accumulation of 12-hydroperoxyeicosatetraenoic acid (12-HpETE) by two orders of magnitude as well as the formation of hepoxilins A(3) and B(3) were observed. The formation of hepoxilins also occurred when 12-HpETE was added to untreated platelets. In selenium-deficient UT7 cells, which were devoid of GPx-1 but not of PHGPx, the reduction of 12-HPETE was retained, albeit with a lower rate than in control cells containing GPx-1. We therefore believe that both GPx-1 and PHGPx are involved in the regulatory network of the 12-lipoxygenase pathway in platelets and other mammalian cells. Moreover, the diminution of hydroperoxide tone in platelets incubated with arachidonic acid leads primarily to the formation of 12-HETE, whereas the increase in hydroperoxide tone (a situation found under oxidative stress or selenium deficiency or on incubation with 12-HPETE) partly diverts the 12-lipoxygenase pathway from the reduction route to the isomerization route, thus resulting in the formation of hepoxilins.

A key area of difficulty for those engaged in pastoral counselling often concerns the adequate integration of pastoral, psychological and spiritual concepts and resources. The roots of this tension can be identified within modernity between what can be known through objective observation and reason over what is known through subjective experience. Pastoral counselling, in general, represents an attempt to hold together both scientific and subjective accounts of human existence. Existing forms of Christian pastoral counselling will benefit, however, through a deeper use of spiritual resources drawing both on transpersonal psychology and the tradition of Christian mysticism.

In earlier reports and reviews, it was suggested that unlike its methyl ester, the free acid form of the 12-lipoxygenase-derived eicosanoid hepoxilin A3 (HXA3) does not enter neutrophils and other cells. Therefore, in the past, most studies on the biological activities of HXA3 on human neutrophils were conducted with its methyl ester. Here, we present evidence that free HXA3 is biologically active towards human neutrophils at submicromolar concentrations, which may occur under certain circumstances in vivo. Thus, HXA3 caused chemotaxis at concentrations as low as 30–40 nM, an effect which was attenuated at higher concentrations of this eicosanoid. Its chemotactic potency proved to be comparable to that of leukotriene B4, but higher than that of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP), and greatly exceeded that of the other 12-lipoxygenase metabolite, 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid, which was inactive at comparable concentrations. The chemotactic activity of HXA3 was not abolished by serum albumin, but it was suppressed by pertussis toxin. Unlike fMLP, at this concentration range HXA3 did not cause respiratory burst or aggregation of the neutrophils or activation of protein kinase C. These observations suggest a remarkably selective and specific receptor-mediated process. At concentrations higher than 1 μM, HXA3 gives rise to an instantaneous release of calcium from intracellular stores which causes, however, only a slight, if any, liberation of arachidonic acid. On the other hand, pretreatment of the neutrophils with submicromolar concentrations of HXA3 significantly blunts the liberation of arachidonic acid caused by fMLP.

We have previously shown that the methyl ester of hepoxilin A3 causes a receptor‐induced rise in intracellular calcium through the release from intracellular stores in suspended human neutrophils. The corresponding free acid was devoid of activity. We now report that the action of the free acid form of hepoxilin A3 is dependent on the type of vehicle used, i.e. it is active in releasing calcium when used in an ethanol vehicle but not in DMSO. The methyl ester is equally active in either vehicle. The pattern of calcium release between the free acid and the methyl ester is qualitatively different. Both compounds show a biphasic pattern, i.e. an initial rapid phase followed by a slow decline in calcium levels but never reaching pre‐hepoxilin A3 baseline levels. The methyl ester appears slightly more potent in the initial phase of calcium release than the free acid (methyl=188±14 S.D., free acid=135±11 S.D. nM, P<0.0005). Both compounds appear to reach the same calcium levels at the plateau of the second prolonged phase (methyl=88±8 S.D., free acid=107±15 S.D. nM, not significant). Lanthanum chloride (an inhibitor of calcium influx) interfered with the second phase of the curve causing calcium levels to return to normal pre‐hepoxilin levels for both compounds. Addition of lanthanum chloride prior to the hepoxilin addition or carrying out the experiments in calcium‐free medium, eliminated the second phase completely, with the calcium peak returning rapidly to normal baseline levels, suggesting that the second phase is due to calcium influx. Again the methyl ester is more active than the free acid (methyl, 189±12; free acid, 145±6 S.D. nM, P<0.005). Additional experiments with tritium‐labelled methyl ester of hepoxilin A3 demonstrated that the compound is hydrolyzed into the free acid intracellularly. These experiments demonstrate that DMSO interacts with hepoxilin free acid, interfering with its entry into the cell while ethanol does not. Once inside the cell, hepoxilin interacts with its own receptor to release calcium rapidly from stores, but it also causes a more prolonged influx of calcium from the extracellular milieu.

Several types of lipoxygenases with various functions occur in mammalian cells. Although the presence of 12-lipoxygenase activity has been reported in uterine tissues, neither its type nor its biological functions have yet been established. Moreover, the putative role of uterine 12-lipoxygenase in cervical cancer has not been addressed before. Homogenates of uterine tissues from women without cancer and from patients with invasive cervical carcinoma were incubated with (1-(14)C)-arachidonic acid under various conditions and the labelled reaction products were analyzed both by thin-layer chromatography and by high-pressure liquid chromatography. 12-Lipoxygenase protein was estimated by Western blot using anti-serum against recombinant human platelet-type 12-lipoxygenase. Highest concentrations and activities of 12-lipoxygenase were found in the exocervix. The formation of 12S-hydroxy-5Z,8Z,10E, 14Z-eicosatetraenoic acid (12-HETE) was stimulated by micromolar concentrations of 13S-hydroperoxy-9Z,11E-octadecadienoic acid, suggesting metabolic control of the 12-lipoxygenase activity via the hydroperoxide tone. Immunohistochemical investigation revealed that the enzyme is mainly located in the squamous epithelium, and is of platelet-type. Significantly lower values for the 12-HETE formation were found in samples from patients with invasive cervical carcinoma, whereas the amount of immunochemically detectable 12-lipoxygenase protein was unaltered. At the same time the expression levels of the bcl-2 gene were enhanced. Thus, it is concluded that during carcinogenesis the hydroperoxide-reducing capacity of the uterine cervix tissue is enhanced, possibly mediated by bcl-2 protein, and in turn metabolically suppresses the 12-lipoxygenase activity. Furthermore, the data suggest an anti-carcinogenic action of 12-lipoxygenase in human cervix, in contrast to its reported pro-carcinogenic action in breast cancer.

Skeletal cells synthesize insulin like growth factors (IGF) and six IGF binding proteins (IGFBP). IGFBP-5 and fragments were reported to stimulate bone cell growth and parameters of osteoblastic function. We investigated the effects of IGFBP-5 1-162 and 1-193 on bone remodeling in transgenic mice overexpressing these fragments under the control of the osteocalcin promoter. Transgenic mice had normal appearance, weight, and bone mineral density. Static and dynamic histomorphometry revealed that transgenic mice overexpressing IGFBP-5 1-162 or 1-193 had normal trabecular bone volume, osteoblast and osteoclast number, and normal bone formation rate. MC3T3 cells transduced with retroviral vectors overexpressing IGFBP-5 1-235, 1-193, and 1-162 fragments displayed normal cell growth and maturation, and failed to enhance the expression of alkaline phosphatase, osteocalcin, and type I collagen mRNA when compared to cells transduced with vector alone. In conclusion, transgenic mice expressing IGFBP-5 1-162 and 1-193 in the bone microenvironment do not exhibit an obvious skeletal phenotype.

Previous studies in our laboratory revealed a high expression of 15-lipoxygenase-1 in human colorectal carcinomas, suggesting the importance of lipoxygenase in colorectal tumor development. In this report, we have investigated the metabolism of arachidonic and linoleic acid by intestinal tissues of Min mice, an animal model for intestinal neoplasia. The polyp and normal tissues from Min mice intestine were homogenized, incubated with arachidonic or linoleic acid, and analyzed by reverse-, straight-, and chiral-phase HPLC. Arachidonic acid was converted to prostaglandins E2 and F2α. Little 12- or 15-hydroxyeicosatetraenoic acid was detected. Cyclooxygenase (COX)-2 was detected in polyps and the adjacent normal tissues by Western immunoblotting, but neither COX-1 nor leukocyte-type 12-lipoxygenase, the murine ortholog to human 15-lipoxygenase-1, was detected. These tissue homogenates converted linoleic acid to an equal mixture of 9(S)- and 13(S)-hydroxyoctadecadienoic acid (HODE). Inhibition of lipoxygenase activity with nordihydroguaiaretic acid blocked HODEs formation, but the COX inhibitor indomethacin did not. Degenerative-nested PCR analyses using primers encoded by highly conserved sequences in lipoxygenases detected 5-lipoxygenase, leukocyte-type 12-lipoxygenase, platelet-type 12-lipoxygenase, 8-lipoxygenase, and epidermis-type lipoxygenase-3 in mouse intestinal tissue. All of these PCR products represent known lipoxygenase that are not reported to utilize linoleic acid preferentially as substrate and do not metabolize linoleic acid to an equal mixture of 9(S)- and 13(S)-HODE. This somewhat unique profile of linoleate product formation in Min mice intestinal tissue suggests the presence of an uncharacterized and potentially novel lipoxygenase(s) that may play a role in intestinal epithelial cell differentiation and tumor development.

We review the methods of the renormalization group, with an illustration of the effective Lagrangian in a model of a scalar field theory (φ4 with a heavy scalar). In the standard model of electroweak interactions, these methods are applied to rare decays of the b quark involving the b→s transition. Examples of rare inclusive and exclusive decays are considered.

We examine the dilepton energy spectrum for the decay b --> sl+l-. The energy spectrum, below the energy of 0.95 GeV, is shown to be more useful than the invariant-mass spectrum for measurements of the top-quark mass in spite of the charmonium resonance effects.

The dimensional reduction regularization method has been thought by some to be a cure for supposed γ 5 problems in D = t − ϵ dimensions. Results obtained in a four-dimensional method are shown to agree with the use of ordinary dimensional regularization, while disagreeing with dimensional reduction. Thus, at least in calculation of the type presented here, the use of dimensional reduction appears to be invalid.

Abstract Nonleptonic charmless B meson decays involving the b→s transition are sensitive to the top quark mass, which may be of order M w or larger. We apply the results of a recent calculation of QCD corrections to b→s+gluons to determine the inclusive branching ratio for these processes as a function of m t .