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The first synthesis of (+/-)-taxifolial A and iso-caulerpenyne was accomplished. The key steps in the sequence are (1) the stereoselective assembly of a vinyltin derived from butynediol and a functionalized aldehyde and (2) the construction of the dienyne moiety via a Stille cross-coupling.
The first stable 3-metalated cephalosporin is reported and shown to be an excellent synthetic precursor to a number of prospective beta-lactamase inhibitors. Reaction: see text.
Addition of Zn(n-Bu(3)Sn)(2) to prochiral aldehydes affords anti-alpha,beta-dialkoxy- and anti-alpha-alkoxy-beta-aminostannanes in good yield (up to 77%) and excellent diastereoselectivity (up to 98% de). syn-Isomers are accessed from the initial adducts via Mitsunobu inversion/saponification. The corresponding thionocarbamates undergo mild Cu(I)-mediated cross-coupling with a variety of organic halides, inter alia, allylic, cinnamylic, propargylic, and acetylenic, with retention of configuration. [reaction: see text]
[reaction: see text]. The intramolecular vinylogous Morita-Baylis-Hillman reaction was explored to access the central cyclopentane ring of FR182877. The reaction manifold and product distribution is strikingly solvent and substrate dependent.
[reaction: see text] A series of asymmetric free-radical-mediated intermolecular conjugate additions using a fluorous oxazolidinone chiral auxiliary has been completed. The fluorous auxiliary facilitated product isolation using fluorous solid phase extractions (FSPE), effectively removing excess organic and organometallic reagents. Parallel reactions carried out with a similar but nonfluorous norephedrine-derived oxazolidinone demonstrated the superior stereoselectivity and purification obtainable with the fluorous chiral auxiliary.
[reaction: see text] A allylation of aldehydes and imines (generated in situ from aldehydes and amines) with allyltributyltin promoted by recoverable and reusable the polymer-supported sulfonamide of N-glycine has been developed. Good to high yields were obtained in various cases. Most of the SnBu(3) residue can be recovered as Bu(3)SnCl. Highly stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 7 was achieved by using the P4a-mediated allylation of Boc-l-phenylglycinal as a key step.
[formula: see text] Dynamic NMR analysis of conformationally mobile and rigid 2-tributylstannyl-N-methylpiperidines revealed an unexpected conformational effect that is manifested in a small energy difference between conformers in which the tin is equatorial and axial. The major reason appears to be a distortion of the conformer in which the C-2-Sn bond is synclinal to the nitrogen lone pair.
In the present study, we show that the immunotoxicant, tributyltin (TBT), induces a dose-dependent activation of caspases followed by typical apoptotic morphology in resting human peripheral blood lymphocytes. TBT also caused an early loss of mitochondrial membrane potential (Delta(Psi)(m)) and release of cytochrome c, suggesting that apoptosis was triggered by the mitochondrial pathway. When CD4+ T-cells were sorted from peripheral blood and exposed to TBT for 30 min, caspase activation and apoptosis were induced. Interestingly, in the sorted CD8+ T-cell population, caspase activation was not observed until 2 h of TBT exposure, suggesting that these cells were more resistant toward TBT. Moreover, a time-dependent induction of caspase activity was also detected in CD3-stimulated peripheral blood lymphocytes. This caspase activation was not associated with cytochrome c release or loss of mitochondrial Delta(Psi) and did not lead to apoptotic morphology, although it did lead to both PARP and DFF cleavage. We also noticed a concomitant induction of Hsp27, and it awaits to be seen if this chaperone may interfere with the processing of nuclear protein substrates downstream from these primary caspase-3 substrates. Moreover, no increase in caspase activation or induction of apoptosis was observed after TBT treatment in these cells. Instead, the cells were directed toward necrotic deletion. Taken together, these data suggest that TBT-induced deletion of peripheral lymphocytes is likely to be a component in the overall risk for immunotoxic responses in exposed humans.
Concern is growing regarding the impact of chemicals suspected of altering the function of the immune system in humans and wildlife. There are numerous examples of links between pollution and increased susceptibility to disease in wildlife species, including immunosuppression in harbour seals feeding on fish from contaminated sites, altered immune function in riverine fish and decreased host resistance in birds exposed to pollutants. Laboratory tests have identified potential immunological hazards posed by a range of anthropogenic chemicals in mammals and higher vertebrates. However, few reports have considered the ecological relevance of pollution-induced immunosuppression in invertebrate phyla, which constitute around 95% of all animal species and occupy key structural and functional roles in ecosystems. In this paper effects of chemicals on immune function in invertebrates are briefly reviewed and biomarkers of immunotoxicity are identified. Examples of new approaches for the measurement of immunological inflammatory reactions and stress in molluscan haemocytes are detailed. The relevance of defining the immune system as a target organ of toxicity in invertebrates is discussed and an integrated approach for the use of immunological biomarkers in environment management is proposed, combining measures of immune function and organismal viability at the biochemical, cellular and population level.
There is little information available regarding the role of inflammatory cells in the pathogenesis of chronic pancreatitis. Therefore, we analyzed the local cytokine profile and infiltrating lymphocytes in a rat model of chronic pancreatitis. Experimental pancreatitis was induced by a single intravenous application of dibultyltin dichloride (DBTC). During a time course of two months we observed the mRNA expression of cytokines using competitive RT-PCR. Lymphocytes were characterized by immunohistochemistry, FACS analysis, and the lymphocyte proliferation test. IL-1beta, IL-6, IL-5, and IL-10 were immediately up-regulated in the acute phase of disease, while lymphocyte-restricted expression of IL-2, IL-2R, and IFN-y was only found in the chronic course. Among the infiltrating lymphocytes, CD4+ cells dominated, but during the chronic process there was an increase of CD8+ cells, resulting in a reduced CD4/CD8 ratio. Mitogen-induced activation of isolated mesenteric lymph node cells increased during the chronic inflammation. Our results suggest that in experimental pancreatitis acute inflammatory reactions are followed by a T-lymphocyte-mediated process.
We recently reported that hyperthermia induces pancreatic expression of heat shock proteins (HSPs), particularly HSP70 isoforms, and protects against cerulein pancreatitis. We have now studied whether a double hyperthermia amplifies these effects and whether hyperthermia also protects against dibutyltin dichloride (DBTC)-induced pancreatitis. A further aim was to examine whether hyperthermia induces changes in transforming growth factor-beta1 (TGF-beta1). Following pretreatment without or with a single or double hyperthermia, pancreatitis was induced by application of cerulein or DBTC. Pancreatic HSP and TGF-beta1 expression were studied by immunoblotting. Pancreas injury was assessed by light microscopy and serum pancreatic enzyme activity. Hyperthermia as well as DBTC induced HSP72, whereas cerulein did not. A double hyperthermia led to a further increase in HSP72 compared to a single heat stress. In both models, hyperthermia significantly reduced pancreatic injury. Although a double hyperthermia slightly decreased the severity of cerulein pancreatitis compared to a single heat treatment, an improved pancreas protection against DBTC cytotoxicity was not achieved. We also found that hyperthermia induces the expression of TGF-beta1. In conclusion, hyperthermia preconditioning exerts protective effects against two pathophysiologically different types of pancreatitis by a mechanism that involves the up-regulation of HSP70 isoforms as well as TGF-beta1.
A comprehensive study of the scientific literature regarding tin content in normal and pathogenic human tissue has disclosed that various organotin materials retard both the onset and growth of cancer in laboratory animals, and decreased tissue tin in humans may be associated with tumour development. Initial studies by the authors have shown that the thymus gland of the mouse possesses a relatively high concentration of tin and is also the major site of accumulation for 14C-labelled tri-n-butyltin fluoride (TBTF). When mammary cancer-prone mice with transplanted tumours were orally dosed continuously with this agent in their drinking water, the tumour growth rate was significantly reduced. Both mouse mammary tumours and human lung tumours show low tin content compared to normal body tissue.
Several cohorts of cancerous mice were continuously dosed with 2,2'-bipyridyl dibutyltin dichloride, 1,10-phenanthroline dibutyltin and histidine dibutyltin; presented at 1 ppm and 10 ppm in drinking water. Tumour growth rates were significantly reduced. Tributyltin fluoride (TBTF) applied dermally, using dimethyl sulfoxide (DMSO) as the carrier, over the tumour site was ineffective. Variation in thymus and spleen weight between controls and tin-exposed mice indicates a lymphatic involvement. Analysis of mouse tissue for total tin content showed high tin concentrations in the thymus and spleen.
Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen alpha1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-alpha production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen alpha1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.
Despite numerous experimental and clinical investigations, there is no unifying concept on pathophysiology and pathogenesis of chronic pancreatitis. Defining the interplay between pancreatic microcirculation and parenchymal tissue, we will provide a basis for the better understanding of pancreatic fibrogenesis using in vivo high-resolution multifluorescence microscopy in dibutyltin chloride (DBTC)-exposed rats. Pancreatic microcirculation at days 3 and 7 after DBTC revealed leukocyte activation with a two-fold higher fraction of rolling cells and a nine- to 10-fold increase of cells firmly adherent to the endothelial lining, followed by subsequent transendothelial migration into tissue, as given by chloracetate esterase histology. In vivo staining of acinar tissue with bisbenzimide presented single cells exhibiting nuclear chromatin condensation and fragmentation. Apoptotic cell death was confirmed by immunohistochemical staining for active caspase-3 as well as by TUNEL analysis. Necrotic cells were found dispersed throughout the exocrine tissue under observation. Both modes of cell death were found highest in extent at days 3 and 7 with 15-20 cells/mm2, but progressively decreased below 10 cells/mm2 up to 28 days after DBTC. By means of in vivo microscopy yellow-green autofluorescent collagen deposits were found at day 7 and progressively increased up to approximately 12% at day 28 after DBTC. Concomitantly, density of capillaries progressively decreased and capillaries failing to conduct blood flow became apparent. Present on-line analysis indicates an early inflammatory response with acinar cell death, most probably triggering progression of disease with collagen deposition, capillary rarefication and manifestation of perfusion failure. These temporal and spatial multiparameter measurements of the in vivo microenvironment provide new insights into the pathological processes of pancreatic fibrogenesis.
The application of the Mussel Watch concept to the assessment of chemical contamination in the coastal environment is still premature, since the relationship between the physiological and ecological aspects of blue mussels and the accumulation of contaminants in their soft tissues remains unclear. We cannot yet directly estimate with known confidence the degree of chemical contamination from the levels of contaminants in the soft tissues of mussels. An understanding of the source and range of variability in the tissue concentrations of contaminants is essential, and the establishment of a biomonitoring sampling strategy to minimize the effect of identified sources of variability is required. The present study was conducted to clarify the characteristics of organotin accumulation in blue mussels under various conditions in Tokyo Bay, and to establish an optimized sampling strategy of mussels as exposure indicators of organotin contamination in Japan. It was clear that the sample number, individual size, spawning activity and vertical habitat were factors causing a variation of tissue concentration. Based on a quantitative estimation of the variability of organotin concentration in mussel tissues under various physiological and natural conditions, we suggest that a composite sample of 30 mussels (3-5 cm in shell length), collected from the infralittoral zone prior to their spawning season, is essential to reduce the variability between individuals and to obtain reproducible analytical values at a sampling site. For monitoring sites where natural blue mussels cannot be collected, an alternative method of transplanting blue mussels from a relatively clean area would be required.
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