Zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)-acetic acid], a membrane-permeant fluorophore specific for Zn(II), was used with spectrofluorimetry and video image analysis to reveal and quantify labile intracellular Zn. Zinquin labelled human chronic-lymphocytic-leukaemia lymphocytes, rat splenocytes and thymocytes with a weak diffuse fluorescence that was quenched when intracellular Zn was chelated with NNN'N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and was greatly intensified by pretreatment of cells with the Zn ionophore pyrithione and exogenous Zn. There was substantial heterogeneity of labile Zn among ionophore-treated cells, and fluorescence was largely extranuclear. The average contents of labile Zn in human leukaemic lymphocytes, rat splenocytes and rat thymocytes were approx. 20, 31 and 14 pmol/10(6) cells respectively. Morphological changes and internucleosomal DNA fragmentation indicated substantial apoptosis in these cells when the level of intracellular labile Zn was decreased by treatment with TPEN. Conversely, increasing labile Zn by pretreatment with Zn plus pyrithione suppressed both spontaneous DNA fragmentation and that induced by the potent apoptosis-induced agents colchicine and dexamethasone. These results suggest that prevention of apoptosis is a function of labile Zn, and that a reduction below a threshold concentration in this Zn pool induces apoptosis.
We used an intracellular zinc-specific fluomphore, Zinquin, in conjunction with fluorescence video image analysis, to reveal labile zinc in panaeatic islet cells, which concentrate this metal for use in synthesis, storage, and secretion of insulia. 2hquin vividly demonstrated zinc in the islet cell secip tory granules, which formed a brightly labeled crescent in the cytoplasm between one side ofthe nudeus and the plasma membrane. Lower but still appreciable amounts of zinc were detected in the remaining cytoplasm, but there was little labeling in the nudeus. Fluorescence intensity varied among islet cells, suggesting Werences in zinc Content. Their average fluorescence intensity greatly surpassed that of the surrounding pancreatic acinar cells in frozen seaions of pan-
A lipid-rich extract, preparared by supercritical fluid extraction of fresh stabilized mussel powder (Lyprinol), showed significant anti-inflammatory (AI) activity given therapeutically and prophylactically po to Wistar and Dark Agouti rats developing either (a) adjuvant-induced polyarthritis or (b) collagen(II)-induced autoallergic arthritis, with ED(50)=15 mg/kg; c.f. naproxen>/=25 mg/kg or various therapeutic oils (flaxseed, evening primrose, fish)>/=1800 mg/kg given orally. Lyprinol showed little or no activity in acute irritation assays (carrageenan, kaolin, histamine) indicating it is not mimicking rapid-acting NSAIDs.Incorporating Lyprinol into arthritigenic adjuvants composed of heat-killed Mycobacterium. tuberculosis suspended in olive oil or squalane, effectively prevented arthritis development at a dose of 5 mg/rat. By contrast, 'dummy adjuvants' prepared with Mycobacterium tuberculosis and flaxseed, evening primrose or fish oils were still arthritigenic in Dark Agouti rats (doses of oil=90 mg/rat).Lyprinol subfractions inhibited leukotriene-B(4) biosynthesis by stimulated human polymorphonuclear leukocytes in vitro, and prostaglandin-E(2) production by activated human macrophages in vitro. Much of this AI activity was associated with polyunsaturated fatty acids and natural antoxidants (carotenoids, etc.).In contrast to NSAIDs, Lyprinol is non-gastrotoxic in disease-stressed rats at 300 mg/kg po and does not seem to affect platelet aggregation (human, rat). These data show Lyprinol to be a reproducible, relatively stable, source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.
NAC in combination with NTG and streptokinase appeared to be safe for the treatment of evolving AMI and was associated with significantly less oxidative stress, a trend toward more rapid reperfusion, and better preservation of left ventricular function.
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