AIMS/HYPOTHESISSyntaxin-1A (Syn-1A) is known to play a negative regulatory role in insulin secretion but the precise mechanisms for its action are not clear. Syn-2, -3 and -4 are also present in islet beta cells but their functions are not known. Here, we investigated the role of these syntaxins in the insulin secretory process.METHODSWe examined the following effects of Syn-1, -2, -3 and -4 expression in insulinoma beta-cell lines. Endogenous insulin secretion was measured by batch radioimmunoassay (RIA) and single cell patch clamp capacitance measurements. The L-type Ca(2+) channel activity was studied by patch clamp electrophysiology. Insulin gene transcription was examined by Northern blotting and measurement of insulin gene promoter activity by the co-expression of cyan fluorescent protein-labelled rat insulin promoter.RESULTSSyn-1A or -3, but not Syn-2 or -4 overexpression, inhibited K(+)-induced insulin release as determined by RIA (49.7 +/- 5.5 % and 49.1 +/- 6.2 %, respectively) and electrophysiologic membrane capacitance measurements (68.0 +/- 21.0 % and 58.0 +/- 13.2 %, respectively). Overexpressed Syn-1A and -3, but not Syn-2, inhibited Ca(2+) channel current amplitude by 39.5 +/- 11.6 % and 52.7 +/- 6.0 %, respectively. Of note, overexpression of Syn-1A and -3 also reduced single cell (by confocal microscopy) and total cellular endogenous insulin content (by RIA) by 24.8 +/- 4.2 % and 31.8 +/- 3.9 %, respectively. This correlated to a reduction in endogenous insulin mRNA by 24.5 +/- 4.2 % and 25.7 +/- 4.2 %, respectively. This inhibition of insulin biosynthesis is mainly at the level of insulin gene transcription as demonstrated by an inhibition of insulin gene promoter activity (53.3 +/- 9.15 % and 39.0 +/- 6.8 %, respectively).CONCLUSIONS/INTERPRETATIONThese results demonstrate that Syn-1A and -3 possess strong inhibitory actions on both insulin exocytosis and insulin biosynthesis whereas Syn-2 and -4 do not inhibit the insulin secretory process.

01 Jul 2000·ChemosphereQ2 · ENVIRONMENTAL SCIENCE & ECOLOGY

Effects of metabolites of benzo(a)pyrene on unschedule DNA synthesis in BALB/3T3 cell line

Q2 · ENVIRONMENTAL SCIENCE & ECOLOGY

Article

Author: Y.G. Liu ; Y.X. Lei ; J.K. Chen ; Z.L. Wu

In order to explore the damage from metabolites of benzo(a)pyrene on DNA of mammalian cells, the effects of four metabolites of benzo(a)pyrene (anti-BPDE, syn-BPDE, 3-OH-BP and 9-OH-BP) on synthesis of DNA and unschedule DNA synthesis (UDS) in BALB/3T3 cells were assayed, by methods of single-labeling and double-labeling. The results showed that all of the four agents were able to increase the synthesis of DNA, but only three of them (apart from syn-BPDE) induced UDS in BALB/3T3 cells. The above indicates that the metabolites of benzo(a)pyrene are able to damage DNA in BALB/3T3 cells, and that this effect may be relative to the sterical structure of metabolites of benzo(a)pyrene.

01 Jan 1990·Archiv fur Geschwulstforschung

In vivo DNA adduct formation by benzo(a)pyrene in mouse and rat epidermal and dermal fibroblasts after topical application of an initiating dose of benzo(a)pyrene.

Article

Author: Rojas-Moreno, M ; Alexandrov, K

In vivo adduct formation by benzo[a]pyrene (BP) has been compared in mouse and rat epidermal keratinocytes and dermal fibroblasts after topical application of an initiating dose of carcinogen. The BP-DNA adducts were analyzed by chromatography and acid hydrolysis of BP-deoxyribonucleoside adducts to BP-tetrols. BP was dissolved in acetone and applied, at similar doses per unit area (100 nmol/mouse and 240 nmol/rat), to 50-day-old Swiss mice and 35-day-old Wistar rats. Epidermal and dermal cells were isolated twenty four hours later. Reverse-phase HPLC of BP-deoxyribonucleoside adducts demonstrated the presence of three BP-deoxyribonucleosides adducts in mouse epidermal cells and one in mouse dermal cells. An unknown product (0.13 and 0.04 pmol/mg mouse epidermal and dermal cell DNA respectively) eluted before the BP-7,10/8,9-tetrol marker, at same relative position as 9-OH-BP-DNA adduct. The major adduct formed in mouse epidermal keratinocytes and dermal fibroblasts was dGuo modified by (+)-anti-BPDE and accounted for more than 70% of the adducts. Acid hydrolysis of the individual BP-DNA adducts was used to identify the BP-DNA adducts formed in mouse epidermal and dermal cells as anti- and syn-BPDE-dGuo. Twenty four hours after topical application of BP, the total levels of modified deoxyribonucleosides and (+)-BPDE-dGuo were 3 times greater in mouse epidermal cells than in dermal cells. The ratios of anti-BPDE to syn-BPDE was 17:1 and 12:1 in mouse epidermal and dermal cells DNA, respectively. This work provides the evidence that, at an initiating dose, 3H modified deoxyribonucleosides of rat epidermal keratinocytes and dermal fibroblasts are not detectable. This may be essential for the resistance of rat skin to the carcinogenic action of benzo[a]pyrene.

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Alzheimer Disease	Preclinical	US	Thera Neuropharma, Inc.	-
Brain Injuries, Traumatic	Preclinical	US	Thera Neuropharma, Inc.	-

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