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PubMed2001

Inhibition of neutrophil spreading during adhesion to fibronectin reveals formation of long tubulovesicular cell extensions (cytonemes).

Human neutrophils developed long thin tubulovesicular extensions (cytonemes) upon adhesion to fibronectin-coated substrata, when spreading was blocked. We observed extension formation when neutrophils were plated to fibronectin-coated substrata in Na(+)-free extracellular medium or in the presence of drugs capable of inhibiting spreading: 4-bromophenacyl bromide, N-ethylmaleimide, 7-chloro-4-nitrobenz-2-oxa-1,3-diazole, and cytochalasin D. Addition of Na(+) ions or washing of inhibitors restored neutrophil spreading. Phase-contrast and scanning electron microscopy revealed two types of extensions: (1) highly dynamic, flexible tubulovesicular extensions with unattached tips 0.2-0.4 microm in diameter, which can achieve 70-80 microm in length during 20 min, and (2) thinner straight extensions with flattened tips, which were formed in the presence of phorbol 12-myristate 13-acetate and connected cells to substratum or to the neighboring cells several cell diameters away. The latter may have derived from the former through tension after attachment of the tips. Spreading and extension formation may represent two states of the cell adhesive and communicative mechanism.

4-Chloro-7-nitrobenzofurazan↗
PubMed2002

Potentiation of tumor necrosis factor-alpha-induced cell death by rottlerin through a cytochrome-C-independent pathway.

The protein kinase C (PKC) signal transduction pathway negatively regulates receptor-initiated cell death. In HeLa cells, tumor necrosis factor-alpha (TNF)-mediated cell death involved mitochondria and was blocked by the overexpression of Bcl-2. The PKC-specific inhibitor bisindolylmaleimide and the PKCdelta inhibitor rottlerin enhanced TNF-induced cell death. We have investigated if potentiation of TNF-induced cell death by rottlerin involved amplification of the mitochondrial pathway. TNF induced cleavage of the proapoptotic protein Bid and release of mitochondrial cytochrome c. Rottlerin enhanced activation of caspase-8 and cleavage of Bid. It also enhanced activation of caspase-9 but it did not increase cytochrome c in the cytosol. It, however, increased release of mitochondrial apoptosis-inducing factor (AIF) to the cytosol. Overexpression of Bcl-2 prevented release of both cytochrome c and AIF to the cytosol. Prolonged exposure (> or =6 h) of HeLa cells to rottlerin and TNF decreased the level of cytochrome c but not of AIF in the cytosol. These results suggest that rottlerin activates a cytochrome-c-independent cell death pathway to potentiate cell death by TNF.

Acetophenones↗
PubMed2002

Conventional protein kinase C mediates phorbol-dibutyrate-induced cytoskeletal remodeling in a7r5 smooth muscle cells.

Phorbol dibutyrate (PDBu) induced the formation of podosome-like structures together with partial disassembly of actin stress fibers in A7r5 smooth muscle cells. These podosomes contained alpha-actinin, F-actin, and vinculin and exhibit a tubular, column-like structure arising perpendicularly from the bottom of PDBu-treated cells. The conventional protein kinase C (PKC) antagonist, GO6976, inhibited PDBu-induced cytoskeletal remodeling at 0.1 microM, whereas the novel PKC antagonist, rottlerin, was ineffective at 10 microM. PDBu induced the translocation of the conventional PKC-alpha but not the novel PKC-delta to the sites of podosome formation in A7r5 cells. Although partial disassembly of actin stress fibers was observed in both Y-27632- and PDBu-treated cells, focal adhesions were much reduced in number and size only in Y-27632-treated cells. Furthermore, PDBu restored focal adhesions in Y-27632-treated cells. Live video fluorescence microscopy of alpha-actinin GFP revealed a lag phase of about 20 min prior to the rapid formation and dynamic reorganization of podosomes during PDBu treatment. These findings suggest that conventional PKCs mediate PDBu-induced formation of dynamic podosome-like structures in A7r5 cells, and Rho-kinase is unlikely to be the underlying mechanism. The podosome columns could represent molecular scaffolds where PKC-alpha phosphorylates regulatory proteins necessary for Ca(2+) sensitization in smooth muscle cells.

Acetophenones↗
PubMed2001

Intracellular signaling pathway of FGF-2-modulated corneal endothelial cell migration during wound healing in vitro.

After wounding, the corneal endothelium heals primarily by migration of adjacent cells into the denuded wound area. In this study, it has been attempted to identify elements of the intracellular signaling pathway activated through basic Fibroblast Growth Factor (FGF-2)- and Protein Kinase C (PKC)-modulated migration, using specific inhibitors and stimulators of second messengers in a cell culture model. Bovine corneal endothelial cells (BCEC) were grown to confluency and experiments performed with first passage cells under serum-free conditions. A central circular 'wound' was made with a specially designed trephine. In different experiments, cells were incubated with either FGF-2 (10 ng ml(-1)), pertussis toxin (PTX; 1-50 ng ml(-1)), phorbol 12-myristate 13-acetate (PMA; 50 ng ml(-1)), 2,4'-di-bromoacetophenone (DAP; 5 microM), 1-(5-iosquinolinesulphonyl)-2-methyl-piperazine dihydrochloride (H7; 10 microM), indomethacin (5 ng ml(-1)), nordihydroguaiaretic acid (NDGA; 10 ng ml(-1)), 2-(4-morpholinyl)-8-pheny-4H-1-benzopyran-4-one (LY294002; 10 microM) or different combinations of these agents. Unsupplemented cultures served as controls. Migration was quantitated by counting the cells inside the denuded area in one randomly chosen section from the wound edge 72 hr after wounding. Cell toxicity was determined with the trypan blue exclusion test. Results were statistically analysed by Student's t-test. FGF-2 and PMA (a protein kinase C activator) both stimulated migration of endothelial cells at 2.2- and 3.1-fold, respectively. The PLA(2) inhibitor DAP and the PKC inhibitor H7 both significantly reduced PMA-stimulated migration to control levels but had no effect (DAP) or even stimulated (H7) FGF-2-modulated migration. PTX did not affect FGF-2-stimulated migration. The phosphoinositol (3)-kinase inhibitor LY294002 significantly reduced FGF-2-mediated stimulation of endothelial migration similar to the rate of control cultures. LY294002 had no effect when applied together with PMA. The cyclooxygenase inhibitor indomethacin did not influence migration rates of the cells added either alone or in combination with PMA and FGF-2, respectively. The lipoxygenase inhibitor NDGA significantly reduced the number of migrating cells in cultures with no other supplements, or of those supplemented with either PMA or FGF-2. FGF-2-induced endothelial migration in vitro is not dependent on PKC/PLA(2) or pertussis-toxin sensitive G-protein pathways but rather requires activation of a phosphoinositol (3)-kinase-like enzyme and/or arachidonic acid release with subsequent liberation of lipoxygenase products. Independent of FGF-2, PKC is a major intracellular effector of corneal endothelial migration activity after wounding and stimulates migration via the PLA(2)-dependent generation of lipoxygenase metabolites.

Acetophenones↗
PubMed1995

Differences in the acute actions of sGnRH and cGnRH-II on gonadotropin release in goldfish pituitary cells.

The signal transduction mechanisms mediating the acute actions of salmon gonadotropin (GTH)-releasing hormone (sGnRH) and chicken GnRH-II (cGnRH-II) on GTH release from goldfish pituitary cells were compared. In cell column perifusion experiments, treatment with inhibitors of phospholipase A2 (50 microM quinacrine or 50 microM bromophenacylbromide) or the lipoxygenase enzyme (50 microM nordihydroguaiaretic acid) reduced the GTH response to 100 nM sGnRH, but not the response to 100 nM cGnRH-II. These results suggest that AA mobilization through phospholipase A2 and the subsequent metabolism of AA through the lipoxygenase pathway are involved in rapid sGnRH-induced GTH secretion, but not in acute cGnRH-II action. Consistent with the idea that calcium entry through voltage-sensitive calcium channels is involved in acute GnRH action, perfusion with 1 microM verapamil, a voltage-sensitive calcium channel inhibitor, reduced both 100 nM sGnRH- and 100 nM cGnRH-II-induced GTH secretion. However, the response to cGnRH-II was decreased to a greater extent compared to sGnRH-elicited release, suggesting a greater dependence on extracellular calcium entry for acute cGnRH-II-stimulated GTH secretion. The metabolism of inositol phosphates (InsPs) following acute sGnRH and cGnRH-II administration was also investigated by monitoring the levels of [3H]InsPs in [3H]inositol-prelabeled goldfish pituitary cells. Incubation with 100 nM sGnRH increased [3H]InsP1 by 5 min and [3H]InsP2, [3H]InsP3, and other higher [3H]InsPs by 10 min. In contrast, following 10 min of stimulation by 100 nM cGnRH-II, only [3H]InsP2 levels were elevated, suggesting that cGnRH-II may activate a different set of enzymes in the phosphoinositide metabolic pathways compared to sGnRH. The lack of an InsP3 response may also reflect the relative ineffectiveness of cGnRH-II to mobilize calcium from intracellular stores. Taken together, these results strongly indicate that the mechanisms mediating rapid sGnRH-induced and cGnRH-II-elicited GTH responses are different as in the case for prolonged GnRH action.

Acetophenones↗
PubMed1996

Role of arachidonic acid and calmodulin in mediating dopamine D1- and GnRH-stimulated growth hormone release in goldfish pituitary cells.

In goldfish, growth hormone (GH) release is stimulated by dopamine via D1 receptors and cAMP-dependent mechanisms and by gonadotropin-releasing hormone (GnRH) through a protein kinase C (PKC) pathway; in addition, both D1 and GnRH actions require extracellular Ca2+. In this study, the involvement of arachidonic acid (AA) and calmodulin (CaM) in mediating the GH responses to D1 and GnRH stimulation was examined using primary cultures of dispersed goldfish pituitary cells. In 2-hr static incubation experiments, the phospholipase A2 inhibitor bromophenacylbromide (BPB; 50 microM) decreased the GH responses to the D1 agonist SKF38393 (1 microM), the adenylate cyclase activator forskolin (10 microM), and the cAMP analog 8Br-cAMP (1 mM), but not the responses to salmon (s)GnRH (100 nM), chicken (c)GnRH-II (100 nM), and AA (50 microM). Similarly, the phospholipase A2 inhibitor quinacrine (50 microM) and an inhibitor of AA metabolism, nordihydroguaiaretic acid (NDGA; 50 microM), reduced the GH responses to SKF38393, forskolin, and 8Br-cAMP. The response to the dopamine agonist apomorphine (1 microM) was also decreased by NDGA. The GH responses to AA did not add to those of forskolin or SKF38393, but were additive to responses to sGnRH and the PKC activator tetradecanoyl phorbol acetate (TPA; 100 nM). In perifusion experiments, treatment with BPB reduced the acute GH response to 1 microM SKF38393, 10 microM forskolin, or 1 mM 8Br-cAMP. Taken together, these results suggest that mobilization and metabolism of AA mediate both acute and prolonged GH responses to D1, but not GnRH. The involvement of AA probably occurs distal to D1-induced cAMP generation. Two-hour static incubation with 10 nM to 10 microM KN62, a CaM-dependent kinase II inhibitor, decreased the GH response to 100 nM sGnRH or cGnRH-II. KN62 (1 microM) similarly decreased the GH response to 1 mu M SKF38393, 10 microM forskolin, 1 mM 8Br-cAMP, or 100 nM TPA. In perifusion studies, KN62 (1 microM) also reduced the acute GH response to 5 min pulses of 100 nM sGnRH, 100 nM cGnRH-II, or 1 microM SKF38393. These results indicate that CaM mediates the acute, as well as the prolonged, GH responses to GnRH and dopamine. The involvement of CaM likely occurs distal to cAMP and PKC.

Acetophenones↗
PubMed2001

The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.

Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha-APA derivative) and HBY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HBY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant.

Acetamides↗
PubMed2001

Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide.

Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.

Acetophenones↗
PubMed1999

The effect of phospholipase A2 inhibitors on proliferation and apoptosis of murine intestinal cells.

BACKGROUND: Group II phospholipase A2 (PLA2) enzymes, the rate controlling enzymes in arachidonic acid metabolism, have been well characterized and subdivided into secretory 14-kDa PLA2 (sPLA2) and cytoplasmic 85-kDa PLA2 (cPLA2). Previous research has demonstrated increased PLA2 in colorectal tumors. The present study was performed to determine the effect of specific PLA2 inhibitors on the proliferation and induction of apoptosis of intestinal epithelial cells. METHODS: A continuously proliferating rat small intestinal cell line (IEC-18) and a mouse colon cancer cell line (WB-2054-M4) were utilized for these experiments. The cells were placed in microwells with serum-free or serum-supplemented media. The effects of serum on proliferation were then evaluated in the presence of the cPLA2 inhibitor, methylarachidonyl fluorophosphate (MAFP), or the sPLA2 inhibitor p-bromophenacyl bromide (BPB). The sPLA2 and cPLA2 protein was estimated by Western blotting. Proliferation of intestinal cells was quantitated by incorporation of [3H]thymidine into DNA and PLA2 activity was evaluated by quantitating arachidonic acid formation and prostaglandin E2 production. RESULTS: Western blotting of IEC-18 and WB-2054 cell protein demonstrated sPLA2 and cPLA2 enzyme in cells incubated in media containing 10% serum. Spontaneous DNA synthesis was present in both cell lines and serum consistently increased proliferation. In IEC-18 cells [3H]thymidine incorporation stimulated by serum was inhibited by MAFP and BPB, while in the malignant cell line, proliferation was inhibited only by BPB. BPB, but not MAFP, produced a dose-dependent increase in apoptotic ratios in both cell lines. Arachidonic acid and PGE2 formation, stimulated by serum, was inhibited by MAFP and BPB. CONCLUSIONS: A differential effect on intestinal cell mitogenesis was seen with different PLA2 inhibitors. The sPLA2 inhibitor, but not the cPLA2 inhibitor, significantly inhibited [3H]thymidine incorporation in the malignant cell line. This occurred with an induction of apoptosis. sPLA2 inhibitors may be specific inhibitors of growth of malignant cells. The inhibition of arachidonic acid and PGE2 production did not correlate with the inhibition of proliferation, suggesting that the two processes may be unrelated.

Acetophenones↗
PubMed1997

Structure-activity of three phospholipid analogues towards inhibition of phospholipase A2 in macrophages.

At concentrations 1-20 microns in culture medium of rat peritoneal macrophages which were stimulated with ionophore A23187, the phospholipid analogues 1-decyl-2-octyl-glycerophosphocholine and 1-dodecyl-2-octanamido-2-deoxy glycerophosphocholine were found more potent inhibitors than 1-octyl-2-deoxy glycerophosphocholine to lower the phospholipase A2 activities. The inhibitory effect was measured by [3H] eicosatetraenoic acid ([3H]20:4) release in macrophages and extracellular fluids and synthesis of [3H] eicosanoids after incubation of macrophages with traces of the molecular species of lecithin 1-octadecanoyl-2-[3H] eicosatetraenoyl glycerophosphocholine. The three phospholipid analogues developed higher inhibitory effects than mepacrine, dexamethasone or bromophenacyl bromide, at corresponding concentrations in medium.

Acetophenones↗
PubMed1999

Differential effects of some cell signalling inhibitors upon nitric oxide synthase expression and nuclear factor-kappaB activation induced by lipopolysaccharide in rat aortic smooth muscle cells.

Treatment of rat aortic smooth muscle cells (RASMC) with 1 or 100 microg ml-1 lipopolysaccharide (LPS) for 20-24 h led to expression of the inducible form of nitric oxide synthase (iNOS) as detected by Western blotting for iNOS protein, and by determination of increased cellular nitrite formation. LPS-induced nitrite production was inhibited almost completely by concomitant treatment of cells with LPS and either (a) pyrrolidine dithiocarbamate (PDTC, 25 microm), an antioxidant inhibitor of NF-kappaB activation; (b) N-tosyl-L-phenylalanine chloromethyl ketone (TPCK, 20 and 40 microm), a proteasomal inhibitor which prevents NF-kappaB activation; (c) nordihydroguaiaretic acid (NDGA, 10 and 50 microm), a lipoxygenase inhibitor; or (d) apocynin (2, 3.5 and 5 m m), an inhibitor of NADPH oxidase. Gel-shift assays using nuclear protein extracts incubated with a 32P-labelled DNA binding probe for NF-kappaB detected two electrophoretically separable complexes containing NF-kappaB. A faster migrating complex obtained when using both LPS-treated and untreated cells appeared to represent a basal or constitutive NF-kappaB activity, whereas a slower band was found only after LPS-treatment. The latter band was abolished when using cells treated for 1 h with LPS in the presence of PDTC (25 microm) or TPCK (20 microm), but was not inhibited by NDGA (50 microm) or apocynin (3.5 m m). The basal band was unaffected by any of the cell signalling inhibitors. Densitometry of Western blots indicated that LPS-induced iNOS protein expression was inhibited to a similar extent (between 74 and 87%) by the latter concentrations of PDTC, TPCK, NDGA and apocynin. The ability of PDTC and TPCK to abolish LPS-specific NF-kappaB activation, while also producing considerable inhibition of iNOS protein expression and nitrite formation, suggests that induction of iNOS by LPS in RASMC involves NF-kappaB-dependent transcription. However, the failure of NDGA and apocynin to prevent NF-kappaB activation, at least during early stages (up to 1 h) of its nuclear accumulation, suggests that these agents may affect cell signalling pathways which regulate iNOS induction by another mechanism to be determined.

Acetophenones↗
PubMed1994

Effects of selected anti-tumor-promoting chemicals on metabolic cooperation between Chinese hamster V79 cells.

Many tumor-promoting chemicals inhibit gap junctional communication between cells. We investigated the possibility that antipromoting chemicals may act inversely and enhance gap junctional communication. The V79/metabolic cooperation assay is an in vitro test that measures gap junctional communication indirectly by determining the extent of metabolic cooperation between mutant and wild-type V79 Chinese hamster lung fibroblasts in culture. Six in vivo antipromoters (caffeine, 3-isobutyl-1-methylxanthine (IBMX), phenidone, dibromoacetophenone, tosylphenylalanine chloromethyl ketone (TPCK), and acetic acid) were tested in this assay to assess their effects on metabolic cooperation. Caffeine, IBMX, phenidone, and dibromoacetophenone had no effect on metabolic cooperation, while TPCK slightly inhibited metabolic cooperation in one V79 assay. Acetic acid appeared to facilitate metabolic cooperation. In tests where an antipromoter was combined with the established tumor promoter phorbol 12-myristate 13-acetate (PMA), acetic acid, caffeine, and IBMX counteracted PMA-induced inhibition of metabolic cooperation, while phenidone, dibromoacetophenone, and TPCK had little effect. These results indicate that some antipromoters interfere with the ability of a tumor-promoting chemical to inhibit metabolic cooperation and suggest that alteration of gap junctional communication can be a mechanism of antipromoter action.

1-Methyl-3-isobutylxanthine↗
PubMed1996

The effects of peroxisome proliferators on protein abundances in mouse liver.

We have investigated the effects of five peroxisome proliferators (PPs : clofibric acid, DEHP, WY14,643, nafenopin, and LY171883) on the abundances of a large number of proteins in the livers of treated mice at 5- and 35-day time points. LY171883 was investigated at a range of doses, and one of its close structural analogs that is not a peroxisome proliferator (LY163443) was included as a negative control compound. Liver samples were analyzed by quantitative 2-D electrophoresis. Data for a selected set of 107 liver protein spots that respond strongly to at least one of the test compounds was subjected to principal component analysis to search for global protein pattern changes. The first component (PC1) accounted for 51% of the total data variance and was identified as a global measure of peroxisome proliferation by its correlation with enzymatic peroxisomal beta-oxidation. Component PC2 (7%) separated 5- and 35-day exposures, and PC3 (5%) separated groups treated with LY163443 from the rest. We used PC1 as a surrogate for equivalent dose in order to examine the effects of diverse compounds, with widely differing potencies, on a common scale. Analyzed in this way, the data indicate that all the peroxisome proliferators tested produce effects over wide time and dose ranges that fall on or near a single curve. Examination of specific protein responses showed that many proteins individually show a unified response curve, but that curves for different proteins were different. In particular, it appears that some constitutive proteins showing modest inductions with a high dose plateau (such as cytosolic epoxide hydrolase) are inducible at lower doses than some proteins showing very strong, nonplateaued inductions (such as the 80-kDa peroxisomal bifunctional enzyme). The results provide support for a unified receptor-based mechanism controlling the main PP response, but demonstrate that individual responsive genes can show quite different dose-response curves.

Acetophenones↗
PubMed1998

A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs.

Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.

Acetophenones↗
PubMed2001

Rottlerin stimulates metallothionein gene expression but inhibits metal transport in Chinese hamster ovary cells.

Metallothionein (MT) can be induced by various metals. We have shown previously that H7, a protein kinase C (PKC) inhibitor, inactivates metal-induced MT gene expression. To investigate whether a specific PKC isoform is involved in the induction process, inhibitors for various PKC isoforms were administered to cadmium-resistant Chinese hamster ovary (Cd(R)) cells. None of the inhibitors used can reduce metal-induced MT gene expression. However, a PKCdelta inhibitor, rottlerin, induced MT mRNA expression in Cd(R) cells in the presence or absence of Cd. Notably, the induction occurs through the activation of the MT transcriptional factor (MTF-1) and is not related to an increase of metal influx. Furthermore, metal accumulation is reduced in the presence of rottlerin. Pulse-labeling analysis indicated that MT protein synthesis increased in Cd(R) cells upon rottlerin treatment. These results suggest that rottlerin blocks metal transport but stimulates MT synthesis in Cd(R) cells. Since rottlerin is capable of reducing the cellular accumulation of Cd, it was expected that the cytotoxic effect of Cd would decrease in the presence of rottlerin. Treating the parental cell of Cd(R) with Cd and rottlerin together indeed showed a decline of cytotoxicity compared to cells treated with Cd alone. We further examined how MTF-1 was activated by rottlerin. Rottlerin-induced MTF-1 activity was not affected in Cd(R) cells by the addition of EDTA. It was, however, diminished by administering an intracellular Zn chelator, TPEN. The result implies a mobilization of intracellular Zn ions after rottlerin treatment in Cd(R) cells. To investigate whether the described results occur in all types of cells, another cell line (GH(3)) was used to study the effect of rottlerin on MT gene expression. The result revealed that rottlerin did not increase the amount of MT mRNA in GH(3) cells. This differential effect between cell lines may be useful for investigating the regulatory mechanism of MT gene expression.

Acetophenones↗
PubMed2001

1,2-diacetylbenzene, the neurotoxic metabolite of a chromogenic aromatic solvent, induces proximal axonopathy.

Several widely used aromatic hydrocarbon solvents reportedly induce blue-green discoloration of tissues and urine in animals and humans. The chomophore has been proposed to result from a ninhydrin-like reaction with amino groups in proteins. The present study examines the neurotoxic property of 1,2-diacetylbenzene (1,2-DAB), the active metabolite of the chromogenic and neurotoxic aromatic solvent 1,2-diethylbenzene. Rats treated with 1,2-DAB, but not with the nonchromogenic isomer 1,3-DAB or with ninhydrin developed blue discoloration of internal organs, including the brain and spinal cord. Only 1,2-DAB induced limb weakness associated with nerve fiber changes, which were most prominent in spinal cord and spinal roots. Changes began with the formation of proximal, neurofilament-filled axonal swellings of the type seen after treatment with 3,4-dimethyl-2,5-hexanedione, a potent derivative of the active metabolite of the neurotoxic aliphatic hydrocarbon solvents n-hexane and methyl n-butyl ketone. These compounds are metabolized to a gamma-diketone that forms pyrroles with target proteins, such as neurofilament proteins. A comparable mechanism is considered for 1,2-DAB, an aromatic gamma-diketone.

Acetophenones↗
PubMed2002

Mechanisms involved in responses to the poroxisome proliferator WY-14,643 on gap junctional intercellular communication in V79 hamster fibroblasts.

WY-14,643, a potent hepatic peroxisome proliferator, decreased gap junctional intercellular communication when used at low and intermediate concentrations (1 nM to 10 microM) in the V79 Chinese hamster fibroblast cell line. It did not decrease intercellular communication in early passage Syrian hamster embryo fibroblasts. The mechanism of WY-14,643-induced suppression of intercellular communication was studied by preexposure of V79 cells to inhibitors of protein kinase C, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, or mammalian target-of-rapamycin before addition of WY-14,643. Only protein kinase C, particularly the delta isoform, appeared involved in the inhibition of communication by WY-14,643. Also clofibrate-induced suppression of GJIC in V79 cells appeared to involve protein kinase Cdelta. Furthermore, WY-14,643 did not cause any activation of the mitogen-activated protein kinases p44/42, p38, or Jun N-terminal kinase. When WY-14,643 was used at a higher concentration (100 microM), intercellular communication was increased both in V79 and Syrian hamster embryo cells. This effect was inhibited by preexposure of V79 cells to brefeldin A. Thus, there may be a pool of connexins in the Golgi complex that could be recruited to the plasma membrane upon exposure to high concentrations of WY-14,643.

Acetophenones↗
PubMed2002

Amino acid and protein targets of 1,2-diacetylbenzene, a potent aromatic gamma-diketone that induces proximal neurofilamentous axonopathy.

The gamma-diketone analogs 1,2-diacetylbenzene (1,2-DAB) and 2,5-hexanedione (2,5-HD), but not the delta-diketone 1,3-diacetylbenzene (1,3-DAB) or the beta-diketone 2,4-hexanedione, induce neuropathological changes in the rodent central and peripheral nervous systems. The molecular targets of these neurotoxic aromatic and aliphatic gamma-diketones, and of their nonneurotoxic structural analogs and ninhydrin, are examined by assessing their differential reactivity with neural and nonneural amino acids and proteins in vitro and in vivo. Whereas 1,2-DAB is chromogenic and forms polymers with amino acids (notably lysine) and proteins (especially lysine-rich proteins), 1,3-DAB lacks these properties. Ninhydrin forms a chromophore without evidence of protein polymerization. 1,2-DAB preferentially targets neurofilament over microtubule protein in vitro and in situ. Based on protein reactivity, 1,2-DAB is three orders of magnitude more reactive than 2,5-HD. Lysine-rich neurofilament protein subunits NF-H and NF-M are more susceptible than lysine-poor NF-L and beta-tubulin to 1,2-DAB. These observations correlate with the development of proximal (1,2-DAB) and distal (2,5-HD) neurofilament-filled axonal swellings and segregated intact microtubules observed during systemic treatment with aromatic and aliphatic gamma-diketones.

Acetophenones↗