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PubMed1989

Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction.

The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 microgram/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41 +/- 17% (SD), left atrial pressure rose 3.5 +/- 1.5 mmHg, and cardiac output fell 18 +/- 8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25 +/- 7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5 +/- 3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4 +/- 1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26 +/- 4%; p = 0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9 +/- 2.8 mmHg; p less than 0.05; the increase in PVR was +1.8 +/- 1.2 mmHg/L/min, p less than 0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5 +/- 8.1% before and 27.0 +/- 7.4% after RG 5901 (p greater than 0.05). The pressor response to hypoxia was +8.9 +/- 2.1 mmHg before and +8.7 +/- 3.7 mmHg after RG 5901 (p greater than 0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.

Acetophenones↗
PubMed1998

Amino acid sequence of piratoxin-I, a myotoxin from Bothrops pirajai snake venom, and its biological activity after alkylation with p-bromophenacyl bromide.

The complete sequence of the 121 amino acid residues of piratoxin-I (PrTX-I), a phospholipase A2 (PLA2)-like myotoxin from Bothrops pirajai snake (Bahia jararacussu) venom, is reported. From the sequence, an M, of 13,825 and an approximate pI of 8.3 were calculated. PrTX-I shows a high sequence homology with Lys-49 myotoxins from other bothropic (approximately 95%) and nonbothropic (approximately 80%) venoms, but only 70-75% homology when aligned with the catalytically active Asp-49 PLA2s. When compared with bothropstoxin-I from Bothropsjararacussu, which is morphologically almost identical to B. pirajai, only two changes out of 121 total amino acid residues have been observed. The approximate minimal lethal dose LD50 (mice, i.p., 24 hr) of PrTX-I was 8 (6.8-9.1) mg/kg, and the minimal edematogenic dose (MED) in a rat paw model was 39.5+/-1.8 ug. After alkylation of His-48 with p-bromophenacyl bromide, the MED was 40.1+/-1.9 ug, but up to 4 LD50 were unable to cause death in any of a group of eight mice after 72 hr. Therefore the edematogenic activity was retained and apparently did not involve His-48, suggesting that at least two biologically active sites are present in PrTX-I.

Acetophenones↗
PubMed2005

Dual effect of 3,4-dihydroxyacetophenone on LPS-induced apoptosis in RAW264.7 cells by modulating the production of TNF-alpha.

To explore the pharmacological effect of 3,4-dihydroxyacetophenone (DHAP) on the apoptosis of RAW264.7 macrophage cells and the mechanism, RAW264.7 macrophage cells were treated with 100 or 500 mg/L lipopolysaccharide (LPS), with or without 10(-5) mol/L DHAP for 24 h. Trypan blue dye exclusion assay was used to assess cell viability. Cell apoptosis was morphological studied and flow cytometric assay was used. Tumor necrosis factor-alpha (TNF-alpha) level was measured by ELISA methods. IkappaB protein was determined by Western blotting. Our results showed that in 100 mg/L LPS-stimulated macrophages, DHAP enhanced the cell apoptosis while in 500 mg/L LPS-stimulated macrophages, DHAP significantly inhibited the cell apoptosis. In both groups, DHAP increased the level of IkappaB but decreased the level of TNF-alpha. It is concluded that DHAP has dual effect on the apoptosis of RAW 264.7 cells treated with different concentrations of LPS. This effect may be due to the inhibition of activation of NF-kappaB and autocrine production of TNFalpha. Our study suggests that DHAP may have anti-inflammatory effect on LPS-activated macrophages.

Acetophenones↗
PubMed1995

Effects of 3,4-dihydroxyacetophenone (3,4-DHAP) on hypoxic pulmonary and systemic vascular response in dogs.

The effects of 3,4-DHAP on hypoxic pulmonary and systemic vascular responses were studied in anaesthetized dogs. The percentage change in pulmonary vascular resistance (delta PVR %) and that in systemic vascular resistance (delta SVR %) induced by 5 min hypoxia decreased significantly. 3,4-DHAP in doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg i.v. caused a decrease in delta PVR% from the control value of 47.27 +/- 22.27% to 24.62 +/- 21.76%, 18.15 +/- 18.73%, and 24.10 +/- 19.76% respectively, and a decrease in delta SVR % from the control value of 12.91 +/- 7.39 % to -0.34 +/- 12.70%, -2.11 +/- 12.76%, and -2.37 +/- 15.52 % respectively. The results showed that 3,4-DHAP could decrease the hypoxic responses of pulmonary and systemic blood vessels. But it did not change delta PVR % or delta SVR % in dose of 30 mg/kg, neither did it influence the heart rate, cardiac output or cerebral blood flow during hypoxia in all the doses used.

Acetophenones↗
PubMed1994

The utero-placental circulation, eugenics and the prevention and treatment of high risk pregnancies.

Through systematic experimental and clinical studies, the physiological regulation of utero-placental circulation and the relation of the disturbance in this acirculation to pathogenic mechanisms of high risk pregnancies-Intrauterine Growth Retardation (IUGR) and Pregnancy-induced hypertension (PIH) were explored. The pharmacological effects and mechanism of a Chinese herbal medicine-Qingxintong in improving, the utero-placental circulation and the therapeutic efficacy in treatment of IUGR and PIH, both accompanied by disturbance of utero-placental circulation, were investigated as well.

Acetophenones↗
PubMed1994

Effects of 3,4-dihydroxyacetophenone on hypoxic vasoconstriction in isolated pulmonary and basilar arterial rings.

The effects of 3,4-DHAP on hypoxic vasoconstriction response in pulmonary (PA) and basilar arterial (BA) rings of rabbits and their mechanism were compared in vitro. 3,4-DHAP in different concentration (2.64 x 10(-4), 7.92 x 10(-4), 2.376 x 10(-3) mol/L) decreased the basal tone of PA rings by 32.39 +/- 9.4 mg, 68.96 +/- 26.54 mg and 145.60 +/- 58.07 mg respectively, while the tension of the BA rings was decreased by 13.80 +/- 5.08 mg, 17.18 +/- 3.36 mg and 25.00 +/- 4.02 mg respectively. In PA rings it also decreased the percentage increase in tension induced by hypoxia (TIH%) from the control value 48.82 +/- 5.75% to 10.02 +/- 3.62%, 2.14 +/- 0.96%, and 0.00% respectively, while in BA rings from 27.27 +/- 5.78% to 11.23 +/- 2.71%, 7.49 +/- 1.62%, and 1.45 +/- 1.13% respectively. The effects of 3, 4-DHAP on TIH% were partially blocked by indomethacin 10 M and L-NAME 10 M. The results showed that 3, 4-DHAP can decrease the hypoxic pulmonary and basilar vasoconstriction in vitro, which can be partially inhibited by cyclooxygenase inhibitor and NO/EDRF inhibitor.

Acetophenones↗
PubMed2004

Effects of 3,4-dihydroxyacetophenone on cytosolic calcium in pulmonary artery endothelial and smooth muscle cells during acute hypoxia.

The effects of 3, 4-Dihydroxyacetophenone (3, 4-DHAP) on cytosolic free calcium [Ca2+]i in pulmonary artery endothelia (PAECs) and smooth muscle cells (PASMCs) during acute hypoxia were studied. Porcine pulmonary artery endothelial and smooth muscle cells (PASMCs) were cultured primarily, and they were divided into 4 groups: groups incubated under normoxia or hypoxia and those with or without treatment with 3,4-DHAP. The [Ca2+]i of both PAECs and PASMCs was measured by determining the fluorescence of fura 2 AM on spetrofluorometer. Our results showed that hypoxia caused significant elevation of [Ca2+]i, in both PAECs and PASMCs, 3,4-DHAP could attenuate the hypoxic elevation of [Ca2+]i only in PASMCs but not in PAECs. It is concluded that 3,4-DHAP decreases the hypoxic elevation of [Ca2+]i in PASMCs. This might contribute to its inhibitory effect on hypoxic pulmonary vasoconstriction.

Acetophenones↗
PubMed2005

Role of NADPH oxidase-mediated generation of reactive oxygen species in the mechanism of apoptosis induced by phenolic acids in HepG2 human hepatoma cells.

Although plant-derived phenolic acids have been reported to have anti-cancer activity, the exact mechanism is not completely understood. In this study, we investigated the role for reactive oxygen species (ROS) as a mediator of the apoptosis induced by caffeic acid (CA) and ferulic acid (FA), common phenolic acids in plants, in HepG2 human hepatoma cells. CA and FA reduced cell viability, and induced apoptotic cell death in a dose-dependent manner. In addition, they evoked a dose-related elevation of intracellular ROS. Treatment with various inhibitors of NADPH oxidase (diphenylene iodonium, apocynin, neopterine) significantly blunted both the generation of ROS and the induction of apoptosis induced by CA and FA. These results suggest that ROS generated through activation of NADPH oxidase may play an essential role in the apoptosis induced by CA and FA in HepG2 cells. These results further suggest that CA and FA may be valuable for the therapeutic management of human hepatomas.

Acetophenones↗
PubMed2006

Inhibitory effects of paeonol on morphine-induced locomotor sensitization and conditioned place preference in mice.

The inhibitory effects of paeonol, a major compound of Paeoniae radix, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated through behavioral experiments. A single administration of morphine produces hyperlocomotion. Repeated administration of morphine develops sensitization (reverse tolerance), a progressive enhancement of locomotion, which is used as a model for studying the drug-induced drug-seeking behaviors, and CPP, which is used as a model for studying drug reinforcement. Paeonol inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, paeonol inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of paeonol. These results provide evidence that paeonol exerts anti-dopaminergic activity, and it is suggested that paeonol may be useful for the prevention and therapy of these adverse actions of morphine.

Acetophenones↗
PubMed2001

Photocleavage of DNA by 4'-bromoacetophenone analogs.

4'-Bromoacetophenone analogs, which are able to generate monophenyl radicals capable of hydrogen atom abstraction, were investigated as possible photoinducible DNA cleaving agents. The potential of 4'-bromoacetophenone as a possible new DNA cleaver is explored. Pyrrolecarboxatmid conjugated 4'-bromoacetophenones, in particular, DNA cleaving activity and sequence-selectivity on the contiguous AT base pair sites.

Acetophenones↗
PubMed2003

Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 activity by 1,2,3,4,6-penta-O-galloyl-beta-D-glucose in murine macrophage cells.

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and produce excessive amounts of nitric oxide (NO) and prostaglandin E2 (PGE2), which play key roles in the processes of inflammation and carcinogenesis. The root of Paeonia lactiflora Pall., and the root cortex of Paeonia suffruticosa Andr., are important Chinese crude drugs used in many traditional prescriptions. 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) is a major bioactive constituent of both crude drugs. PGG has been shown to possess potent anti-oxidant, anti-mutagenic, anti-proliferative and anti-invasive effects. In this study, we examined the inhibitory effects of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) isolated from the root of Paeonia lactiflora Pall. on the COX-2 and iNOS activity in LPS-activated Raw 264.7 cells, COX-1 in HEL cells. To investigate the structure-activity relationships of gallate and gallic acid for the inhibition of iNOS and COX-2 activity, we also examined (-)-epigallocatechin gallate (EGCG), gallic acid, and gallacetophenone. The results of the present study indicated that PGG, EGCG, and gallacetophenone treatment except gallic acid significantly inhibited LPS-induced NO production in LPS-activated macrophages. All of the four compounds significantly inhibited COX-2 activity in LPS-activated macrophages. Among the four compounds examined, PGG revealed the most potent in both iNOS (IC50 approximately 18 microg/mL) and COX-2 inhibitory activity (PGE2: IC50 approximately 8 microg/mL and PGD2: IC50 approximately 12 microg/mL), respectively. Although further studies are needed to elucidate the molecular mechanisms and structure-activity relationship by which PGG exerts its inhibitory actions, our results suggest that PGG might be a candidate for developing anti-inflammatory and cancer chemopreventive agents.

Acetophenones↗
PubMed1997

Phospholipase A2 stimulates rat gastric epithelial cell line (RGM-1) migration.

OBJECTIVE AND METHODS: The effect of phospholipase A2 (PLA2) and its phospholipid metabolites on gastric epithelial migration was examined using an in vitro wounding model of confluent monolayers of rat gastric epithelial cell line RGM-1. RESULTS: Lysophosphatidylcholine (lysoPC) (0.01 100 ng/ml) as well as PLA2 (0.01-100 mU/ml) dose-dependently increased the cell migration. Lysophosphatidic acid (10 ng/ml) also increased the migration, but no significant increase in migration was observed when stimulated by lysophosphatidylethanolamine (10 ng/ml) or lysophosphatidylserine (10 ng/ml). Addition of 4-bromophenacyl bromide (BPB), a PLA2 inhibitor, completely blocked the effect of PLA2. However, addition of piroxicam (a cyclooxygenase inhibitor) or nordihydroguaiaretic acid (a lipoxygenase inhibitor) had no significant effect. Combination of PLA2 (10 mU/ml) with lysoPC (10 ng/ml) had no additive effect on migration. Moreover, lysoPC levels were increased in the cells after incubation with PLA2 (10 mU/ml). After pretreatment of RGM-1 cells with replication-inhibiting doses of mitomycin C. PLA2 and lysoPC still increased the cell migration. CONCLUSIONS: These data suggest that PLA2 may, independently of proliferation, increase gastric epithelial migration mainly via lysoPC production.

Acetophenones↗
PubMed1999

Phospholipase A2 inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes.

Phospholipase A2 (PLA2) has been postulated to play a role in the regulation of cytokine expression. Therefore, the objective of the present study was to investigate the effects of PLA2 inhibitors p-bromophenacyl bromide (BPB) and arachidonyl trifluoromethyl ketone (AACOCF3) on interleukin-2 (IL-2) expression in murine primary splenocytes. Pretreatment of the splenocytes with both BPB and AACOCF3 suppressed phorbol 12-myristate 13-acetate plus ionomycin-induced IL-2 secretion in a concentration-dependent manner. Inhibition > 90% of IL-2 secretion was observed at 1 microM BPB and 10 microM AACOCF3 compared to the respective vehicle control. Likewise, IL-2 steady-state mRNA expression was inhibited by both PLA2 inhibitors in a concentration-dependent fashion with > 90% inhibition at 1 microM BPB and 20 microM AACOCF3. Taken together, these data demonstrated that PLA2 inhibitors BPB and AACOCF3 are robust inhibitors of IL-2 expression at both the mRNA and protein levels in murine splenocytes. Moreover, these findings suggest that drugs and chemicals which inhibit PLA2 may have marked effects on T-cell function.

Acetophenones↗
PubMed2005

Extraction of p-hydroxyacetophenone and catechin from Norway spruce needles. Comparison of different extraction solvents.

The phenolic compounds p-hydroxyacetophenone and catechin have been extracted from Norway spruce needles with pure methanol, 80 and 50% (v/v) aqueous methanol, pure acetonitrile, 80% (v/v) aqueous acetonitrile, and pure water. Extraction efficiency of the individual solvents was compared. Although 80% aqueous methanol is the solvent most frequently used for extraction of soluble phenolic compounds from needles, it was found that pure methanol is a more suitable extraction solvent. Surprisingly, a two-step procedure based on the extraction of crushed needles with water then re-extraction with methanol proved a good alternative to direct extraction with methanol. Extraction of uncrushed spruce needles might indicate that relatively more p-hydroxyacetophenone than catechin was located in the surface layer of the needle.

Acetonitriles↗
PubMed2003

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide.

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.

Acetophenones↗
PubMed2000

Acute and chronic toxicity of the herbicide benzofenap (Taipan 300) to Chironomus tepperi Skuse (Diptera: Chironomidae) and Isidorella newcombi (Adams and Angas) (Gastropoda: Planorbidae).

Acute and chronic toxicity tests were conducted on the herbicide benzofenap (Taipan 300) using two Australian freshwater invertebrates. The commercial formulation of benzofenap and a blank formulation containing only the adjuvants of Taipan 300 were tested against final instar larvae of the midge Chironomus tepperi and adults of the aquatic snail Isidorella newcombi. In 24-h acute bioassays the midge larvae did not show significant mortality at a nominal concentration of 1.2 mg/L active ingredient (AI), double the maximum notional concentration expected in rice fields after application of Taipan 300 at the permit rate of 2 L/ha. No significant snail mortality was recorded in acute bioassays (24-h exposure, 48-h recovery) at nominal concentrations up to 76 mg/L AI, which is over 120 times the maximum notional field concentration. In chronic assays, the pupation and emergence of C. tepperi was monitored after a 4-h pulse exposure of final instar larvae to Taipan 300 (nominal concentrations 0.001 to 0.1 mg/L AI) and adjuvant-only (0.1 mg/L equivalent) treatments. No statistically significant effects were observed, although emergence appeared to be delayed by higher benzofenap concentrations and by the adjuvant-only treatment. During snail bioassays, egg and feces production were monitored for 21 days after 24-h exposure to Taipan 300 (nominal concentrations 1.2 mg/L to 60 mg/L AI) and adjuvant-only treatments (60 mg/L equivalent). No significant chronic effects were proven against I. newcombi, despite a decline in egg mass production following exposure to all treatments and a reduction in the total numbers of eggs produced at the highest nominal concentrations tested (60 mg/L AI and adjuvant-only treatments). Similarly, feces production by snail pairs exposed to the majority of treatments declined, but these differences were not statistically significant. It is concluded that Taipan 300 does not represent a significant risk to mature C. tepperi larvae or adult I. newcombi in downstream environments when applied to rice fields at the permit rate of 2 L/ha.

Acetophenones↗
PubMed2005

Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta.

Substance P receptor (SPR), a G protein-coupled receptor (GPCR), is found in human glioblastomas, and has been implicated in their growth. Consistent with a role for SPR in cell growth, activation of SPR in U373 MG human glioblastoma cells leads to the phosphorylation of mitogen-activated protein kinases [extracellular signal-regulated kinase 1 and 2 (ERK1/2)] and stimulation of cell proliferation. The purpose of the present study was to elucidate the pathway through which these actions occur. Using either the epidermal growth factor receptor (EGFR) kinase inhibitor, AG 1478, or a small-interfering RNA (siRNA) directed against human EGFR, we found that transactivation of EGFR by SPR is only marginally involved in SP-dependent ERK1/2 phosphorylation. Src, however, is shown to be a major component of SPR signaling because the Src kinase inhibitor, PP2, and a kinase-dead Src mutant both inhibit SP-dependent ERK1/2 phosphorylation. We also report that SPR stimulates the phosphorylation of protein kinase Cdelta(PKCdelta), and that this stimulation is blocked by PP2. SP-dependent ERK1/2 phosphorylation is also blocked by rottlerin, a PKCdelta inhibitor, and the calcium scavenger, BAPTA/AM. Finally, rottlerin and PP2 were both found to inhibit the growth of several glioblastoma cell lines, underscoring the potential of these agents to block glioblastoma growth.

Acetophenones↗