The synthesis and characterization of three complexes with a potent nonsteroidal anti-inflammatory drug niflumic acid {2-3-(trifluoromethyl)phenylaminonicotinic acid} with formula Cu(niflumato)
2L ...(L=H
2O, DMSO=dimethylsulfoxide, DMF=
N,
N-dimethylformamide) were investigated. The crystal and molecular structure of the {Cu(niflumato)
2(DMSO)}
2 was reported. Crystallographic data are as follows: monoclinic system, space group
P2
1/
n,
Z=2,
a=11.1318(8),
b=17.513(2),
c=15.336(1) Å,
β=103.316(8)°,
V=2909.4(4) Å
3. The structure was refined to
R=0.030 and
w
R=0.037 for 3702 reflections with
I>
σ(
I). It consists of centrosymmetric binuclear units with the Cu–Cu
i (symmetry code i: 1−
x, −
y, 1−
z) distance between two centrosymmetrically related ions of 2.6272(5) Å. Each Cu(II) ion in Cu
2(DMSO)
2(μ-niflumato)
4 is coordinated to an apical dimethylsulfoxide O atom on the one hand and to the equatorial carbonyl and carboxylic O atoms of two crystallographically independent niflumate moieties and their centrosymmetric counterparts on the other hand. In spite of the low-temperature (190 K) crystal measurements, one –CF
3 grouping exhibits some disorder. The biological activities of these complexes were compared to that of niflumic acid. Niflumic acid and its various copper complexes significantly inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism, as assessed by chemiluminescence and
O
−
2
generation measurement. This effect was dose-dependent. All copper complexes exerted a similar inhibiting effect which was always significantly higher than that exerted by the parent drug.
Reactive oxygen species (ROS) are released during the inflammation of the synovial membrane associated with cartilage degradation in osteoarthritis. In this work, we exposed synoviocytes to ...superoxide anions at concentrations that may cause either apoptosis or necrosis. We studied membrane organization, dehydrogenase mitochondrial activity and nuclear morphology and integrity, to determine the nature of the death process initiated by superoxide anions and tried to counteract ROS effects with α-tocopherol. We found that oxidative stress caused synoviocytes to undergo a process of cell death of an apoptotic nature rather than necrotic. Mitochondrial injury occurred at an early stage, and the FITC-annexin-V-positive/propidium iodide-positive cells occurred later than the metabolic changes. DNA strand breaks were evident at 8h and nuclear condensation at 24h. No LDH activity was detected in culture supernatants. In our experimental conditions, α-tocopherol had little effect on stress damage; the antioxidant properties of this molecule did not affect the apoptosis caused by superoxide anions.
The kinetic behaviour of bovine erythrocyte Cu‐‐Zn SOD was investigated in Sprague Dawley male rats after subcutaneous and oral administrations of doses ranging from 0·5 to 20 mg kg−1. Studies have ...been carried out with SOD and SOD encapsulated into liposomes containing or not containing ceramides. The maximum concentration (Cmax) in blood cell pellets ranged from 8·65 to 11·03 U/mg haemoglobin (Hb) after subcutaneous injection, and from 4·48 to 8·23 U/mg Hb after oral administration. The maximum concentrations were reached in 5 h (t max) for the two routes. Comparison between the areas under the curves (AUCs) obtained after subcutaneous and oral administration allowed the calculation of relative bioavailability (F ′). The maximum bioavailability after oral administration was 14% for free SOD, 22% for SOD encapsulated into liposomes, and 57% when ceramides were added to liposomes.
Poor SOD bioavailability was enhanced by liposome encapsulation, and ceramide addition seemed to be beneficial for oral encapsulated SOD administration.
The biological functions of alpha-1 acid glycoprotein (AGP) are poorly understood but appear to depend on glycan microheterogeneity. Variations of AGP glycan structure (in terms of concanavalin A ...(ConA) reactivity) have been observed during the inflammatory process. We studied these modifications in AGP from patients with chronic renal impairment and investigated the effects of AGP microheterogeneity on healthy polymorphonuclear leukocyte (PMN) chemotaxis and oxidative metabolism. AGP was extracted by a two-step procedure from sera from ten patients with various degrees of renal impairment, selected according to AGP glycan heterogeneity determined by crossed immunoaffinity electrophoresis with ConA. AGP (0.5 g/l) significantly inhibited the chemotactic response of PMN to formyl-methionyl-leucyl-phenylalanine (10(-7) mol/l) and complement fraction C5a, regardless of ConA reactivity. AGP also inhibited superoxide anion generation in response to phorbol myristate acetate (10(-7) mol/l). After stimulation by opsonized zymosan (1 g/l), the effect of AGP appeared to depend on its glycan structure (r = 0.70, P < 0.05), decreasing with ConA non-reactivity. These data suggest that AGP can down-regulate neutrophil responsiveness, an effect that depends in part on its glycan microheterogeneity. Alterations of AGP microheterogeneity in various pathological states, particularly renal failure, may be related to the inflammatory process.
Ginkgolide B (GKB) is a bioactive component of the standardized extract from the leaves of the
Ginkgo biloba tree (EGb 761), which is used in Chinese and in occidental medicine. GKB is known as a ...platelet-activating factor receptor antagonist. Here, we provide evidence that GKB per se (0.25–5
μM) stimulated tyrosine phosphorylation of proteins, phospholipase D activation, calcium transients, and activation of p38 but not p44/42 Map kinases in human polymorphonuclear leukocytes (PMN). These stimulatory effects remained relatively weak and primed PMN for subsequent stimulation of respiratory burst (RB) or directed locomotion by the chemoattractant fMet-Leu-Phe (fMLP) or complement-derived factor C5a. A similar RB priming was observed with rat exudate PMN after in vivo administration of EGb 761 (25 and 50
mg/kg) to rats before pleurisy induction. Thus, GKB primarily induces activation of intracellular signaling events and has the potential to prime cellular functions such as PMN defense activities.
The concentration and concanavalin A (ConA)-dependent microheterogeneity of serum and urinary alpha 1-acid glycoprotein (AGP) were studied in patients with various degrees of renal impairment and ...compared with healthy control values. Serum concentrations of AGP were significantly higher in hemodialyzed and uremic patients than in the control subjects (1.54 +/- 0.42 g/l, p < 0.05, and 1.20 +/- 0.40 g/l, p < 0.05, respectively, versus 0.83 +/- 0.17 g/l). There was a similar increase in serum alpha 1-protease inhibitor and haptoglobin concentrations in the uremic patients (r = 0.87 and r = 0.70; p < 0.001). Urinary concentrations of AGP were also significantly higher in the hemodialyzed and uremic patients than in the control subjects, despite wide variability in the patients (20 +/- 14 mg/24 h, p < 0.05, and 126 +/- 160 mg/24 h, p < 0.05, respectively, versus 3 +/- 1 mg/24 h). AGP clearance was significantly higher in the uremic patients than in the hemodialyzed patients (p < 0.01) and the control subjects (p < 0.01). The proportions of strongly ConA-reactive AGP fractions were higher in the serum of the hemodialyzed (18.6 +/- 5.2%; p < 0.05) and uremic patients (18.1 +/- 5.3%; p < 0.05) than in the control subjects (14.5 +/- 2.5%). There was a similar difference in the urine samples (26.7 +/- 8.2%, p < 0.01; 20.1 +/- 6.2%, p < 0.01, respectively, versus 10.3 +/- 4.8%), with also a significant difference between the hemodialyzed and uremic patients (p < 0.05).
The effect of ornithine α-ketoglutarate (OKG) on cytochrome P-450 enzyme activities was studied in a well-defined model of injury (burn followed by fasting then subsequent hypocaloric diet) ...administered to young rats for 3 d. Hepatic microsomes were prepared by ultracentrifugation and levels of cytochromes P-450 were determined spectrophotometrically. The activities of ethoxy-resorufin-O-deethylase (EROD), benzyloxy-resorufin-O-dealkylase (BROD), and erythromycin demethylase were measured as markers of P-450 IA, 2A, and 3A isotypes respectively. The level of total hepatic microsomal proteins (8 mg/mL) remained constant. The level of cytochrome P-450 (1.14 ± 0.08 nmol/mg microsomal proteins) was decreased by a hypocaloric diet (23%,
P = 0.003) and burn further enhanced this phenomenon (15%,
P = 0.03). Both healthy and burned rats receiving OKG showed the same level of cytochrome P-450 as the rats fed ad libitum. OKG supplementation counteracted the enhancement (40%) of EROD activity induced by hypocaloric diet but did not influence BROD and erythromycin demethylase activities. OKG sustained cytochrome P-450 levels in rats fed a hypocaloric diet, even after burning. These findings indicate that OKG may favor drug metabolism in this injured population.
Ceramides and distearoylphosphatidylcholine (DSPC) were incorporated in various liposomes preparations in comparison with dipalmitoylphosphatidylcholine alone. Preparations were introduced in an ...‘Artificial Stomach-Duodenum’ model to improve their stability. Better results were observed for DSPC and ceramide-containing liposomes. Entrapment of CuZn Superoxide dismutase (SOD) in liposomes have been carried out for oral administration. The efficiency of entrapment of SOD was 35.4% for liposomes without ceramides, and from 24.3% to 46.1% for ceramide-containing liposomes.
Elastase‐a 1 proteinase inhibitor (Ea1PI) concentrations were assessed in gingival crevicular fluids and evaluated in relation to the clinical signs of periodontal disease. 7 gingivitis patients ...(group G), 38 patients with adult periodontitis and clinically stable lesions (group AP), 21 patients with rapidly progressive periodontitis and clinically stable lesions (group RPP) and 11 patients with either adult periodontitis or rapidly progressive periodontitis and clinically progressive lesions (group Pr) were studied. 6 healthy subjects served as the control group (group H). Significant differences were observed in the Ea1PI concentration between the healthy, gingivitis, clinically stable periodontitis and clinically progressive periodontitis group. In the control group, no Ea1PI was detected. Groups G, AP and RPP showed mean Ea1PI concentrations of 10.95 ± 4.96 μg/ ml. 35.55 ± 18.64 /μg/ml and 38.56 ± 20.89 μg/ml, respectively. In these groups, high enzyme levels were correlated with clinical signs of inflammation. The highest Ea1PI levels were observed in the clinically progressive lesions. However, they were not necessarily associated with bleeding on probing or clinical evidence of inflammation. These data suggest that a significant increase in crevicular Ea1PI levels may be an early manifestation of a progressive or potentially progressive periodontal lesion.
