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991.
Effects of nonsteroidal anti-inflammatory drugs and prostaglandins on osteoblastic functions. 总被引:3,自引:0,他引:3
It has been reported that nonsteroidal anti-inflammatory drugs (NSAIDs) suppress bone repair and bone remodeling but only mildly inhibit bone mineralization at the earlier stage of the repair process. We proposed that the proliferation and/or the earlier stage of differentiation of osteoblasts may be affected by NSAIDs. This study was designed to investigate whether NSAIDs affect the proliferation and/or differentiation of osteoblasts and whether these effects are prostaglandin (PG) mediated. The effects of PGE1 and PGE2, indomethacin, and ketorolac on thymidine incorporation, cell count, intracellular alkaline phosphatase (ALP) activity, and Type I collagen content in osteoblast-enriched cultures derived from fetal calvaria were evaluated. The results showed that both PGs and NSAIDs inhibited DNA synthesis and cell mitosis in a time- and concentration-dependent manner. However, intracellular ALP activity and Type I collagen content were stimulated at an earlier stage of differentiation in osteoblasts. These results suggested that (i) the inhibitory effect of ketorolac on osteoblastic proliferation contributes to its suppressive effects on bone repair and remodeling in vivo; (ii) PGEs and NSAIDs may be involved in matrix maturation and biologic bone mineralization in the earlier stage of osteoblast differentiation; and (iii) the effects of ketorolac and indomethacin on cell proliferation and differentiation may not be through the inhibition of the synthesis of PGE1 or PGE2. 相似文献
992.
993.
In the present study, we showed that 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, could potentiate H2O2-induced inhibition of platelet aggregation and increase of platelet cGMP levels. The synergistic effect of YC-1 and H2O2 on platelet aggregation and increases of cGMP were almost completely prevented by catalase and a selective soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or partially attenuated by the hydroxyl radical scavenger mannitol. In contrast, superoxide dismutase failed to influence H2O2/YC-1-induced inhibition of aggregation. Furthermore, YC-1 could enhance the activation of soluble guanylate cyclase caused by FeSO4/H2O2 and, this effect was prevented markedly by mannitol. These results suggest that YC-1 may enhance the antiaggregatory effect of H2O2 via the sensitization of platelet soluble guanylate cyclase. In addition, this phenomenon is, at least in part, dependent on H2O2-derived hydroxyl radical. 相似文献
994.
The inhibitory effect of ambroxol on hypochlorous acid-induced tissue damage and respiratory burst of phagocytic cells 总被引:2,自引:0,他引:2
Ambroxol (100 microM and 1 mM) and the thiols (all 1 mM), glutathione, tiopronin and cysteine, significantly attenuated the myeloperoxidase, H(2)O(2) and Cl(-) system-caused destruction of alpha(1)-antiproteinase and the HOCl-induced destruction of collagen, whereas they did not affect the elastase-induced destruction of collagen. Glutathione, tiopronin and cysteine almost completely decomposed both HOCl and H(2)O(2), while ambroxol up to 1 mM did not show a scavenging action on H(2)O(2). Ambroxol (1 to 100 microM) and 1 mM thiol compounds markedly inhibited the HOCl-induced alteration of elastase activity. Thiol compounds significantly attenuated the HOCl production caused by degraded immunoglobulin G-activated neutrophils. Ambroxol depressed superoxide and H(2)O(2) production induced by degraded immunoglobulin G-activated neutrophils and by lipopolysaccharide-activated alveolar macrophages in a dose-dependent manner. The results show that ambroxol may interfere with oxidative tissue damage and decrease proteolytic tissue destruction by attenuation of oxidative stress-induced inactivation of alpha(1)-antiproteinase through both decomposition of HOCl and inhibition of the respiratory burst in phagocytic cells. 相似文献
995.
Ding CZ Batorsky R Bhide R Chao HJ Cho Y Chong S Gullo-Brown J Guo P Kim SH Lee F Leftheris K Miller A Mitt T Patel M Penhallow BA Ricca C Rose WC Schmidt R Slusarchyk WA Vite G Yan N Manne V Hunt JT 《Journal of medicinal chemistry》1999,42(25):5241-5253
2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(t rifluo romethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC(50) value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 microM and had an EC(50) of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice. 相似文献
996.
S J O'Connor K J Barr L Wang B K Sorensen A S Tasker H Sham S C Ng J Cohen E Devine S Cherian B Saeed H Zhang J Y Lee R Warner S Tahir P Kovar P Ewing J Alder M Mitten J Leal K Marsh J Bauch D J Hoffman S M Sebti S H Rosenberg 《Journal of medicinal chemistry》1999,42(18):3701-3710
The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line. 相似文献
997.
Lee CT Kuo BI Chen CY Chang FY Lee SD 《European journal of clinical pharmacology》1999,54(11):817-820
Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients
undergoing omeprazole treatment.
Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological
effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females,
aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured
before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels.
Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml−1, SD 32.0 pg · ml−1 vs 133.9 pg · ml−1, SD 71.6 pg · ml−1, P < 0.01), and pepsinogen I (111.0 ng · ml−1, SD 36.7 ng · ml−1 vs 253.6 ng · ml−1, SD 64.8 ng · ml−1, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD
67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating
characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity
to predict antral H. pylori clearance.
Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia
I probably provides a non-invasive alternative for predicting H. pylori clearance.
Received: 22 August 1996 / Accepted in revised form: 1 October 1998 相似文献
998.
The effect of 1-[β-[3-(4-methoxyphenyl)pro- poxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF 96365) on Ca2+ signaling in Madin Darby canine kidney (MDCK) cells was examined. SKF 96365 at 25–100 μM evoked a robust [Ca2+]i transient in a dose-dependent manner, measured by fura-2 fluorimetry. A concentration of 10 μM SKF 96365 did not have an
effect. The transient consisted of a slow rise, a gradual decay, and a sustained plateau in physiological Ca2+ medium. Removal of extracellular Ca2+ reduced the Ca2+ signals evoked by 50–100 μM SKF 96365 by nearly half in the area under the curve, suggesting that SKF 96365 induced intracellular
Ca2+ release and also extracellular Ca2+ influx. A concentration of 100 μM SKF 96365 caused significant Mn2+ quench of fura-2 fluorescence, which was partly inhibited by La3+ (1 mM) or Gd3+ (0.1 mM), indicating that the SKF 96365-induced Ca2+ influx had two components: one is sensitive to La3+ (1 mM) or Gd3+ (0.1 mM), the other is not. The internal Ca2+ source for the SKF 96365-induced [Ca2+]i transient was the endoplasmic reticulum Ca2+ store because, pretreatment with thapsigargin and cyclopiazonic acid, two inhibitors of the endoplasmic reticulum Ca2+ pump nearly abolished the SKF 96365-induced [Ca2+]i increase in Ca2+-free medium. In contrast, pretreatment with 100 μM SKF 96365 only partly depleted the thapsigargin-sensitive Ca2+ store. Addition of 10 mM Ca2+ induced a significant [Ca2+]i increase after prior incubation with 100 μM SKF 96365 in Ca2+-free medium, demonstrating that SKF 96365 induced capacitative Ca2+ entry. This capacitative Ca2+ entry was about 40% of that induced by 1 μM thapsigargin. Additional to inducing its own capacitative Ca2+ entry, 100 μM SKF 96365 partly inhibited thapsigargin- or uridine trisphos-phate (UTP)-induced capacitative Ca2+ entry. We also investigated the mechanisms underlying the decay of the SKF 96365-induced [Ca2+]i transient. Inhibition of the plasma membrane Ca2+ pump with La3+ or Gd3+, or lowering extracellular Na+ level to 0.35 mM, significantly increased the SKF 96365-induced [Ca2+]i transient. In contrast, the mitochondrial uncoupler carbonylcyanide m-chlorophenylhydrazone had little effect. In Ca2+-free medium, the thapsigargin-induced [Ca2+]i increase was greatly reduced by pretreatment with SKF 96365. Collectively, we have found that besides its well-known inhibitory
action on capacitative Ca2+ entry in many cell types, in MDCK cells SKF 96365 exerted multiple and complex effects on Ca2+ signaling. It induced a considerable increase in [Ca2+]i by releasing Ca2+ from the endoplasmic reticulum store followed by capacitative Ca2+ entry. It also caused a direct Ca2+ entry. The decay of the SKF 96365 response was significantly governed by efflux via the plasma membrane Ca2+ pump or Na+/Ca2+ exchange. Sequestration by mitochondria or the endoplasmic reticulum played a minor role. We caution use of SKF 96365 as
an inhibitor of capacitative Ca2+ entry.
Received: 21 September 1998 / Accepted: 2 December 1998 相似文献
999.
Neuroprotective mechanism of glial cell line-derived neurotrophic factor on dopamine neurons: role of antioxidation. 总被引:5,自引:0,他引:5
Recombinant human GDNF was infused into the rat striatum either acutely or subchronically. Its effects and its interactions with MPP+ on antioxidant enzyme activities were examined. Results indicated that acute GDNF infusion significantly increased glutathione peroxidase, superoxide dismutase and catalase activities. Subchronic GDNF treatment decreased the DA level and enhanced DA turnover. Pre-treatment with GDNF markedly protected DA neurons against MPP+-induced toxicity. These results suggest that GDNF protects DA neurons through its activation of the antioxidant enzyme systems. 相似文献
1000.
Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 microg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 +/- 0.6 vs. 5.5 +/- 0.3, p < 0.01) and in sham-operated rats (3.4 +/- 0.7 vs. 5.1 +/- 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury. 相似文献