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PubMed1987

D1 and D2 dopamine binding site up-regulation and apomorphine-induced stereotypy.

Treatments with drugs to up-regulate specific receptors is a strategy often employed in mechanism of action studies. In this type of experiment, changes in the numbers of receptors and concomitant changes in an animal's sensitivity to the drug have been used as evidence for the participation of the binding site in the behavior. In these studies, to test for the role of D1 and D2 receptors in apomorphine-induced stereotypy (AIS), dopamine binding sites were up-regulated by appropriate pre-treatments and the ability of these pre-treatments to alter AIS was subsequently investigated. In the first experiment, 19 days of pre-treatment with SCH 23390 or haloperidol selectively increased by 35 and 40% the numbers of striatal D1 and D2 binding sites, respectively, without affecting their affinities. However, when challenged with apomorphine, only the animals pre-treated with the D2 antagonist showed behavioral supersensitivity. In the second experiment, reserpine pre-treatment (30 mg/kg IP, 24-hr pre-test) increased the numbers of D1 binding sites by 18%, but did not significantly alter the numbers of striatal D2 binding sites. Behaviorally, these rats were supersensitive to apomorphine's stereotypy-inducing effects; however, they also showed an increased sensitivity to the ability of either haloperidol or SCH 23390 to block AIS. Moreover, this blockade was only attenuated by a D2 (but not a D1) agonist. Collectively, these data suggest that AIS is mediated by both D1 and D2 binding sites, but that D2 binding sites have a more important role.

Animals↗
PubMed2006

Prolonging the ultrasound signal enhancement from thrombi using targeted microbubbles based on sulfur-hexafluoride-filled gas.

RATIONALE AND OBJECTIVES: The objective of this study is to develop and characterize new microbubbles based on lipids and sulfur hexafluoride (SF6) for targeting thrombi as an improved ultrasound contrast agent. MATERIALS AND METHODS: Bioconjugate ligands were inserted into the lipid-coated membranes of SF6 gas microbubbles, and their physicochemical properties were determined. Diagnostic efficacies of SF6-filled microbubbles and the contrast agent SonoVue (Bracco Imaging, Geneve, Switzerland) were compared in dogs. RESULTS: Suspensions of lyophilized powder were reconstituted by injecting saline containing 3.1 x 10(8) SF6 microbubbles/mL with a mean diameter of 4.4 microm. More than 90% of microbubbles had diameters between 1 and 10 microm. After reconstitution, echogenicity and microbubble characteristics were unchanged for 8 hours. Targeted microbubbles increased the echogenicity of thrombi significantly and provided a longer period of optimal signal enhancement compared with nontargeted microbubbles. CONCLUSIONS: Our thrombus-targeting microbubble contrast agent shows high echogenicity and stability and thereby enhances the visualization of intravascular thrombi and prolongs the duration of the diagnostic window.

Animals↗
PubMed2005

The use of intravenous recombinant tissue plasminogen activator in acute ischemic stroke.

We sought to determine the frequency of use of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) in patients presenting to our institution with acute ischemic stroke (AIS). This observational study involved keeping a log of all patients presenting to our institution with symptoms consistent with AIS who were potential candidates for emergency thrombolysis over a 3-year period. The log included brain computed tomography (CT) scan results, whether or not rt-PA was administered, and contraindications to thrombolysis. It also included each patient's time flow through the system, from symptom onset to decision time regarding (and administration of) thrombolytics. Over the 36-month period of the study, there were 142 patients who presented to the Emergency Department (ED) who initially were thought to be potential candidates for thrombolysis for AIS. Ninety-five (68.5%) of these 142 patients had a confirmed diagnosis of AIS. On further clarification of symptom onset, 77 (81%) of these 95 patients with AIS actually presented within 3 h, and 17 (22%) of these 77 patients met criteria for thrombolysis and had no contraindications. All 17 (100%) patients with AIS presenting within 3 h of onset and without contraindications received i.v. rt-PA in the ED. In conclusion, i.v. rt-PA can be administered for AIS within the 3-h window if a hospital is committed to providing this treatment. Thrombolysis remains a treatment for a minority of AIS patients.

Acute Disease↗
PubMed2003

Prognostic factors affecting the outcome of nasopharyngeal carcinoma.

BACKGROUND: The aim of the study is to evaluate patients with nasopharyngeal carcinoma treated with multisegmental intensity-modulated radiotherapy with or without chemotherapy and analyze patient, tumor and treatment characteristics, determining outcome. METHODS: From June 1999 through to April 2003, we treated in our institution 83 patients with nasopharyngeal carcinoma, 70 males and 13 females, their ages ranging from 25 to 85 years (median, 48 years). Nineteen patients had T1 tumors, 35 had T2 tumors, six had T3 tumors and 23 had T4 tumors. Sixty-four patients had cervical lymph node metastasis. Twenty patients were treated with radiation therapy alone and 63 patients with concurrent chemoradiotherapy. Cumulative radiation dose to primary tumor ranged from 70.2 to 77.4 Gy (median, 75.6 Gy). Follow-up ranged from 3 to 41.53 months (median, 17 months). RESULTS: Local complete response was achieved in 81 patients (97.5%). Local failure was observed in two patients, nodal failure in one patient and systemic failure in 14 patients. Overall survival, disease-free survival and disease-specific survival were 83, 84 and 93%, respectively, at 1 year, 82, 74 and 88%, respectively, at 2 years and 82, 61 and 88%, respectively, at 3 years. In univariate analysis, T stage of disease was a significant predictor of disease-free survival favoring those with early-stage (T1 + T2) disease (P = 0.040). Cumulative radiation dose to primary tumor was a significant predictor of disease-specific survival favoring those with >75.6 Gy (P = 0.010). Stage of disease (P = 0.007), N-classification (P = 0.046) and cumulative dose to primary tumor (P = 0.046) were significant prognostic factors for overall survival. CONCLUSIONS: High locoregional control for nasopharyngeal carcinoma was achieved with multisegmental intensity-modulated radiotherapy. Distant metastases are still the main impact on survival. More effective chemotherapy regimens and other systemic agents are needed to decrease the rate of distant metastasis.

Adult↗
PubMed2006

A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients.

BACKGROUND: Hyperglycaemia on presentation with acute ischaemic stroke (AIS) is associated with poor outcome, but intervention is unproven. We investigated the safety and tolerability of one method of glycaemic control. METHODS: Patients within 24 h of AIS and plasma glucose 8-20 mmol/l were randomised to receive either rigorous glycaemic control (RC) or standard management (SM) for 48 h. RC comprised i.v. insulin at a variable rate adjusted for target glucose concentration of 5-8 mmol/l, and intravenous crystalloid. The SM group received intravenous crystalloid alone in an open-label design. RESULTS: Thirteen patients were randomised to RC and 12 to SM (age 75 +/- 6.2 years; 40% male; 20% lacunar stroke; time to treatment 8 +/- 6.1 h; plasma glucose 10.6 +/- 0.9 mmol/l; known diabetes 52%; NIHSS 8, range 2-28). The glucose concentration-time curve was reduced in the RC group (AUC 324 +/- 15 versus 385 +/- 28 h.mmol/l, p = 0.04). By 48 h, plasma glucose in both groups was 6.8 +/- 1.1 and 7.5 +/- 1.3 mmol/l respectively, but mean hourly insulin requirements in the RC group had dropped from 3.25 +/- 0.32 units to 1.25 +/- 0.5 units (p < 0.01). One transient episode of hypoglycaemic symptoms occurred in the RC group. CONCLUSION: Glycaemic control with sliding scale insulin for 48 h is feasible and well-tolerated after AIS. Treatment after 48 h may be unnecessary.

Aged↗
PubMed2003

Intelligence with representation.

Behaviour-based robotics has always been inspired by earlier cybernetics work such as that of W. Grey Walter. It emphasizes that intelligence can be achieved without the kinds of representations common in symbolic AI systems. The paper argues that such representations might indeed not be needed for many aspects of sensory-motor intelligence but become a crucial issue when bootstrapping to higher levels of cognition. It proposes a scenario in the form of evolutionary language games by which embodied agents develop situated grounded representations adapted to their needs and the conventions emerging in the population.

Adaptation, Physiological↗
PubMed1989

Myocardial uptake and clearance of T1-201 in healthy subjects: comparison of adenosine-induced hyperemia and exercise stress.

Pharmacologic stress testing with dipyridamole is useful in patients undergoing thallium-201 myocardial perfusion scintigraphy who cannot adequately exercise. Because dipyridamole increases coronary blood flow by reducing the metabolism of adenosine, the authors compared the uptake and clearance of T1-201 following exercise stress testing (EST) and resting intravenous infusion of adenosine (AI) in crossover fashion in 20 healthy men. No perfusion defects or areas of redistribution were noted in any of the scans. Mean absolute myocardial T1-201 uptake was 1.3 times greater with AI than with EST. Mean absolute extracardiac uptake was 2.0 times greater with AI. Mean T1-201 myocardial clearance was virtually the same in all AI and EST views. During AI, 70% of the subjects experienced subjective side effects, mean arterial blood pressure decreased by 15%, and heart rate increased by 48%. The effects of adenosine on T1-201 kinetics in the myocardium are similar to those of EST. Adenosine may be useful as a pharmacologic stress agent in patients undergoing T1-201 myocardial perfusion scintigraphy.

Adenosine↗
PubMed2003

Manipulating expression of endogenous oncogenic proteins using an antisense oligonucleotide approach in prostate cancer cells.

It has been shown that antisense oligodeoxynucleotide (ODN) treatments provide an effective, specific approach to inhibiting the function of target proteins. Using this method, we have acquired additional evidence that protein kinase C-epsilon functions as an oncogenic protein in the progression of recurrent human prostate cancer. This chapter describes the use of antisense ODN to directly target cellular protein kinase C-epsilon as a potential chemotherapeutic agent for blocking the advance of prostatic adenocarcinoma to androgen-independence. Using Lipofectin as the carrier, phosphorothioate-modified antisense ODNs were transferred into prostate cancer cells with high efficiency, effectively inhibiting the expression of endogenous protein kinase C-epsilon and the androgen-independent (AI) proliferation of several independent human prostate cancer cell lines.

Gene Expression Regulation, Neoplastic↗
PubMed2003

Combined targeted inhibition of bcl-2, bcl-XL, epidermal growth factor receptor, and protein kinase A type I causes potent antitumor, apoptotic, and antiangiogenic activity.

PURPOSE: This study investigated whether the functional and structural interactions between epidermal growth factor receptor (EGFR), protein kinase AI (PKAI), and bcl-2/bcl-xL could be exploited to obtain cooperative antitumor effects against models of human colon and breast cancer. EXPERIMENTAL DESIGN: Antisense bcl-2/bcl-xL (4625), antisense PKAI (AS-PKAI), and ZD1839 ("Iressa"), a selective EGFR tyrosine kinase inhibitor, were administered as single agents and in combination against GEO colon and ZR-75-1 breast cancer cell lines in vitro and to mice bearing s.c. GEO human tumor xenografts in vivo. Effects on growth inhibition, vascular endothelial growth factor secretion, and induction of apoptosis were assessed. RESULTS: Antisense bcl-2/bcl-xL inhibited the growth of GEO and ZR-75-1 cells in vitro, reducing bcl-2 and bcl-xL expression and vascular endothelial growth factor secretion. Supra-additive growth inhibition and apoptosis induction were observed when 4625 was combined with ZD1839 or AS-PKAI. Combining all three agents resulted in a complete growth inhibitory effect in vitro. Antisense bcl-2/bcl-xL, AS-PKAI, and ZD1839 administered in vivo as single agents caused growth inhibition of GEO xenografts. Combining all three agents caused a marked and sustained effect, with 50% growth inhibition and 50% of mice tumor free 5 weeks after treatment withdrawal. The combination was well tolerated. CONCLUSIONS: The combination of 4625, AS-PKAI, and ZD1839 resulted in a strong antiproliferative, proapoptotic, and antiangiogenic response, suggestive of a functional interaction between EGFR, PKAI, and bcl-2/bcl-xL and providing a rationale for the selection of specific molecular treatments for the development of therapeutic strategies. Iressa is a trademark of the AstraZeneca group of companies.

Animals↗
PubMed2004

[Efficacy of chemotherapy for tuberculosis in patients who isolate drug-resistant strains of M. tuberculosis with different genotypes].

Two hundred and twenty-four patients with pulmonary tuberculosis and bacterial isolation were examined to study the efficiency of chemotherapy in patients who isolated drug-resistant strains of Mycobacterium tuberculosis (MBT) of different genotypes. According to the pattern of susceptibility to antituberculous drugs (ATDs), the patients were divided into 3 groups: 1) those who were found to have ATD-susceptible MBT; 2) those who had multiresistant MBT susceptible to all ATDs, other than isoniazid and rifampicin; 3) those with multidrug resistance. MBT genotyping in accordance with the polymorphism of the length of restriction fragments IS6110 has indicated that the strains of the families W and AI were prevalent in all the groups. However, the strains of mycobacteria of the W family were most frequently (62%) detected among the patients with tuberculosis with slight drug resistance. Treatment was performed in accordance with the data of tests of MBT for their susceptibility to chemical agents. Comparison of the efficiency of therapy failed to reveal any relationship of the genotype of the causative agent within the groups of patients with tuberculosis with different resistance of Mycobacteria, including those with slight drug resistance. At the same time, the pattern of drug susceptibility of MBT largely determined the frequency and trends of bacterial isolation cessation.

Antitubercular Agents↗
PubMed2007

Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells.

Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Se-methylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer.

Androgens↗
PubMed2005

Vasodilatation vs. immunotherapy to prevent delayed graft function: delayed graft function as an indication of immune activation.

Delayed renal allograft function (DGF) is a factor for acute rejection and chronic allograft nephropathy. Cold ischemia time (CIT) is associated with an increased in DGF. Twenty patients receiving allografts with CIT>12 were enrolled in a double-blinded, randomized (1:1), placebo-controlled study to assess vasodilatation with fenoldopam (Abbott; dopamine-1 receptor agonist) on DGF. Fenoldopam infusion began at arterial anastomosis at 0.025 microg/kg/min and titrated to 0.1 microg/kg/min continued for 48 h postop (PO). Immunosuppression included steriods, MMF, and calcinurin inhibitors begun 36 h PO. Antibody induction (AI) using antithymocyte globulin (rabbit) (AT-G(r); Sangstat) was added halfway through the study to African-Americans and for PRA>40%. The need for dialysis, cumulative urine output (UOP), and creatinine (Cr) at PO day 7, 14, and 30 were compared. Eighteen patients completed the study drug infusion. Demographics of groups were not different. There was no difference between fenoldopam and controls for dialysis, UOP at 48 and 72 h, or Cr at 7, 14, or 30 days. There was a difference in UOP when AI (n=7) was compared to non-AI (n=11). At 48 h non-AI UOP 4796+/-3284 ml compared to AI UOP 8960+/-5130 ml (p=0.050). At 72 h, non-AI patients had UOP of 6824+/-4547 ml compared to AI patients with UOP of 12196+/-5868 ml (p=0.044). There was a trend to a lower Cr at day 7 for AI 2.7+/-2.1mg/dl compared to 4.9+/-3.0 mg/dl in non-AI (p=0.11). There was no difference in dialysis or Cr at day 14 and 30 between the AI and non-AI patients. AI with AT-G(r) significantly increases UOP in allografts with CIT>12 h, whereas vasodilatation did not. Therapy for DGF may include AT-G(r) AI.

Adult↗
PubMed2003

Mechanical and histomorphometric evaluations of titanium implants with different surface treatments inserted in sheep cortical bone.

Improvement of the implant-bone interface is still an open problem and the interest in chemical modification of implant surfaces for cementless fixation has grown steadily over the past decade. Mechanical and histomorphometric investigations were performed at different times on implants inserted into sheep femoral cortical bone to compare the in vivo osseointegration of titanium screws ( X 3.5 x 7 mm length) with different surface treatments. After 8 weeks of implantation, the push-out force of anodized and hydrothermally treated implants (ANODIC) was significantly higher than that of machined implants (MACH) (36%, p<0.0005), whereas a decrease of 39% was observed for acid-etched implants (HF) when compared to other surface treatments. After 12 weeks of implantation, the push-out force values of HF implants were still significantly lower than those observed for MACH (-19%, p<0.01) and hydroxyapatite vacuum plasma-sprayed implants (HAVPS, -25%, p<0.0005), and the highest push-out force was found in HAVPS (p<0.001) implants. After 8 and 12 weeks of implantation, the AI of HF implants was significantly (p<0.05) lower ( approximately -25%) than that of MACH, HAVPS and ANODIC implants. In conclusion, results appear to confirm that there are no specific differences between ANODIC and HAVPS implants in terms of behavior. Moreover, although MACH implants show some surface contaminating agents, they appear to ensure good osseointegration within 12 weeks both mechanically and histomorphometrically, as do ANODIC and HAVPS implants. However, further studies are required to investigate bone hardness and mineralization around implants.

Animals↗
PubMed2002

Design, synthesis, and evaluation of new chemosensitizers in multi-drug-resistant Plasmodium falciparum.

A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems-phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration (FIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.

Animals↗
PubMed2007

Przewalskin B, a novel diterpenoid with an unprecedented skeleton from Salvia przewalskii maxim.

Przewalskin B (1), a novel diterpenoid possessing a unique skeleton, was isolated from a Chinese medicinal plant Salvia przewalskii. Its structure and relative stereochemistry were elucidated by extensive NMR analysis and a single-crystal X-ray study. A possible biosynthetic pathway for 1 was proposed. Compound 1 exhibited modest anti-HIV-1 activity with EC50 = 30 microg/mL. [structure: see text].

Anti-HIV Agents↗
PubMed1997

Characterization of angiotensin II formation in human isolated bladder by selective inhibitors of ACE and human chymase: a functional and biochemical study.

1. Functional recordings of smooth muscle tension and biochemical experiments on membrane fractions were performed to characterize angiotensin II (AII) formation in human isolated bladder smooth muscle. 2. A novel human chymase inhibitor CH 5450 (Z-Ile-Glu-Pro-Phe-CO2Me) and a recently developed human chymase substrate Pro11-,D-Ala12)-angiotensin I, claimed to be resistant to angiotensin converting enzyme (ACE) and carboxypeptidase, were used. 3. Angiotensin I (AI) (0.3 microM) induced a contractile response amounting to 58 +/- 5% (n=12) of the initial K+ (124 mM)-induced contractions. This response was reduced to 36 +/- 3% (n=8) by the ACE-inhibitor enalaprilat (10 microM), while pretreatment with soybean trypsin inhibitor (STI 200 microg ml(-1)) or CH 5450 (10 microM) had no effect. However, the combination of enalaprilat and STI reduced the AI-induced contractions to 19 +/- 5% (n=6), and the combination of enalaprilat and CH 5450 caused an almost complete inhibition of the AI-induced contractions to 1+/-1% (n=6). 4. The substrate (Pro11-,D-Ala12)-AI (3 microM) produced contractions which amounted to 57 +/- 4% (n=13) of the initial K+ (124 mM) contractions. These contractions were not affected by enalaprilat (10 microM). On the other hand, STI (200 microg ml(-1)) and CH 5450 (10 microM) added separately, depressed the (Pro11-,D-Ala12)-AI-induced contractions to 34 +/- 5% (n=6) and 24 +/- 4% (n=6), respectively. The combination of enalaprilat and STI or enalaprilat and CH 5450 did not produce any further inhibition. 5. Experiments with detrusor membrane fractions incubated with AI (50 microM) were performed. In the presence of enalaprilat (100 microM), carboxypeptidase inhibitor CPI (10 microg ml(-1)) and aprotinin (15 microM), CH 5450 (10 nM-1 microM) caused a concentration-dependent inhibition of AII formation. 6. The results confirm that AII is a potent contractile agent in the human isolated detrusor muscle. They also indicate that the serine protease responsible for AII formation in the human bladder in vitro is human chymase or an enzyme similar to human chymase.

Aged↗
PubMed2000

Increased high-density lipoprotein-3 binding to leukocytes following weight loss and improved glycemic control in type 2 diabetic patients.

This study evaluates the effect on high-density lipoprotein (HDL) binding activity in cultured granulocytes before and after metabolic control of non-insulin-dependent diabetes mellitus ([NIDDM] type 2 diabetes) patients. In 20 type 2 diabetic patients, diabetic control was accomplished by administration of oral antidiabetic agents and dietary restrictions. Adequate metabolic control was reflected by a decrease in the fasting glucose, glycosylated hemoglobin (HbA1c), mean insulin, and body mass index (BMI). After control of the diabetes, the mean HDL3 cholesterol was increased from 0.918 +/- 0.05 to 1.008 +/- 0.05 mmol/L (P < .05) and apolipoprotein AI (apo AI) was increased from 103 +/- 5.8 to 115 +/- 5.1 mg/dL (P < .01). The HDL3 maximum specific binding was higher after versus before diabetic control, 77 +/- 6 versus 122 +/- 8 ng/mg cell protein (P < .01). This increase was related to an increase in maximum binding ([Bmax] from 4.97 x 10(-10) to 8.3 x 10(-10) mol/L, P < .001), and no significant changes were observed in the Kd (from 1.47 x 10(-7) v 2.04 x 10(-7) mol/L). These results suggest that the metabolic control of type 2 diabetes increases HDL3 binding activity.

Adult↗
PubMed2002

Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages.

Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as antioxidant and anticarcinogen. In the present study, we compared the antioxidant activity of carnosol and other compounds extracted from rosemary. Carnosol showed potent antioxidative activity in alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radicals scavenge and DNA protection from Fenton reaction. High concentrations of nitric oxide (NO) are produced by inducible NO synthase (iNOS) in inflammation and multiple stages of carcinogenesis. Treatment of mouse macrophage RAW 264.7 cell line with carnosol markly reduced lipopolysaccharide (LPS)-stimulated NO production in a concentration-related manner with an IC50 of 9.4 microM; but other tested compounds had slight effects. Western blot, reverse transcription-polymerase chain reaction, and northern blot analyses demonstrated that carnosol decreased LPS-induced iNOS mRNA and protein expression. Carnosol treatment showed reduction of nuclear factor-kappaB (NF-kappaB) subunits translocation and NF-kappaB DNA binding activity in activated macrophages. Carnosol also showed inhibition of iNOS and NF-kappaB promoter activity in transient transfection assay. These activities were referred to down-regulation of inhibitor kappaB (IkappaB) kinase (IKK) activity by carnosol (5 microM), thus inhibited LPS-induced phosphorylation as well as degradation of IkappaBalpha. Carnosol also inhibited LPS-induced p38 and p44/42 mitogen-activated protein kinase (MAPK) activation at a higher concentration (20 microM). These results suggest that carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-kappaB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.

Abietanes↗