Cardioprotective Effects of Mebudipine in a Rat Model of Doxorubicin-Induced Heart Failure.

Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods: The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA. Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine. Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22).

The Effect of Noscapine on Oxygen-Glucose Deprivation on Primary Murine Cortical Neurons in High Glucose Condition.

In the present work we set out to investigate the neuroprotective effects of noscapine (0.5-2 µM) in presence of D-glucose on primary murine foetal cortical neurons after oxygen-glucose deprivation/24 h. recovery. Cell viability, nitric oxide production and intracellular calcium ((ca(2+))i) levels were evaluated by MTT assay, the modified Griess method and Fura-2 respectively. 25 and 100 mM D-glucose could, in a concentration dependent manner, improve cell viability and decrease NO production and (ca(2+))i level in neuronal cells after ischemic insult. Moreover, pre-incubation of cells with noscapine, noticeably enhanced protective effects of 25 and 100 mM D-glucose compared to similar conditions without noscapine pre-treatment. In fact, noscapine attenuated NO production in a dose-dependent fashion, after 30 minutes (min) OGD, during high-glucose (HG) condition in cortical neurons. Pretreatment with 2 µM noscapine and 25 or 100 mM D-glucose, was shown to decrease the rise in (ca(2+))i induced by Sodium azide/glucose deprivation (chemical OGD) model. These effects were more pronounced than that of 25 or 100 mM D-glucose alone. The present study demonstrated that the neuroprotective effects of HG before an ischemic insult were augmented by pre-treatment with noscapine. Our results also suggested that the neuroprotection offered by both HG and noscapine involve attenuation of NO production and (ca(2+))i levels stimulated by the experimental ischemia in cortical neurons.

A novel effect of Noscapine on patients with massive ischemic stroke: A pseudo-randomized clinical trial.

BACKGROUND: Massive ischemic stroke causes significant mortality and morbidity in stroke patients. The main treatments for massive ischemic stroke are recombinant tissue plasminogen activator (rtPA), craniotomy, and endovascular interventions. Due to destructive effects of bradykinin on the nervous system in ischemic stroke, it seems reasonable that using Noscapine as a Bradykinin antagonist may improve patients' outcome after ischemic stroke. The effect of Noscapine on massive ischemic stroke was shown by the previous pilot study by our group. This pseudo-randomized clinical trial study was designed to assess the result of the pilot study. METHODS: Patients who had clinical symptoms or computed tomography scan indicative of massive stroke (in full middle cerebral artery territory) were entered to the study. The cases received the drugs according to their turns in emergency ward (pseudo-randomized). The patient group received Noscapine, and the control group received common supportive treatments. The patients and data analyzer were blinded about the data. At the end of the study, to adjust confounding variables we used logistic regression. RESULTS: After 1-month follow-up, 16 patients in the control group and 11 patients in the case group expired (P = 0.193). Analyzing the data extracted from Rankin scale and Barthel index check lists, revealed no significant differences in the two groups. CONCLUSION: Despite the absence of significant statistical results in our study, the reduction rate of 16% for mortality rate in Noscapine recipients is clinically remarkable and motivates future studies with larger sample sizes.

Neuroprotective effect of noscapine on cerebral oxygen-glucose deprivation injury.

BACKGROUND: The present study aims to investigate the effect of noscapine (0.5-2.5 µM), an alkaloid from the opium poppy, on primary murine fetal cortical neurons exposed to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. METHODS: Cells were transferred to glucose-free DMEM and were exposed to hypoxia in a small anaerobic chamber. Cell viability and nitric oxide production were evaluated by MTT assay and the Griess method, respectively. RESULTS: The neurotoxicities produced by all three hypoxia durations tested were significantly inhibited by 0.5 µM noscapine. Increasing noscapine concentration up to 2.5 µM produced a concentration-dependent inhibition of neurotoxicity. Pretreatment of cells with MK-801 (10 µM), a non-competitive NMDA antagonist, and nimodipine (10nM), an L-type Ca(2+) channel blockers, increased cell viability after 30 min OGD, while the application of NBQX (30 µM), a selective AMPA-kainate receptor antagonist partially attenuated cell injury. Subsequently, cells treated with noscapine in the presence of thapsigargin (1 µM), an inhibitor of endoplasmic reticulum Ca(2+) ATPases. After 60 min OGD, noscapine could inhibit the cell damage induced by thapsigargin. However, noscapine could not reduce cell damage induced by 240 min OGD in the presence of thapsigargin. Noscapine attenuated nitric oxide (NO) production in cortical neurons after 30 min OGD. CONCLUSIONS: We concluded that noscapine had a neuroprotective effect, which could be due to its interference with multiple targets in the excitotoxicity process. These effects could be mediated partially by a decrease in NO production and the modulation of intracellular calcium levels.

Effects of berberine on ß-secretase activity in a rabbit model of Alzheimer's disease.

INTRODUCTION: Relevant aspects of Alzheimer's disease (AD) can be modeled by aluminium-maltolate injection into specific regions of the brain. The possible role of berberine chloride (BC) as an anti-inflammatory agent in the brain has been previously addressed. MATERIAL AND METHODS: Rabbits were divided into control (C), untreated lesion (L) and BC-treated + lesion (L + BC) groups. Animals in L + BC received BC (50 mg/ kg) orally 1 day after surgery and daily for 2 weeks. The lesion was induced by injection of 100 µl of either vehicle or water containing 25 mM aluminium-maltol into intraventricular fissure. Weight loss, ataxia, paralysis and tremor were monitored. For histopathology, Bielschowsky silver and H&E staining were employed. ß-Secretase activity in hippocampus was finally assessed. RESULTS: All L animals died on days 12-15 after lesion. Seven to 10 days after lesion, abnormal symptoms as well as cachexia were seen in over 90% of cases. L rabbits lost an average of 0.5 kg which was significant on days 10 and 12 (p < 0.05); this was not completely prevented by BC. Up to day 15, all L animals had lost their lives (p < 0.001). BC treatment protected the hippocampus from degeneration, altered the behavior and decreased the activity of ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1). CONCLUSIONS: Considering the findings in regard to physiological abilities, histological changes and BACE-1 activity in hippocampus changes, it is concluded that BC treatment could be an effective therapy in restoring Al maltol-induced behavioral derangements in the rabbit model of AD.

Anti-inflammatory effects of anti-hypertensive agents: influence on interleukin-1ß secretion by peripheral blood polymorphonuclear leukocytes from patients with essential hypertension.

The effects of clinically relevant concentrations of anti-hypertensive agents on lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1ß) secretion by polymorphonuclear leukocytes (PMNs) were investigated in vitro. Lipopolysaccharide-induced secretion of IL-1ß by PMNs from 15 hypertensive and 15 normotensive subjects after incubation with losartan, captopril, amlodipine, atenolol, and hydrochlorothiazide were assessed. IL-1ß secretion by PMNs markedly increased in hypertensive patients versus normotensive subjects. Losartan, captopril, and amlodipine caused a concentration-dependent attenuation of IL-1ß levels in both groups. Losartan, captopril, and amlodipine demonstrated marked in vitro anti-inflammatory effects at clinically relevant serum concentrations but atenolol and hydrochlorothiazide did not.

Effect of the two new calcium channel blockers mebudipine and dibudipine on vascular flow of isolated kidney of normal and diabetic rats.

BACKGROUND AND AIMS: Calcium channel blockers (CCBs) are powerful drugs in the treatment of hypertension. These agents also preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. There is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. In previous researches mebudipine and dibudipine two newly synthesized CCBs, improved normal rat kidney perfusion. The study was designed to investigate the effects of these new drugs on vascular flow of isolated kidney from diabetic rats comparing to nifedipine, also to test that the effects of the new DHPs and nifedipine on renal blood flow in the isolated perfused kidney might be altered in experimental diabetic rats. METHODS: In this study normal and STZ-induced 6- to 7-week diabetic rats were used. Following the establishment of renal perfusion with a constant baseline pressure of 85-95mmHg, the renal vasculature was constricted by phenylephrine (PE) injection. Changes in the baseline perfusion pressure were recorded. Then DHP CCBs prepared in perfusion medium was fed to the kidney for 30min. Finally alterations in the baseline pressure arising from PE administrations in the presence of DHPs were recorded and data analyses were done. RESULTS: Mebudipine and dibudipine (1-10µM) were more effective in the inhibition of phenylephrine (PE)-induced perfusion pressure in isolated kidney of diabetic rats compared to nifedipine at similar concentrations. Based on the obtained EC(50) values for DHPs-induced inhibition of prefusion pressure, it is referred that lower concentrations of mebudipine and dibudipine are needed to inhibit PE-evoked increments of renal perfusion pressure in diabetic rats. CONCLUSION: Mebudipine and dibudipine have more potency in inhibiting PE-elicited perfusion pressure in isolated kidney from diabetic rats compared to normal rats.

Berberine-induced apoptosis via decreasing the survivin protein in K562 cell line.

Berberine is an isoquinoline alkaloid with multiple pharmacological activities, including anti-inflammatory and anti-diarrhea effect, the induction of apoptosis and anti-cancer effect. It has been reported that berberine exerts its anti-inflammatory effect via suppressing nuclear factor-kappa B (NF-κB) expression. Survivin and inducible nitric oxide synthase (iNOS) proteins may contribute to the causal relationship between anti-inflammatory and anti-apoptotic function. To investigate the mechanism of berberine-induced apoptotic activities, the human erythro-myeloblastoid leukemia cell line (K562 cell line) was treated with different concentrations of berberine (25-100 µM). The most significant cellular growth arrest and apoptotic effects were observed in the cells treated with 75 µM of berberine for 72 h. The results indicate that survivin and iNOS protein levels were decreased in berberine-treated cells. However, decrease in the iNOS activity did not affect the cell growth and apoptosis. Moreover, the addition of NO donor, sodium nitroprusside, to culture medium decreased the cell growth in the present cell line, but it seemed that its concentration was too low to induce apoptosis. So despite its production by iNOS in untreated cells, NO does not play a significant role in carcinogenesis in this cell line. These results indicate that the apoptotic activity of berberine may be mediated through the reduction of survivin in K562 cells, but iNOS level and its activity does not play a significant role in berberine-induced apoptosis.

In vitro and in vivo activities of Peganum harmala extract against Leishmania major.

BACKGROUND: In vitro and in vivo antileishmanial activities of crude hydroalcoholic extract of peganum harmala seeds were investigated against Leishmania major. METHODS: The extract of aerial parts of P harmala was obtained by maceration. The in vitro experiments were performed on promastigotes to assess antileishmanial activity of the extract using amphotericin B as a reference. The in vivo studies were carried out on cutaneous leishmaniasis in outbred mice to evaluate the effects of topical application of the ointment-based extract. RESULTS: The in vitro experiments showed a concentration-dependent decrease of parasites number caused by the extract with an IC50 value of 59.4 µg/ml. In vivo studies demonstrated a significant post-treatment decrease in the lesion size and parasite count in infected animals, compared to placebo and control groups. High performance liquid chromatography (HPLC) of the crude extract demonstrated the existence of harmaline and harmine as beta-carboline alkaloids. CONCLUSIONS: P harmala seeds extract showed significant in vitro and in vivo antileishmanial activities. Most biological activity of the extract could be attributed to its beta-carboline content. However, another alkaloid of P harmala seeds extract, peganine, has also been reported to have antileishmanial activity. These beneficial effects can be attributed to the cumulative effects of various biologically active components present in it.

Evaluation of mutagenicity of mebudipine, a new calcium channel blocker.

Mebudipine is a new dihydropyridine calcium channel blocker, synthesized in our laboratory, for treatment of hypertension. It has shown a better efficacy than other drugs in this group. For assessing the risks of this drug, certain safety tests in the preclinical stage have been performed. In this study mutagenic effect of mebudipine was evaluated using Ames assay that could assess the mutagenicity of drugs and their metabolites using liver enzymes (S-9 mix). This procedure is approved as a predictive test, with a high predictive value. Salmonella TA102 (Ames assay) was used with and without S-9 in this study. For preparing S-9 mix, rat liver enzymes induced by phenobarbital were separated in KCl 0.154 M (0.154 M), as the solvent. Mebudipine was dissolved in polyethylenglycol 400. Mutagenicity test was performed in 6 doses from 39 µg to 1250 µg per every plate, in the presence and absence of the S-9 mix. The positive control sodium azide was dissolved in a dose of 5 µg/plate dissolved in polyethylenglycol 400 and negative control was polyethylenglycol 400 with no added agent. The colony counts of all doses in plates with S-9 were between 200-400 and in plates without S9 was between100-300. The colony counts in both states (with and without S-9) of all doses were in the range suggested by Ames assay for the safe drugs and were different from the positive control groups and equal to the negative controls. Mebudipine and its metabolites were not found to be mutagen on Salmonella TA102, based on Ames assay.

Construction, calibration, and validation of a simple patch-clamp amplifier for physiology education.

A modular patch-clamp amplifier was constructed based on the Strickholm design, which was initially published in 1995. Various parts of the amplifier such as the power supply, input circuit, headstage, feedback circuit, output and nulling circuits were redesigned to use recent software advances and fabricated using the common lithographic printed circuit board fabrication process and commercially available electronic components. The calibration, validation, and regular recording procedures along with the results of an actual recording of inward Ca(2+) currents from PC12 neuronal cells are described in detail. This work describes the construction of a low-cost patch-clamp amplifier and setting up an electrophysiology recording system in a laboratory with regular technical expertise. The constructed amplifier provides an inexpensive yet practical tool for research and teaching purposes while the experience obtained during construction and setting up of the patch-clamp amplifier provides the basic and advanced understanding required for operating an advanced cell potential recording apparatus.

Berberine reduces the hypoxic-ischemic insult in rat pup brain.

Berberine, an isoquinoline alkaloid extracted from medicinal herbs, has been used as antipyretic, antidiarrheal, bactericide and anti-inflammatory agent. In this study, berberine effects on neuronal damage have been examined. The right carotid artery of seven-day-old rat pups was ligated (ischemic insult), then berberine solution (0.2, 0.5, 1 or 2 mg/kg) was injected intra-peritoneally, and 30 minutes later pups were passed through hypoxic condition with breathing in air containing 10% oxygen and 90% nitrogen(hypoxic insult). The day after that the brains of pups were enucleated for pathologic assessment. Pathologic review of the samples obtained from rats treated with different doses of berberine in comparison with samples from pups treated by normal saline showed that there was a significant reduction of brain injury and edema in the rats treated with berberine. Our study also demonstrates that berberine reduces brain ischemic-hypoxic injury dose-dependently. Therefore, beberine may be considered as useful anti-stroke agent.

Neuroprotective effects of mebudipine and dibudipine on cerebral oxygen-glucose deprivation/reperfusion injury.

In the present study, we investigated the effects of mebudipine and dibudipine, two new Ca(2+) channel blockers, on primary murine cortical neurons exposed to oxygen-glucose deprivation/reperfusion. The experiments were performed on cells after 11-16 days of culture. To initiate oxygen-glucose deprivation /reperfusion, the culture medium was replaced by glucose-free medium, and the cells were transferred to a humidified incubation chamber in a mixture of 95% N(2) and 5% CO(2) at 37 degrees C for 30 min. The cultures were pretreated with mebudipine and dibudipine 3 h prior to oxygen-glucose deprivation/reperfusion, in order to explore their effects on neurons under oxygen-glucose deprivation conditions. Cell viability and nitric oxide (NO) production were assessed by MTT assay and the modified Griess method, respectively. Exposure of murine cortical neuronal cells to 30 min oxygen-glucose deprivation significantly decreased cell viability and increased NO production. Pretreatment of the cultures with mebudipine and dibudipine significantly increased cell viability and decreased NO generation in a dose-dependent manner. However, the drugs had no protective effect in cells subjected to oxygen-glucose deprivation for 60 min. Pretreatment of cultures with MK-801 (10 microM), a non-competitive NMDA antagonist, decreased neuronal death after 30-min oxygen-glucose deprivation, while application of NBQX (30 microM), a selective AMPA-kainate receptor antagonist, partially attenuated the cell injury. oxygen-glucose deprivation -induced cytotoxicity and NO production were also inhibited by N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor and MK-801. We conclude that mebudipine and dibudipine could protect cortical neurons against oxygen-glucose deprivation /reperfusion-induced cell injury in a dose-dependent manner, and that this could be mediated partially by decreased NO production.

The anti-cancer activity of noscapine: a review.

Noscapine is an isoqiunoline alkaloid found in opium latex. Unlike most other alkaloids obtained from opium latex, noscapine is not sedative and has been used as antitussive drug in various countries. Recently, it has been introduced as an anti-mitotic agent. This drug can be used orally. When the resistance to other anti-cancer drugs such as paclitaxel manifests, noscapine might be effective. Therefore, noscapine and its analogs have great potential as novel anti-cancer agents.

Ciprofloxacin: a novel therapeutic agent for iron overload?

OBJECTIVE: Major thalassemia is one of the hematological diseases requiring multiple blood transfusions, which results in iron overload in the liver, heart and other organs. Current iron chelation therapy consists of intravenous (IV) deferoxamine and oral deferasirox and deferiprone. Although these chelators are effective, many side effects are reported. In the present study, the iron-chelating effect of ciprofloxacin with good oral absorption was investigated. METHODS: Thirty male albino Wistar rats were used for the study. Ciprofloxacin (7 or 14 mg/kg per day) was administered simultaneously with iron (0.03 g/kg per day) or after one-month administration of iron. Ciprofloxacin effect on iron absorption in the liver and heart was studied carefully using atomic absorption. RESULTS: A significant decrease in the liver and heart iron following the ciprofloxacin (14 mg/kg per day) administration was observed, when compared with the control group. This ciprofloxacin-induced tissue iron depletion was more pronounced when it was administered simultaneously with iron, when it was administered for a longer duration (2 months rather than 1 month) and when it was given in higher doses (14 mg/kg per day). CONCLUSION: Administration of ciprofloxacin may help to decrease the burden of parenteral administration, thereby improving compliance and also the life expectancy of thalassemic patients.

An image processing technique for diagnosis of Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) reportedly exhibit hypersensitivity to much diluted tropicamide solution (0.005%), a M4 muscarinic receptor antagonist. Therefore intraocular application of 0.005% tropicamide may be useful for screening dementia. The aim of this study was to simplify the pupil response test by using a new image analyzing system, which consists of a cheap, simple, and easy to use web-camera and a computer. METHODS: Intraocular tropicamide of 0.005% concentration was administered in 3 groups: Alzheimer's disease patients (n = 8, average age = 76 ± 5), non-Alzheimer's disease elderly (n = 6, average age = 65 ± 7), and young subjects (n = 8, average age = 28 ± 5). Every 5 minutes for 60 minutes, image of the eye's shape were taken, and the diameter of the pupils was measured. RESULTS: The results showed that differences in pupil dilation rate between Alzheimer's disease and non-Alzheimer's disease subjects were statistically significant. ROC analysis showed that after 35 minutes the sensitivity and specificity of the test were 100%. CONCLUSIONS: Based on our results, we concluded that this recording system might be an appropriate and reliable tool for pupil response diagnosis test of Alzheimer's disease.

Mebudipine and dibudipine protect PC12 cells against oxygen-glucose deprivation and glutamate-induced cell death.

The protective effect of two new L-type calcium-channel blockers, mebudipine and dibudipine on neurotoxic effects induced by glutamate and oxygen-glucose deprivation (OGD) in PC12 cells was investigated. PC12 cells were intoxicated with two different methods. First, the cells were incubated with glutamate (10muM/L), glutamate and mebudipine (10muM/L), dibudipine (10muM/L) or nimodipine (10muM/L), on three different treatment schedules (concurrently, pre-3h and pre-24h). In the second method PC12 cells were exposed to in vitro oxygen-glucose deprivation for 30min and 60min alone or with the drugs in the same time schedules described above. Cellular viability was assessed by MTT assay. Glutamate-induced cell death and OGD-induced cell injury were attenuated significantly by mebudipine, dibudipine in comparison with nimodipine in all three different treatment schedules. Application of MK801 (10muM/L), an antagonist of NMDA glutamate receptors inhibited PC12 cell death in both methods. Our study suggests that mebudipine and dibudipine, like nimodipine, may have protective effects against glutamate and oxygen-glucose deprivation-induced neurotoxicity.

Effects of pioglitazone on erectile dysfunction in sildenafil poor-responders: a randomized, controlled study.

PURPOSE: The effects of pioglitazone on sildenafil responsiveness in men with erectile dysfunction(ED) and a history of poor response to sildenafil were assessed. METHODS: In a double-blinded study,38 men aged 47 +/- 1.5 years with moderate-to severe ED and poor response to sildenafil were randomly assigned to take a premedication of pioglitazone 30 mg (n=19) or placebo (n=19) once daily for 9 weeks along with on-demand use of sildenafil during the last month of pioglitazone treatment.Erectile function (EF) scores, assessed by EF domain of International Index of Erectile Function (IIEF), along with responses to Global Assessment Questions (GAQs) were major outcome measures. Serum levels of total testosterone (T),dehydroepiandrosterone sulfate (DHEAS), glucose,lipid profile and liver function test were minor outcome measures. RESULTS: Pioglitazone significantly improved major outcome measures compared with placebo. The decrease from baseline of total cholesterol level was more in pioglitazone than in placebo-treated groups. In 84% (32 out of 38) of the sildenafil poor-responders, at least one of the associated risk factors of ED was found. There was undiagnosed hypercholesterolemia in 34% of the subjects. Serum levels of T, DHEAS, glucose and other parameters remained unchanged in both groups. The intervention was well tolerated. CONCLUSIONS: Pioglitazone increased sildenafil response to improve ED of men with prior sildenafil failure and seems to be safe based on the present preliminary study. This improvement is likely regardless of fasting glucose and sex hormones levels.

Apoptotic pathway induced by noscapine in human myelogenous leukemic cells.

It has been shown that noscapine, an opium-derived phthalideisoquinoline alkaloid that is currently being used as an oral antitussive drug, induces apoptosis in myeloid leukemia cells. The molecular mechanism responsible for the anticancer effects of noscapine is poorly understood. In the current study, the apoptotic effects of noscapine on two myeloid cell lines, apoptosis-proficient HL60 cells and apoptosis-resistant K562 cells, were analyzed. An increase in the activity of caspase-2, -3, -6, -8 and -9, poly(ADP ribose) polymerase cleavage, detection of phosphatidylserine on the outer layer of the cell membrane, nucleation of chromatin, and DNA fragmentation suggested the induction of apoptosis. Noscapine increased the Bax/Bcl-2 ratio with a significant decrease of Bcl-2 expression accompanied with Bcl-2 phosphorylation. Using an inhibitory approach, the activation of the caspase cascade involved in the noscapine-induced apoptosis was analyzed. We observed no inhibitory effect of the caspase-8 inhibitor on caspase-9 activity. In view of these results and taking into consideration that K562 cells are Fas-null, we suggested that caspase-8 is activated in a Fas-independent manner downstream of caspase-9. In conclusion, noscapine can induce apoptosis in both apoptosis-proficient and apoptosis-resistant leukemic cells, and it can be a novel candidate in the treatment of hematological malignancies.

Paraoxonase phenotype distribution in a healthy Iranian population.

Human serum paraoxonase (PON1) is a high-density lipoprotein-associated esterase that protects against organophosphate neurotoxicity, and is proposed to play a role in lipid metabolism and the onset of cardiovascular disease. In the present study, paraoxonase activities and phenotype distribution in serum of 132 healthy Iranian individuals aged 17-68 years were assessed using dual substrate method. In the study population, a wide interindividual variability (up to 15-fold) of paraoxonase activity was found. The mean of basal, salt-stimulated paraoxonase and arylesterase activities were 81.8 +/- 57 U/ml, 153.1 +/- 117.5 U/ml and 80.7 +/- 12.8 kU/l, respectively. The ratio of salt-stimulated paraoxonase activity to arylesterase activity was used for definition of phenotypes. Based on the observed ratios, three distinct phenotypes AA (low activity), AB (intermediate activity) and BB (high activity) were determined. The PON1 ratio varied from 0.5 to 6.8. The paraoxonase phenotype frequencies were approximately 48% (AA), 41% (AB) and 11% (BB). In this work, serum triglycerides had significant positive correlation (r = 0.334, P < 0.05) with paraoxonase activity, whereas high-density lipoprotein did not. No significant decrease in paraoxonase activity by smoking was observed. Age and sex had no influences on PON1 activities. In conclusion, the distribution of paraoxonase phenotypes in this Iranian population was trimodal and comparable to that of Caucasians from North America; however, overall enzyme activity was lower than that reported for Caucasians.