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At least 937 records · Page 52Linked to original sources
PubMed1999

Competitive antagonism of the mouse 5-hydroxytryptamine3 receptor by bisindolylmaleimide I, a "selective" protein kinase C inhibitor.

We examined the effects of several protein kinase C (PKC) inhibitors on the murine 5-hydroxytryptamine3 (5-HT3) receptor to determine whether they acted directly on the receptor. The 5-HT-evoked currents in Xenopus laevis oocytes expressing the recombinant 5-HT3 receptor were measured with the two-electrode voltage-clamp technique. The PKC inhibitors bisindolylmaleimide I (BIM, GF109203x) and staurosporine, but not calphostin C or chelerythrine, decreased the 5-HT3 receptor-mediated currents when coapplied with 5-HT. BIM blocked 0.5 microM 5-HT-elicited currents with an IC50 value of 7 nM, whereas in the presence of 5 microM staurosporine, 42% inhibition of 0.5 microM 5-HT-mediated currents was observed. Increasing concentrations of BIM resulted in a rightward shift of the 5-HT concentration-response curve, without altering efficacy. A Schild plot was generated, which had a slope of -1.01, suggesting competitive antagonism. The Ki value of BIM was determined to be 29 nM. To confirm competitive antagonism, a competitive binding assay was performed on Sf21 insect cells infected with the mouse 5-HT3 receptor cDNA in a baculovirus expression vector. BIM completely displaced binding of the selective 5-HT3 receptor antagonist [3H]GR65630. BIM bound to the 5-HT3 receptor with a Ki value of 61 nM, which was slightly less potent than that of the selective 5-HT3 receptor antagonist MDL72222 (27 nM). The PKC inhibitor BIM is a potent competitive antagonist at the 5-HT3 receptor.

Alkaloids↗
PubMed1999

Effect of protopine on cytosolic Ca2+ in rabbit platelets.

AIM: To study the influence of protopine (Pro) on the cytoplasmic free Ca2+ concentration ([Ca2+]i) in rabbit platelets. METHODS: Measurement of [Ca2+]i of platelets in vitro by Fura 2-AM fluorescence technique. RESULTS: In the presence of CaCl2 1 mmol.L-1, Pro 10, 20, and 40 mumol.L-1 attenuated the rise in [Ca2+]i evoked by ADP from (420 +/- 57) to (320 +/- 26), (264 +/- 21), and (180 +/- 14) nmol.L-1, respectively, by arachidonic acid (AA) from (280 +/- 36) to (210 +/- 17), (184 +/- 21), and (143 +/- 16) nmol.L-1, respectively, and by platelet-activating factor (PAF) from (350 +/- 42) to (282 +/- 31), (223 +/- 30), and (165 +/- 15) nmol.L-1, respectively. In the presence of egtazic acid 1 mmol.L-1, Pro 10, 20, and 40 mumol.L-1 reduced the Ca2+ release induced by ADP, AA, and PAF, respectively. Pro 10, 20, and 40 mumol.L-1 also decreased ADP-, AA-, and PAF-induced Ca2+ influx. CONCLUSION: Pro inhibited not only Ca2+ release but also the influx of Ca2+.

Adenosine Diphosphate↗
PubMed1999

Hyperosmotic pretreatment reduces infarct size in the rat heart.

Preconditioning of the heart can be achieved by an ischemia/reperfusion stimulus, but also by stretching of the heart by an acute volume overload. Since manipulations of the extracellular osmolality affects cell size, we hypothesized that hyperosmotic pretreatment of the isolated perfused rat heart could reduce infarct size following regional ischemia (RI). Langendorff perfused rat hearts were subjected to 30 min RI by ligature of the main branch of the left coronary artery followed by 120 min reperfusion (control group). Ischemic preconditioning (IP-5') was achieved by 5 min total global ischemia and 5 min reperfusion prior to RI. Hyperosmotic pretreatment was accomplished by perfusion with a hyperosmotic buffer (600 mOsm/kg H2O by adding mannitol) for 1 min, 2 min or 5 min. At the end of the experiments, the hearts were cut into 2 mm slices, incubated with triphenyltetrazoliumchloride before scanning and computerized for estimation of infarct size. The average infarct size (as percentage of area at risk) in the control group was 42% and was significantly reduced to 16% by ischemic preconditioning and to 17% by 2 min hyperosmotic pretreatment. Neither 1 min nor 5 min hyperosmotic pretreatment reduced infarct size as compared to the controls. The infarct reducing effect of 2 min hyperosmotic pretreatment was not blunted by inhibition of protein kinase C (chelerytrine chloride), the Na+/H+-exchanger (HOE 694) or stretch-activated anion channels (gadolinium chloride). The results indicate that short-lasting hyperosmotic perturbations of the extracellular environment may precondition the heart to a subsequent ischemic insult.

Alkaloids↗
PubMed2000

The role of phosphodiesterase in mediating the effect of protein kinase C on cyclic AMP accumulation upon kappa-opioid receptor stimulation in the rat heart.

This study determined whether phosphodiesterase (PDE) was activated by protein kinase C (PKC) upon kappa-receptor stimulation, and if so, to identify the isozyme. We first studied the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulphonate (U50,488H), a selective kappa-opioid receptor (OR) agonist, and phorbol-12-myristate-13-acetate (PMA), a PKC activator, on cAMP accumulation and PDE activity in rat ventricular myocytes when PKC and PDE were inhibited by respective inhibitors. Like PMA, U50,488H decreased the forskolin-stimulated cAMP accumulation and dose-dependently stimulated the PDE activity, which were antagonized by 10(-6) M chelerythrine and bisindolylmaleimide I, selective PKC antagonists. In addition, 3-isobutyl-1-methylxanthine, a PDE inhibitor, dose-dependently attenuated the inhibition on forskolin-stimulated cAMP accumulation and abolished the stimulation on PDE activity by U50,488H and PMA. The observations suggest that PKC may enhance cAMP degradation through activating PDE upon kappa-OR stimulation. To identify the isozyme(s) mediating the effect of PKC upon kappa-OR stimulation, selective inhibitors were used. We found that 10(-5) M Ro-20-1724, a selective cAMP-specific PDE (PDE-IV) inhibitor, abolished the inhibitory effects of U50,488H and PMA, whereas 8-methoxymethyl-3-isobutyl-1-methylxanthine, erythro-9-(2-hydroxy-3-nonyl) adenine, cilostamide, and zaprinast, selective inhibitors of Ca(2+)/calmodulin-dependent PDE (PDE-I), cGMP-stimulated PDE (PDE-II), cGMP-inhibited PDE (PDE-III), and cGMP-specific PDE (PDE-V), respectively, had no effect. Moreover, rolipram, another selective PDE-IV inhibitor, also dose-dependently attenuated the inhibition on forskolin-stimulated cAMP accumulation and stimulation on PDE activity by U50,488H and PMA. In conclusion, this study has provided evidence for the first time that PKC and PDE-IV mediate the action of kappa-OR.

1-Methyl-3-isobutylxanthine↗
PubMed2000

In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo.

Although clonogenic or divisional death is the main mechanism by which DNA-damaging agents demonstrate antitumor activity, recent data indicate that strategies specifically designed to trigger apoptosis may also prove to be useful antitumor agents. Protein kinase C (PKC) isoenzymes are involved in the regulation of cell proliferation, differentiation, and survival. Whereas pharmacological inhibition of PKC activity triggers apoptosis in most mammalian cells, cell line and tissue differences in sensitivities to these inhibitors remain. Whereas PKC inhibitors have potential as antitumor agents, issue of kinase specificity and solubility have remained obstacles to their clinical use. In this report, we investigated the antitumor activity of the PKC inhibitor chelerythrine chloride (chelerythrine), a selective inhibitor of group A and B PKC isoforms. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. On the basis of the finding that radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro, we assessed the effects of this agent on p53-deficient SQ-20B HNSCC cells in vivo. The results demonstrate that chelerythrine treatment of nude mice bearing SQ-20B is associated with significant tumor growth delay. Significantly, treatment with chelerythrine resulted in minimal toxicity. These findings demonstrate a potential for chelerythrine as an antitumor drug against squamous cell carcinoma.

Alkaloids↗
PubMed2000

Direct block by bisindolylmaleimide of rat Kv1.5 expressed in Chinese hamster ovary cells.

The interaction of bisindolylmaleimide (BIM), widely used as a specific protein kinase C (PKC) inhibitor, with rat brain Kv1.5 (rKv1.5) channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. BIM (I) and its inactive analog, BIM (V), inhibited rKv1.5 currents at +50 mV in a reversible concentration-dependent manner with an apparent K(d) value of 0.38 and 1.70 microM, respectively. BIM (I) accelerated the decay rate of inactivation of rKv1.5 currents but did not significantly modify the kinetics of current activation. Other specific PKC inhibitors, chelerythrine and PKC 19-36, had no effect on rKv1.5 and did not prevent the inhibitory effect of BIM (I). The inhibition of rKv1.5 by BIM (I) and BIM (V) was highly voltage-dependent between -30 and 0 mV (voltage range of channel opening), suggesting that both drugs interact preferentially with the open state of the channel. The additional inhibition by BIM (I) displayed a voltage dependence (delta = 0.19) in the full activation voltage range positive to 0 mV, but was not shown in BIM (V) (delta = 0). The rate constants of association and dissociation for BIM (I) were 9.63 microM(-1) s(-1) and 5.82 s(-1), respectively. BIM (I) increased the time constant of deactivation of tail currents from 26. 35 to 45.79 ms, resulting in tail crossover phenomenon. BIM (I) had no effect on the voltage dependence of steady-state inactivation. BIM (I) produced use-dependent inhibition of rKv1.5, which was consistent with the slow recovery from inactivation in the presence of drug. These results suggest that BIM (I) directly inhibits rKv1.5 channels in a phosphorylation-independent, and state-, voltage-, time-, and use-dependent manner.

Algorithms↗
PubMed2000

Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells.

Sanguinarine, derived from the root of Sanguinaria canadendid, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Here we compared the antiproliferative and apoptotic potential of sanguinarine against human epidermoid carcinoma (A431) cells and normal human epidermal keratinocytes (NHEKs). Sanguinarine treatment was found to result in a dose-dependent decrease in the viability of A431 cells as well as NHEKs albeit at different levels because sanguinarine-mediated loss of viability occurred at lower doses and was much more pronounced in the A431 carcinoma cells than in the normal keratinocytes. DNA ladder assay demonstrated that compared to vehicle-treated control, sanguinarine treatment of A431 cells resulted in an induction of apoptosis at 1-, 2-, and 5-microM doses. Sanguinarine treatment did not result in the formation of a DNA ladder in NHEKs, even at the very high dose of 10 microM. The induction of apoptosis by sanguinarine was also evident by confocal microscopy after labeling the cells with annexin V. This method also identified necrotic cells, and sanguinarine treatment also resulted in the necrosis of A431 cells. The NHEKs showed exclusively necrotic staining at high doses (2 and 5 microM). We also explored the possibility of cell cycle perturbation by sanguinarine in A431 cells. The DNA cell cycle analysis revealed that sanguinarine treatment did not significantly affect the distribution of cells among the different phases of the cell cycle in A431 cells. We suggest that sanguinarine could be developed as an anticancer drug.

Alkaloids↗
PubMed2000

Influence of 3-methylcholanthrene pretreatment on sanguinarine toxicity in mice.

We examined the effect of 3-methylcholanthrene (3-MC) on the liver toxicity of sanguinarine in mice. Administration of 10 mg sanguinarine/kg bw ip to male mice resulted in significant decreases in liver glutathione and P450 enzymes activities, and increased in sorbitol dehydrogenase and alanine aminotransferase levels in serum suggestive of liver damage. However, pretreatment with 20 mg 3-MC/kg/d ip, an inducer of P450 enzymes, for 3 d mitigated the sanguinarine toxic effects suggesting 3-MC induced cytochrome P450 enzymes that promote detoxification of sanguinarine.

Alkaloids↗
PubMed1997

[Minor alkaloids from the capsule of Papaver nudicaule L].

Two minor alkaloids were isolated from the capsule of Papaver nudicaule. On the basis of physicochemical methods and spectroscopic analysis, they were identified as chelidonine, 5-hydroxy-2-hydroxymethylpyridine. Chelidonine was isolated from this plant and 5-hydroxy-2-hydroxymethylpyridine was isolated from genus for the first time.

Alkaloids↗
PubMed2001

Histamine increases interstitial adenosine concentration via activation of ecto-5'-nucleotidase in rat hearts in vivo.

We examined whether histamine enhances the production of interstitial adenosine via stimulation of ecto-5'-nucleotidase (a key enzyme responsible for adenosine production) using microdialysis techniques in in situ rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused in the presence of adenosine 5'-monophosphate (AMP). Histamine (10-500 microM) administered into the perfusate had a tendency to increase the adenosine concentration. In the presence of prazosin (50 microM), an antagonist of alpha1-adrenoceptors, or of chelerythrine (10 microM), a protein kinase C (PKC) inhibitor, and in reserpinized rats, histamine failed to increase the AMP-primed dialysate adenosine concentration. Accumulation of norepinephrine in the extracellular fluid elicited by pargyline (100 microM), a monoamine oxidase inhibitor, significantly increased histamine-induced adenosine production. Okadaic acid (50 microM), an inhibitor of protein phosphatase, enhanced the histamine-induced increase in adenosine concentration. Norepinephrine is known to activate alpha1-adrenoceptors and PKC. Taken together, the results demonstrate that histamine-released norepinephrine activates both alpha1-adrenoceptors and PKC, which increased ecto-5'-nucleotidase activity and augmented release of adenosine in rat hearts.

5'-Nucleotidase↗
PubMedDate not supplied

Opioid receptor stimulation acts as mediator of protection in ischaemic preconditioning.

Involvement of the opioid receptors in preconditioning-induced protection has recently been described. The aims of this study were to establish whether: (i) opioid receptor stimulation acts as a trigger ( during the preconditioning protocol) or as a mediator ( during sustained ischaemia) of cardioprotection using either morphine or [D-ala(2), D-leu(5)] enkephalin (DADLE), a synthetic delta-opioid receptor agonist; ( ii) the beneficial effects of DADLE are protein kinase C ( PKC) -mediated; and (iii) inhibitory 'cross-talk' occurs between the beta-adrenergic and phosphatidylinositol pathways activated by release of endogenous catecholamines and opioids respectively during sustained ischaemia. The isolated, perfused working rat heart, subjected to 25 minutes' global ischaemia and 30 minutes' reperfusion, was used as the experimental model. The results showed that delta-opioid receptor stimulation with DADLE (10(-8) M), when administered for 3 x 5 minutes, had no effect, while when given 10 minutes before sustained ischaemia the drug significantly improved functional recovery during reperfusion. This indicates that opioid receptor stimulation acts as a mediator rather than a trigger in the protection elicited. Morphine ( 3 x 10(-7)) when administered in the same manner was without effect. Opioid receptor stimulation caused a marked reduction in the beta -adrenergic response to isoproterenol, indicating inhibitory cross-talk between the phosphatidyl-inositol and beta-adrenergic signal transduction pathways. However, reduction of the beta-adrenergic response to ischaemia does not appear to be the mechanism of opioid-induced protection, as indicated by 3',5' -cyclic adenosine monophosphate (cAMP) levels at the end of 25 minutes' global ischaemia. Opioid receptor-mediated protection against ischaemic damage is PKC-dependent, since DADLE-induced protection could be abolished by the inhibitor chelerythrine.

Adrenergic beta-Agonists↗
PubMed2000

A comparative pilot study of the effects of a dentifrice containing green tea bioflavonoids, sanguinarine or triclosan on oral bacterial biofilm formation.

The aim of the present study was to evaluate the effect of a green tea bioflavonoid/zinc ascorbate-containing dentifrice (Natural Antioxidant Toothpaste) on bacterial plaque biofilm accumulation. Plaque biofilms were formed and observed on saliva-conditioned synthetic hydroxyapatite disks (HA) over 4 days. Two test treatments were performed daily over a 4-day experimental period for a total of 8 treatments. Four test dentifrices were evaluated: a 0.1% bioflavonoid/0.2% zinc ascorbate; a non-active control test dentifrice; a 0.075% sanguinarine/2.0% zinc chloride dentifrice; and a 0.3% triclosan dentifrice. The repeated treatment of the HA with the green tea bioflavonoid/zinc ascorbate, the sanguinarine/zinc chloride, or the triclosan dentifrice resulted in significant reductions in total viable plaque biomass when compared to a non-active placebo control dentifrice.

Alkaloids↗
PubMed1997

[Protective action of corynoline, acetylcorynoline and protopine against experimental liver injury in mice].

Oral administration of two doses of corynoline, acetylcorynoline or protopine at 50 and 100 mg.kg-1 in an interval of 8 to 24 h before i.p. injection of CCl4, acetaminophen or thioacetamide significantly impeded the elevation of serum transaminase (SGPT) and liver damage in mice. The three compounds were found to inhibit CCl4-induced microsomal lipid peroxidation and CCl4 conversing to carbon monoxide in liver microsomes in vitro. Of these compounds, acetylcorynoline was shown to be more potent than corynoline and protopine. In addition, all the three compounds exhibited biphasic effects on the hepatic cytochrome P450, i.e. inhibition followed by induction, in mice.

Acetaminophen↗
PubMed2000

Hypoxic preconditioning upregulates KATP channels through activation of protein kinase C in rat ventricular myocytes.

AIM: To test: 1) if hypoxic preconditioning upregulates the activity of KATP channels in isolated adult rat cardiac myocytes; 2) if the upregulation involves protein kinase C (PKC). METHODS: By the whole-cell patch-clamp recording technique, KATP channel currents (IKATP) were measured in the cardiomyocytes with no pretreatment (CON), hypoxic exposure preceding reoxygenation (HPC), phorbol 12-myristate 13-acetate (PMA), and chelerythrine addition with HPC (CH + HPC), respectively. RESULTS: At 0 mV and 5 min after 2, 4-dinitrophenol (DNP) perfusion, the membrane currents for the CON, HPC, PMA, and CH + HPC were (3.5 +/- 1.9), (7.7 +/- 1.5), (7.5 +/- 3.3), (4.6 +/- 2.4) nA, respectively. Compared with the CON, the IKATP in the HPC and PMA were significantly augmented (P < 0.01) while the IKATP in the CH + HPC remained similar to the CON (P > 0.05). CONCLUSION: 1) hypoxic preconditioning stimulated the activity of PKC and markedly enhanced the activity of KATP channels in the isolated rat cardiac myocytes; 2) PKC activation was involved in the upregulation of KATP channels.

Alkaloids↗
PubMedDate not supplied

Molecular aspects on the interaction of sanguinarine with B-form, Z-form and HL-form DNA structures.

The interaction of sanguinarine with right-handed (B-form), left-handed (Z-form) and left-handed (HL-form) structures of poly(dG-dC).poly(dG-dC) has been investigated by measuring the circular dichroism (CD) and UV-absorption spectral analysis. Sanguinarine binds strongly to the B-form DNA and does not bind to Z-form or HL-form, but it converts the Z-form and the HL-form back to the bound right handed form as evidenced from CD spectroscopy. Sanguinarine inhibits the rate of B to Z transition under ionic conditions that otherwise favour the left-handed conformation of the polynucleotides. UV absorption kinetic studies show that the Z-form reverses back to B-form to B-form on binding to sanguinarine. Binding isotherms obtained from spectrophotometric data show that sanguinarine binds strongly to the B-form polymer in a non-cooperative manner, in sharp contrast to the highly cooperative interaction under Z-form and HL-form polynucleotides. These studies reveal that the alternating GC sequence undergoes defined conformational changes and interacts with sanguinarine which may be an important aspect in understanding its extensive biological activities.

Alkaloids↗
PubMedDate not supplied

Synthesis and biological activity of O-acyl and O-alkyl chelidonine derivatives.

A group of 11 derivatives of chelidonine was obtained by acylations and/or alkylations of the secondary hydroxyl group with the aim of testing their biological activity. This paper focuses on the new derivatives influence on CNS in mice. The highest activity was observed for compounds 2c, 3c and 4, which produced antinociceptive and antiserotoninergic effects, not recorded for the parent alkaloid 1.

Alkaloids↗
PubMed2001

[Determination of nitidine in different parts of Zanthoxylum nitidum].

OBJECTIVE: To determine the nitidine in different parts of Zanthoxylum nitidum (Roxb.) DC. METHODS: HPLC method was used. The column was HYPERSIL BDS C18. The mobile phase was 0.02 mol/L monobasic potassium phosphate: acetonitrile (66:34). The detective wavelength was 328 nm. RESULTS: The average recoveries and RSD for nitidine was 100.24%, 1.83% respectively. The root contained more nitidine than other parts. CONCLUSION: The method can be used for the quality control of Zanthoxylum nitidum (Roxb.) DC. The roots were the best part for medicine.

Benzophenanthridines↗