Interaction of sanguinarine with human serum albumin.
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Alkaloids↗
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Signaling by hemolytically inactive C5b67, an agonist of polymorphonuclear leukocytes.
The hemolytically inactive complement component complex C5b67, designated iC5b67, can signal human polymorphonuclear leukocytes (PMN) both as a pertussis toxin-inhibitable agonist for chemotaxis and as an antagonist for C5a- and FMLP-stimulated chemotaxis and superoxide production. The signaling pathways utilized by iC5b67 have been further investigated. In contrast to mastoparan, iC5b67 failed to directly activate G proteins to stimulate inositol phosphate formation in COS cells that had been transfected with G alpha 16. In COS cells co-transfected with both G alpha 16 and the C5a receptor, iC5b67 could neither activate phospholipase C nor inhibit C5a receptor-mediated activation of phospholipase C. iC5b67 stimulated GTPase activity in a membrane-enriched fraction from PMN. These data support the hypothesis that iC5b67 signals through a unique receptor, likely G protein linked, but distinct from the C5a receptor. iC5b67 was able to mobilize intracellular stores to elicit increases in intracellular Ca2+. Based on the effects of herbimycin A, wortmannin, and chelerythrine on iC5b67-induced PMN chemotaxis, iC5b67 signaling involved activation of tyrosine and phosphatidylinositol 3-kinases, but not protein kinase C. Relevant to the capacity of iC5b67 to antagonize PMN superoxide production, iC5b67 induced rapid and sustained increases in intracellular cAMP, which others have shown can inhibit superoxide formation. Although iC5b67 antagonizes C5a and FMLP receptor-mediated superoxide generation, iC5b67 had no effect on PMA-induced superoxide formation. The distinct agonist and antagonist signaling pathways activated by iC5b67 in the PMN diverge soon after initial iC5b67 receptor-mediated transduction steps.
Alkaloids↗
Role of c-jun in human myeloid leukemia cell apoptosis induced by pharmacological inhibitors of protein kinase C.
Recent study results suggest that protein kinase C [PKC (EC 3.1.4.3)] -dependent up-regulation of c-jun may be involved in leukemic cell programmed cell death, or apoptosis, occurring in response to various chemotherapeutic agents. The current study was undertaken to further evaluate the contribution of c-jun in apoptosis with the use of two highly specific pharmacological inhibitors of PKC (calphostin C and chelerythrine). To address this issue, two human leukemic cell lines, HL-60 and U937, and a U937 subline stably expressing a dominant negative c-jun mutant (TAM67) were exposed to calphostin C and chelerythrine, and c-jun expression was monitored at both the mRNA and protein levels. Both PKC inhibitors induced the classic morphological features of apoptosis as well as internucleosomal DNA degradation in a concentration- and schedule-dependent manner. Concomitant with these changes, unequivocal increases were observed in c-jun mRNA (U937 and HL-60) and protein (U937). In contrast, up-regulation of c-jun mRNA and protein in TAM67-expressing cells exposed to both PKC inhibitors was markedly attenuated relative to effects observed in parental U937 cells. Importantly, despite impaired up-regulation of c-jun at both the message and protein levels, TAM67-expressing cells were equally susceptible to PKC inhibitor-induced apoptosis as parental and empty vector U937 cells. Collectively, these findings raise the possibility that c-jun up-regulation in human myeloid leukemia cells undergoing PKC inhibitor-associated apoptosis represents a response to, rather than a cause of, apoptotic events. They further suggest that this phenomenon involves pathways that do not require PKC activation.
Alkaloids↗
Subgingival irrigation effects of chlorhexidine or sanguinarine on gingivitis in orthodontic patients.
This clinical investigation examined the effect of a single subgingival irrigation of chlorhexidine 0.2% or sanguinarine on gingivitis affecting orthodontically banded first molars in adolescent patients. Eighteen patients with gingivitis participated in the study. Probing depth, papilla bleeding index and plaque index were recorded at four sites for three molars at baseline, 2 weeks and 4 weeks by one investigator. A second investigator irrigated a single application of 3 ml of either chlorhexidine, sanguinarine or saline. The gingival bleeding as determined by papilla bleeding index was almost eliminated in the 4 week period. A reduction of the plaque index and probing depth was observed in all three groups. A significant difference related to probing depth between the effect of saline and chlorhexidine (p<0.01) was noted.
Adolescent↗
Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase.
We report that WEHI-231 undergo apoptosis following exposure to the protein kinase C inhibitors chelerythrine chloride and calphostin C. Following the addition of chelerythrine or calphostin C to WEHI-231 cells, ceramide production increased over baseline levels with a concurrent decrease in sphingomyelin. More detailed examinations determined that the ceramide accumulation resulted from activation of neutral, but not acidic, sphingomyelinase. These results suggest an antagonistic relationship between protein kinase C activity and ceramide in the signaling events preceding apoptosis.
Alkaloids↗
Benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine: biological activities and dental care applications.
This article reviews chemical, pharmacological, and toxicological research relating to two principal benzo[c]phenanthridine alkaloids, namely sanguinarine and chelerythrine, in the period 1980-1994. The medical applications of these alkaloids in relation to their biological activities are discussed.
Alkaloids↗
Alcohol-containing mouthwasheses: effect on composite color.
This study investigated whether commercially available mouthwashes could affect or change the color of a hybrid composite resin. Twenty-four disks were fabricated and divided into eight equal groups for testing. At baseline, six colorimetric recordings and color parameters (L*, a*, b*) were recorded for each grouping of disks using a Chroma Meter CR-300 in reflectance mode. The groups of disks were immersed in their respective mouthwashes for 2 minutes a day in a vibratory fashion over a 6-month period. At the end of 6 months, color differences, delta E, were calculated between the base line and test recordings. The results indicate that rinsing with mouthwashes for 6 months can cause a hybrid resin to undergo color variations. Except for one product the color variations were not clinically significant.
Alkaloids↗
[Cell cultured of Macleaya cordata--a producer of antimicrobial benzo[c]phenanthridine alkaloids].
It was shown that a suspension culture of Macleaya cordata accumulated benzo(c)phenanthridine alkaloids in the cell biomass. By the composition of the alkaloids and their content the cell culture markedly differed from the intact plant and callus tissue. The benzo(c)phenanthridine compounds in the cell culture were mainly represented by the reduced forms: dihydrosanquinarin and dihydrochelirubin. In the green plant they were mainly represented by the oxidized forms: sanquinarin and chelerithrin. The cell culture practically contained no chelerithrin characteristic of the intact plant.
Alkaloids↗
Effect of quaternary benzo[c]phenanthridine alkaloids sanguinarine, chelerythrine and fagaronine on some mammalian cells.
The effects of benzo[c]phenanthridine alkaloids sanguinarine (SA), chelerythrine (CHE), fagaronine (FA) and their dihydroderivates were tested on human leukocytes and lymphocytes, rat peritoneal mastocytes and primary cultured hepatocytes. The cytotoxicity of SA and CHE on hepatocytes is dose (35-100 microM) and time (1-3 h) dependent. Both alkaloids decrease chemiluminiscence of leukocytes and inhibit a creation of active E-rosets. The degranulation of mastocytes is inhibited only by CHE. Dihydroderivates of SA and CHE did not display any effect on studied cells, dihydrofagaronine exhibits a hepatotoxicity after 3 h.
Alkaloids↗
Protein kinase C inhibitor, chelerythrine, potentiates the adrenaline-mediated aggregation of human platelets through calcium influx.
The role of protein kinase C (PKC) using its selective inhibitor, chelerythrine, in agonist mediated platelet aggregation was studied. Chelerythrine had no effect on the aggregation induced by adrenaline, PAF, collagen and ADP at the maximum doses of these agonists. However, it potentiated the aggregatory response of low doses of adrenaline (0.4-1 microM). Such an effect was blocked by Ca(++)-channel blockers, verapamil and diltiazem indicating the likely involvement of Ca++ influx in the platelet aggregation during the cascade.
Adrenergic alpha-Agonists↗
Bidirectional regulation of protein kinase M zeta in the maintenance of long-term potentiation and long-term depression.
Long-term potentiation (LTP) and long-term depression (LTD) are persistent modifications of synaptic efficacy that may contribute to information storage in the CA1 region of the hippocampus. Persistently enhanced phosphorylation has been implicated in the maintenance phase of LTP. This hypothesis is supported by our previous observation that protein kinase M zeta (PKM zeta), the constitutively active catalytic fragment of a single protein kinase C isoform (PKC zeta), increases in LTP maintenance. In contrast, dephosphorylation may be important in LTD maintenance, because phosphatase inhibitors reverse established LTD, in addition to blocking its induction. Because phosphorylation is determined by a balance of phosphatases and kinases, both increases in phosphatase activity and decreases in kinase activity could contribute to LTD. We now report that the reduction of protein kinase activity by H7, as well as selective inhibition of PKC by chelerythrine, mimics and occludes the maintenance phase of homosynaptic LTD in rat hippocampal slices. Conversely, saturated LTD occludes the synaptic depression caused by chelerythrine. Biochemical analysis demonstrates a decrease of PKM zeta, as well as PKCs gamma and epsilon, in LTD maintenance and a concomitant loss of constitutive PKC activity. LTD and the downregulation of PKM zeta are prevented by NMDA receptor antagonists and Ca(2+)-dependent protease inhibitors. Both LTD and the downregulation of PKM zeta are reversible by high-frequency afferent stimulation. Our findings indicate that the molecular mechanisms of LTP and LTD maintenance are inversely related through the bidirectional regulation of PKC.
Alkaloids↗
Endothelin-1 can reduce infarct size through protein kinase C and KATP channels in the isolated rat heart.
OBJECTIVE: Protection from ischaemic preconditioning (IP) is dependent on activation of protein kinase C (PKC), and preconditionings protection can be mimicked by stimulation of various membrane receptors which are known to activate PKC. It is well known that KATP channel activation is cardioprotective. We tested the hypothesis that preischaemic treatment with endothelin-1 (ET-1) can protect against infarction by a PKC-dependent mechanism and by activating KATP channels. METHODS: Buffer-perfused isolated rat hearts were subjected to 30 min regional ischaemia and 120 min reperfusion. Risk zone was determined by fluorescent particles, and infarct size by TTC staining. RESULTS: Treatment with ET-1 in a dose of 1 nM prior to ischaemia significantly reduced infarct size in % of the risk zone compared to the control group (infarct size: 14.1 +/- 2.6 vs. 41.9 +/- 3.4%), while ET-1 0.1 nM did not protect (infarct size: 40.9 +/- 3%). AS the protective dose of ET-1 resulted in a significant reduction of coronary flow, a control group with a similar preischaemic flow-reduction was included (infarct size: 48.1 +/- 4.2%). Both the nonselective ETA/ETB receptor antagonist bosentan (1 microM) and the ET(A)-receptor-selective antagonist BQ 123 (2 microM) abolished protection from ET-1 (infarct size: 43.3 +/- 3.5 and 41.3 +/- 3.3%, respectively), as did the PKC inhibitor chelerythrine (2 microM) (infarct size: 41.1 +/- 5.2%) and the KATP blocker 5-hydroxydecanoate (infarct size: 41.7 +/- 2.9%). None of the ET receptor antagonists bosentan and BQ-123 influenced infarct size alone (infarct size: 42.7 +/- 2.5 and 41.3 +/- 3.3%, respectively). IP, similarly to ET-1, reduced infarct size (infarct size: 6.1 +/- 1.4%), but the nonselective ET receptor antagonist bosentan did not interfere with preconditioning's protection (infarct size: 13.2 +/- 4.3%). CONCLUSIONS: ET-1 treatment prior to ischaemia can protect against infarction via ETA receptors by a PKC-dependent mechanism and by activating KATP channels, but ET does not mediate IP in the isolated rat heart.
Alkaloids↗
Loss of ceramide production confers resistance to radiation-induced apoptosis.
Ionizing radiation mediates cell death, in part, through chromosomal damage following one or more cell divisions. X-rays also induce programmed cell death (apoptosis) in some cell types both in vitro and in vivo. Both neutral and acidic sphingomyelinases, which generate the lipid second messenger ceramide, are reported to induce apoptosis following ionizing radiation and other death signals such as tumor necrosis factor alpha and Fas ligand. Herein we report that a loss of ceramide production from a neutral sphingomyelinase generates a radioresistant phenotype as measured by a marked decrease in apoptosis. A WEHI-231 subline made deficient in ceramide production was found to be resistant to apoptosis compared with the parental subline following treatment with X-rays. The resistant subline underwent two to three subsequent cell divisions following X-irradiation, confirming that X-rays induce cell death through both mitotic and apoptotic mechanisms. These data suggest that loss of ceramide production following X-rays represents an extranuclear mechanism for the development of radioresistance. Modulation of extranuclear signals may increase tumor cell killing following radiation and represent new cellular targets for cancer therapy.
Alkaloids↗
Effects of substances affecting protein kinase C on histamine-evoked stimulation of cyclic AMP formation in chick cerebral cortex.
In membrane preparation of chick cerebral cortex, HA (histamine) did not affect both basal and forskolin-stimulated adenylyl cyclase activity. However, in slices of chick cerebral cortex prelabeled with [3H]adenine, HA, as well as 2-methylHA, 4-methylHA, and N alpha-methylHA, potently increased [3H]cyclic AMP accumulation in a concentration-dependent manner. The stimulatory effect of the HA-ergic compounds on cyclic AMP formation was antagonized by HA H2-receptor blockers (aminopotentidine, ranitidine), and by chelerythrine (50 microM), a potent and selective inhibitor of PKC (protein kinase C). Of the two other tested PKC inhibitors H-7 (100 microM) significantly reduced the HA action, while the effect of staurosporine (1 microM) did not reach the level of statistical significance. Preincubation of chick cerebral cortical slices with a PKC activator, PDB (4 beta-phorbol 12,13-dibutyrate, 1 microM), markedly enhanced the accumulation of cyclic AMP evoked by HA, 2-methylHA, 4-methylHA and N alpha-methylHA. 4 beta-Phorbol, inactive on PKC, was ineffective. A possible role of PKC in the regulation of HA-induced cyclic AMP synthesis in chick cerebrum has been discussed.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
In vitro effects of alcohol-containing and alcohol-free mouthrinses on microhardness of some restorative materials.
Daily application of mouthrinses has been recommended for the prevention and control of caries and periodontal disease. The aim of this study was to evaluate the effect of alcohol-containing and alcohol-free mouthrinses on the microhardness of three restorative materials. Materials tested included visible light cured (VLC) composite resin (Amelogen), VLC glass-ionomer cement (Fuji II LC) and a fissure sealant (Ultra Seal XT). Eighteen cylinders of each restorative were fabricated and initially stored in distilled water for 24 h. Six samples of the restoratives were stored for 12 hours to simulate a 2 min/day for 1 year exposure to mouthrinses in the following solutions: distilled water (control), alcohol-containing mouthrinse (Viadent) and alcohol-free mouthrinse (Rembrandt). At the end of the test period microhardness was measured with a Tukon microhardness tester. Kruskal-Wallis one-way analysis of variance was used to analyse the data. Both mouthrinses affected the hardness of the materials tested.
Alkaloids↗
Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway.
We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.
Alkaloids↗
Cholera toxin triggers apoptosis in human lung cancer cell lines.
Cholera toxin (ChT) inhibits signals generated by multiple growth factors in human lung cancer cells, resulting in cell growth inhibition. We now report that ChT triggers apoptosis as shown by DNA fragmentation and activation of caspases cleaving poly(ADP-ribose) polymerase and lamin B. Apoptosis induced by ChT in a small cell lung cancer cell line is not affected by manipulations of intracellular cAMP through preincubation with isobutylmethylxanthine but can be modestly increased through inhibition of protein kinase C with chelerythrine. Thus, apoptosis is actively suppressed in lung cancer cells by a ChT-sensitive-growth regulatory pathway, and these observations may have significant implications in the development of novel strategies for lung cancer treatment.
1-Methyl-3-isobutylxanthine↗
Chelerythrine inhibits the secretory response of human blood platelets without specifically inhibiting protein kinase C.
Chelerythrine (chloride) has previously been documented to be a potent and selective inhibitor of the serine/threonine-specific protein kinase C (PKC). In this study, it was shown that 10 microM chelerythrine completely inhibited serotonin secretion and partially inhibited phosphatidic acid formation in human blood platelets activated by thrombin (1U/ml). However, there was no effect on PKC activity as assessed by the level of phosphorylation of the 47K protein. Therefore, chelerythrine has been shown not to be a specific inhibitor of PKC. Without specifically affecting PKC activity, it is nevertheless capable of completely inhibiting platelet secretion, indicating that it may affect the signal transduction pathway responsible for platelet secretion at a point downstream or independent of PKC.
Alkaloids↗