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PubMed1997

Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores.

The alkaloids berberine, palmatine and sanguinarine are toxic to insects and vertebrates and inhibit the multiplication of bacteria, fungi and viruses. Biochemical properties which may contribute to these allelochemical activities were analysed. Acetylcholine esterase, butyrylcholinesterase, choline acetyl transferase, alpha 1- and alpha 2-adrenergic, nicotinergic, muscarinergic and serotonin2 receptors were substantially affected. Sanguinarine appears to be the most effective inhibitor of choline acetyl-transferase (IC50 284 nM), while the protoberberines were inactive at this target. Berberine and palmatine were most active at the alpha 2-receptor (binding with IC50 476 and 956 nM, respectively). Furthermore, berberine and sanguinarine intercalate DNA, inhibit DNA synthesis and reverse transcriptase. In addition, sanguinarine (but not berberine) affects membrane permeability and berberine protein biosynthesis. In consequence, these biochemical activities may mediate chemical defence against microorganisms, viruses and herbivores in the plants producing these alkaloids.

Acetylcholinesterase↗
PubMed2000

Distribution of morphinan and benzo[c]phenanthridine alkaloid gene transcript accumulation in Papaver somninferum.

The opium poppy Papaver somniferum L. produces the antimicrobial benzo[c]phenanthridine alkaloid sanguinarine and the narcotic analgesic morphinan alkaloid morphine. Transcripts of three genes of alkaloid biosynthesis in P. somniferum in developing seedlings, mature plants and plant cell suspension culture were monitored for temporal/spatial or for methyl jasmonate-induced accumulation by RNA gel blot analysis. These genes encoded (S)-N-methylcoclaurine 3'-hydroxylase (CYP80B1) that is common to morphine and sanguinarine biosynthesis, the berberine bridge enzyme (BBE) that lies on the pathway to sanguinarine, and codeinone reductase (COR) the penultimate enzyme of morphine biosynthesis. In developing P. somniferum seedlings, the morphine precursor thebaine was present throughout the first twenty days of germination. In contrast, sanguinarine was present in detectable quantities only after day five after germination and continued to increase at least until day twenty. Accumulation of cyp80b1, bbe1 and cor1 gene transcripts paralleled these differences. In the mature poppy plant, cyp80b1, bbe1 and cor1 gene transcripts were detected in the root, the stem, the leaf lamina and the leaf mid rib. Only cyp80b1 and cor1, however, were found in the flower bud and the capsule. Consistent with the fact that sanguinarine accumulation, but not that of morphine, can be induced in opium poppy cell suspension culture by addition of methyl jasmonate to the culture medium, cyp80b1 and bbe1, but not cor1 transcript accumulated in response to elicitor treatment.

Alkaloids↗
PubMed1998

Downregulation of protein kinase C by phorbol ester increases expression of epidermal growth factor receptors in transformed trophoblasts and amplifies human chorionic gonadotropin production.

Epidermal growth factor (EGF) and its homologue, transforming growth factor-alpha (TGF-alpha), regulate human chorionic gonadotropin (hCG) synthesis in the human placenta. The current study was designed to investigate the involvement of the protein kinase C pathway in EGF-mediated hCG-beta production by JAr choriocarcinoma cells. Downregulation of protein kinase C activity by chronic exposure to the phorbol ester, phorbol 12,13-dibutyrate (PDB), produced a greater increase in hCG-beta secretion than did activation of protein kinase C activity by short-term exposure to PDB. Pretreatment with the protein kinase C inhibitors calphostin and chelerythrine also resulted in enhanced basal and EGF-stimulated hCG-beta production. Individual concentrations (5 nM EGF and 500 nM PDB) that maximally stimulated hCG production, were additive in combination. The additive effect of PDB on EGF-induced hCG-beta secretion was mediated in part by increased JAr cell EGF-receptor concentrations detected by Western blot and Scatchard analyses. The results suggest that EGF and PDB stimulate hCG production in JAr cells by different but interactive mechanisms. It is speculated that downregulation of protein kinase C stimulates basal and EGF-mediated hCG-beta production by uninhibiting other signalling pathways that regulate hCG-beta secretion in trophoblasts.

Alkaloids↗
PubMed2004

Exocytosis of a complement component C3-like protein by tunicate hemocytes.

This study investigates the exocytic responses of invertebrate hemocytes to pathogen-associated antigens. It demonstrates that a homologue of complement component C3, a key defensive protein of the innate immune system, is expressed by phagocytic hemocytes (non-refractile vacuolated cells) of the tunicate, Styela plicata. C3-like molecules are localized in sub-cellular vesicles and are rapidly exocytosed after stimulation with bacterial, fungal or algal cell surface molecules. Signal transduction analysis indicated that the induced secretion of C3-like molecules is mediated by a G-protein dependent signaling pathway, which modulates tubulin microtubules. All of this evidence indicates that hemocytes can contribute to host defense responses by rapidly exocytosing C3-like proteins at sites of infection.

Alkaloids↗
PubMed2003

A double-lumen intrathecal catheter for studies of modulation of spinal opiate tolerance.

Studies of spinal opioid tolerance frequently employ a spinal infusion model in which a single-lumen intrathecal (IT) catheter is connected to an osmotic mini pump. We have modified this model by developing a double-lumen catheter system that permits continuous delivery of the toleragen to the IT space and allows for examination of the effects of concurrent IT drug administration without interruption of the ongoing infusion. The catheter is constructed of two pieces of PE10 tubing fused to the lumens of a dual-lumen catheter (8 cm) with one PE10 tube used as an infusion line connected to an osmotic pump and the other for injection. The catheter is inserted through the cisterna magna. Most implanted rats (66 out of 73) showed full recovery of motor and sensory function without detectable neurological deficit. The profile of the tolerance development and the response to drug manipulation using the double-lumen catheter are similar to previous findings in the spinal infusion model which used a single-lumen catheter. Most importantly, we demonstrate that concurrent probe drug testing and/or concurrent drug treatment can be achieved without interruption of spinal infusion of morphine. Using the double-lumen catheter model expands the range of possibility for studies of spinal opiate tolerance and spinal drug delivery.

2-Amino-5-phosphonovalerate↗
PubMed2000

Transforming growth factor-beta1 regulation of resting zone chondrocytes is mediated by two separate but interacting pathways.

Previous studies have shown that transforming growth factor-beta1 (TGF-beta1) stimulates protein kinase C (PKC) via a mechanism that is independent of phospholipase C or tyrosine kinase, but involves a pertussis toxin-sensitive G-protein. Maximal activation occurs at 12 h and requires new gene expression. To understand the signaling pathways involved, resting zone chondrocytes were incubated with TGF-beta1 and PKC activity was inhibited with chelerythrine, staurosporine or H-7. [(35)S]Sulfate incorporation was inhibited, indicating that PKC mediates the effects of TGF-beta1 on matrix production. However, there was little, if any, effect on TGF-beta1-dependent increases in [(3)H]thymidine incorporation, and TGF-beta1-stimulated alkaline phosphatase was unaffected, indicating that these responses to the growth factor are not regulated via PKC. TGF-beta1 caused a dose-dependent increase in prostaglandin E(2) (PGE(2)) production which was further increased by PKC inhibition. The increase was regulated by TGF-beta1-dependent effects on phospholipase A(2) (PLA(2)). Activation of PLA(2) inhibited TGF-beta1 effects on PKC, and inhibition of PLA(2) activated TGF-beta1-dependent PKC. Exogenous arachidonic acid also inhibited TGF-beta1-dependent increases in PKC. The effects of TGF-beta1 on PKC involve genomic mechanisms, but not regulation of existing membrane-associated enzyme, since no direct effect of the growth factor on plasma membrane or matrix vesicle PKC was observed. These results support the hypothesis that TGF-beta1 modulates its effects on matrix production through PKC, but its effects on alkaline phosphatase are mediated by production of PGE(2) and protein kinase A (PKA). Inhibition of PKA also decreases TGF-beta1-dependent proliferation. We have previously shown that PGE(2) stimulates alkaline phosphatase through its EP2 receptor, whereas EP1 signaling causes a decrease in PKC. Thus, there is cross-talk between the two pathways.

Alkaline Phosphatase↗
PubMed2001

Protein kinase C regulation of cell spreading in the molluscan Biomphalaria glabrata embryonic (Bge) cell line.

Cellular adhesion and spreading are critical components involved in the processes of cell and tissue development, and immune responses in molluscs, but at present, little is known regarding the signaling pathways involved in these basic cellular functions. In the present study, the molluscan Biomphalaria glabrata embryonic (Bge) cell line was used as an in vitro model to study the signal transduction pathways regulating molluscan cell adhesion and spreading behavior. Western blot analysis using antibodies specific to mitogen-activated protein kinase (MAPK) revealed the presence of an MAPK-like immunoreactive protein in Bge cells, that was phosphorylated upon exposure to phorbol myristate acetate (PMA). Moreover, Bge cell treatment with inhibitors of protein kinase C (PKC), Ras and MAPK kinase (Mek) suppressed PMA-induced expression of activated MAPK, suggesting that PKC-, Ras- and Mek-like molecules may be acting upstream of MAPK. Similarly, in vitro Bge cell-spreading assays were performed in conjunction with the same panel of inhibitors to determine the potential involvement of PKC, Ras and Mek in cellular adhesion/spreading. Results revealed a similar pattern of inhibition of cell-spreading behavior strongly implying that the Bge cell spreading also may be regulated through a MAPK-associated signal transduction pathway(s) involving proteins similar to PKC, Ras and Mek.

Alkaloids↗
PubMed1997

Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation.

We have previously demonstrated an obligatory requirement for intracellular reactive oxygen species generation during T lymphocyte activation, and have proposed that intracellular reactive oxygen species may act as signalling agents in the regulation of certain cellular processes, for example, during cell cycle entry. To test this hypothesis, we have been interested to determine which, if any, cell cycle entry events are affected by oxidative signalling. In earlier studies, we have identified the transcription factors NF-kappa B and AP-1 as molecular targets for oxidative signalling processes during cell cycle entry, and have shown that oxidative signalling is involved in the regulation of early changes in gene expression during the G0 to G1 phase transition. To extend these initial observations, we have examined the effect of antioxidant treatment on the activity of the mitogen-activated protein kinases erk1 and erk2, as members of a signal transduction pathway known to directly regulate transcription factor function. Using as a probe cysteamine, an aminothiol compound with both antioxidant and antiproliferative activity, we have identified erk2, a key element of the MAP kinase pathway, as being responsive to oxidative signalling during lymphocyte activation. These observations provide further evidence to suggest a role for intracellular oxidant generation as a regulatory mechanism during cell cycle entry, and establish a link between oxidative signalling and other aspects of the intracellular signalling network that is activated in response to mitogenic stimulation.

Alkaloids↗
PubMed2001

Differentiation of bipolar CG-4 line oligodendrocytes is associated with regulation of CREB, MAP kinase and PKC signalling pathways.

Undifferentiated bipolar CG-4 cell line oligodendrocytes provide a model system for the O-2A progenitor cell from which oligodendrocytes are derived both in vivo and in vitro. The exchange of neuroblastoma conditioned basal media for basal media causes differentiation of undifferentiated bipolar CG-4 cells into multipolar oligodendrocyte-like cells whilst replacement with basal media containing 20% foetal bovine serum favours the formation of type-2 astrocyte-like cells. Here, we demonstrate that activation of these differentiation pathways correlates with distinct changes both in cell metabolism and in signal transduction. Exchange of neuroblastoma conditioned media for basal media correlates with stimulation of basal metabolic activity, reduced phosphorylation of p44/42 MAP kinase and reduced phosphorylation of the transcription factor CREB. In contrast, differentiation with basal medium containing 20% foetal bovine serum (FBS), into type 2 astrocyte-like cells, correlates with reduction in basal metabolic activity, increased phosphorylation of p44/42 MAP kinase and increased phosphorylation of the transcription factor CREB. Inhibition of protein kinase C blocked both the metabolic and morphological changes associated with differentiation towards mature multipolar oligodendrocyte-like cells. Inhibition of PKA and MEK did not effect metabolic activity. The rapid return of neuroblastoma conditioned basal media to cells treated with basal media, increased phosphorylation of CREB and MAP kinase. These results demonstrate that protein kinase C and p44/42 MAP kinase signalling pathways are modulated during bipolar CG-4 cell differentiation and demonstrate that the transcription factor CREB may play a pivotal role in differentiation along oligodendrocyte-or astrocyte-lineages.

Alkaloids↗
PubMed1998

Gene expression in the electrically stimulated differentiation of PC12 cells.

Cell differentiation of PC12 cells was electrically induced to grow neurites in the absence of nerve growth factor (NGF) on the electrode surface, of which potential was modulated by a rectangular wave of potential. The electric stimulation induced the c-fos expression which is essential for cell differentiation. Non-specific calcium channel blocker, lanthanum ion, inhibited the electrically induced differentiation, while NGF-induced differentiation was not suppressed. An L-type calcium channel blocker, nifedipine, also inhibited the electrically induced calcium influx and c-fos expression. Moreover, a stretch-activated (SA) channel blocker, gadolinium ion, inhibited the electrically stimulated differentiation by blocking the calcium influx, but gave no prominent effects on the potassium ion-induced differentiation. Chelerythrine, a specific protein kinase C (PKC) inhibitor, almost inhibited the cell differentiation by the electric stimulation but not by the NGF treatment. These results indicate that the alternative potential may stimulate cell differentiation through a PKC cascade.

Alkaloids↗
PubMed1999

Endothelin-1 stimulates c-fos mRNA expression in C6 glioma cells via MAP kinase pathway.

Exposure of C6 glioma cells to endothelin-1 (ET-1) caused dose-dependent (10(-11) M to 10(-7) M) increments in intracellular calcium concentration ([Ca2+]i) and c-fos mRNA expression (4.5-fold) that were abolished by the endothelinA receptor antagonist, BQ610, and by inhibition of phospholipase C with U73122. ET-1 stimulated c-fos mRNA expression was also inhibited by protein kinase C inhibition (chelerythrine) and by the MAP kinase kinase inhibitor PD98059, but not by inhibitors of tyrosine kinases, protein kinase A type I or II, calmodulin kinase II, or calcium channel blockade. C6 cells treated with ET-1 demonstrated a significant increase in MAP kinase activity as evidenced by Western blotting. These results indicate a mechanism of long-term signaling by ET-1 involving an ET(A) receptor-mediated, phospholipase C(beta)-linked pathway that is dependent on protein kinase C and MAP kinase activation.

Alkaloids↗
PubMed2003

PMA decreases the proliferation of retinal cells in vitro: the involvement of acetylcholine and BDNF.

Protein kinase C (PKC) is involved in several cell events including proliferation, survival and differentiation. The aim of this work was to investigate the role of PKC activation on retinal cells proliferation. We demonstrated that PKC activation by phorbol 12-myristate 13-acetate (PMA), a tumor promoter phorbol ester, is able to decrease retinal cells proliferation. This effect was mediated by M1 receptors and dependent on intracellular Ca(2+) increase, tyrosine kinase activity, phosphatidylinositol 3-kinase activity, polypeptide secretion and activation of TrkB receptors. The effect of PMA was not via activation of mitogen-activated protein (MAP) kinase. Carbamylcholine and brain derived neurotrophic factor were both able to decrease retinal cells proliferation to the same level as PMA did. Our results suggest that PKC activation leads to a decrease in retinal cells proliferation through the release of acetylcholine and brain derived neurotrophic factor in the culture, and activation of M1 and TrkB receptors, respectively.

Acetylcholine↗
PubMed2001

17beta-oestradiol stimulates capacitative Ca2+ entry in human endometrial cells.

Oestrogen plays an essential role in regulating growth and differentiation in the human endometrium which undergoes dynamic morphological and functional changes during the menstrual cycle in preparation for implantation. In this tissue, it has been suggested that intracellular calcium could be a key signal in transducing early responses to steroid hormones. Here, we have investigated the rapid effects of 17beta-oestradiol on [Ca2+]i in a human endometrial cell line (RL95-2). Using confocal imaging microscopy, we show that physiological concentrations of 17beta-oestradiol trigger rapid and transient increases in [Ca2+]i. Our results demonstrate that 17beta-oestradiol-induced [Ca2+]i variations are critically dependent on calcium influx via lanthanum-sensitive calcium channels. Moreover, the 17beta-oestradiol-induced Ca2+ influx is significantly increased by the depletion of intracellular stores by thapsigargin and decreased by chelerythrine chloride, an inhibitor of protein kinase C. These data indicate a non-genomic action of 17beta-oestradiol to stimulate capacitative Ca2+ entry through store-operated calcium channels via a PKC-sensitive pathway.

Alkaloids↗
PubMed2003

Effects of a phorbol ester and cyclosporin A on hippocampal synaptic plasticity in streptozotocin-induced-diabetic rats: reduced sensitivity to phorbol esters.

In streptozotocin-induced diabetic (STZ-diabetic) rats, an animal model of diabetes mellitus, a reduced expression of long-term potentiation (LTP) and enhanced long-term depression (LTD) are observed. This study examined the role of protein kinase C (PKC) and protein phosphatase 2B in hippocampal synaptic transmission in STZ-diabetic rats. The phorbol ester 4beta-phorbol-12,13-dibutyrate (PDB) induced a concentration-dependent potentiation of synaptic responses in area CA1 that could partially be inhibited by the PKC inhibitor chelerythrine. In slices from STZ-diabetic rats the effectivity of PDB to increase synaptic transmission was reduced compared to slices from control animals. In STZ-diabetic rats the protein phosphatase 2B (PP2B) inhibitor cyclosporin A inhibited LTD induction, but did not affect the induction of LTP. In conclusion, these data show a reduced response to PDB in STZ-diabetic rats, and indicate that the lack of LTP induction in these animals is not due to increased PP2B activity.

Alkaloids↗
PubMed1997

Activation and inhibition of protein kinase C protect rat neuronal cultures against ischemia-reperfusion insult.

The effect of activation and inhibition of protein kinase C (PKC) on the capacity of neurons to resist subsequent ischemic and ischemia-reperfusion-induced cell injury, was studied in a model of primary rat neuronal cultures, subjected to chemical ischemia. Activation of PKC by 1,2 dioctanoyl-rac-glycerol (DOG; 1 microM), or phorbol 12-myristate 13-acetate (PMA; 1 microM), as well as inhibition of the enzyme by chelerythrine (10 microM), or by calphostin C (0.2 microM), 10 min before the ischemic insult, resulted in acquisition of resistance against the two insults. The length of the 'time window of protection' induced by exposure to DOG and to chelerythrine was studied and found to last for several days. The results demonstrate an apparently 'paradoxical' phenomenon, in which both activation and inhibition of PKC in the same tissue induce protection. This may be explained by differential activation of various PKC isoforms.

Alkaloids↗
PubMed1999

Protein kinase C inhibition has only a transient growth arresting effect on in vitro regenerating mouse sensory neurons.

Adult mice sensory ganglia were cultured in an extracellular matrix gel. Analyses of extending axons were made 48 h (long-term) or immediately (short-term) after addition of protein kinase inhibitors. Long- and short-term growth was insensitive to protein kinase A/G inhibition by HA-1004. Long-term protein kinase C inhibition by chelerythrine affected only certain, long axons. In the short-term virtually all axon growth was arrested, but largely recovered on the following day. When combined, the drugs inhibited all long- and short-term growth and largely prevented the recovery of the latter. The transient effect by chelerythrine, and the permanent inhibition after combination with HA-1004, suggests compensatory mechanisms, perhaps via other kinases.

Alkaloids↗
PubMed2000

Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion.

It has been hypothesized that spinal morphine tolerance results from protein kinase C (PKC) mediated phosphorylation. Chronic lumbar intrathecal (i.t.) infusion of morphine (20 nmol/microl/h) was shown to produce antinociception on day 1 (d1) that disappeared by d5 (tolerance). On d6, a bolus i.t. probe dose of morphine (60 nmol) produced a more profound antinociception in saline-infused rats than in morphine-infused rats. Coinfusion of morphine with a PKC inhibitor, chelerythrine, prevented tolerance to the probe morphine dose. Bolus i.t. chelerythrine or GF109203X (GF), another PKC inhibitor, on d5, but not the inactive homologue of GF Bisindolymaleimide V, also blocked development of tolerance after 24 h. I.t. morphine infusion, but not saline, produced a 2-fold increase in dorsal horn PKC phosphorylating activity and in the expression of PKCalpha/gamma. Bolus chelerythrine on d5 after spinal morphine infusion blocked upon an increase in PKC activity, confirming that at the behaviorally active dose the drug had the intended biochemical effect upon spinal PKC activity. PKC activity and protein expression did not change when assessed 1 h after bolus i.t. morphine in naive rats. Thus, tolerance produced by morphine infusion is dependent upon an increase in local phosphorylating activity by PKC. Blocking the PKC activity prevents expression of the morphine tolerance.

Alkaloids↗
PubMed2001

Hemicholinium-3 mustard reveals two populations of cycling choline cotransporters in Limulus.

Cholinergic neurons have both a low-affinity and a high-affinity choline transport process. The high-affinity choline transport is sodium dependent and thus it can be referred to as choline cotransport. Choline cotransport has been shown to be up-regulated by neuronal activity. Protein kinase C has also been shown to regulate choline cotransport. Both forms of regulation appear to modulate transport by altering the numbers of choline cotransporters in the nerve terminal membrane. The present study centers on choline cotransporter trafficking in Limulus brain hemi-slice preparations. The competitive, reversible, non-permeant ligand, [3H]hemicholinium-3, was used in binding studies to estimate the relative number of choline cotransporters in plasma membranes. The hemicholinium-3 mustard derivative has been shown to be an irreversible, highly selective, non-permeant ligand for the choline cotransporter, and was also used. Hemicholinium-3 mustard binding to the choline cotransporter blocked [3H]choline transport and [3H]hemicholinium-3 binding. Antecedent elevated potassium exposure of cholinergic tissues has been shown to up-regulate choline transport by the recruitment of additional choline cotransporters to surface membranes. This treatment was also effective in the recruitment of cotransporters following maximal inhibition by hemicholinium-3 mustard of brain hemi-slices. Long-term washout of hemicholinium-3 mustard in hemi-slices resulted in a time-dependent restoration of choline cotransport. Full recovery occurred within 2h. In uninhibited slice preparations, both staurosporine and chelerythrine, protein kinase C inhibitors, stimulated choline uptake. However, within a 1-h washout recovery of uptake following hemicholinium-3 mustard inhibition, the staurosporine responsive but not chelerythrine responsive transport had returned. On the basis of these findings, we hypothesize the existence of two distinct populations of cycling choline cotransporters, which includes inactive or "silent" transporters.

Alkaloids↗