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PubMed2005

Efficient induction of ginsenoside biosynthesis and alteration of ginsenoside heterogeneity in cell cultures of Panax notoginseng by using chemically synthesized 2-hydroxyethyl jasmonate.

Chemically synthesized 2-hydroxyethyl jasmonate (HEJA) was for the first time employed to induce the ginsenoside biosynthesis and to manipulate the product heterogeneity in plant cell cultures. The dose response and timing of HEJA elicitation were investigated in cell suspension cultures of Panax notoginseng. The optimal concentration and timing of HEJA addition for both cell growth and ginsenoside accumulation was identified to be 200 microM added on day 4. It was interestingly found that HEJA could stimulate ginsenosides biosynthesis and change their heterogeneity more efficiently than methyl jasmonate (MJA), i.e., the total ginsenoside content and the Rb/Rg ratio increased about 60 and 30% with HEJA elicitation than that by MJA, respectively. The activity of Rb1 biosynthetic enzyme, i.e., UDPG-ginsenoside Rd glucosyltransferase (UGRdGT), was also higher in the former case. A maximal production titer of ginsenoside Rg1, Re, Rb1, and Rd was 47.4+/-4.8, 52.3+/-4.4, 190+/-18, and 12.1+/-2.5 mg/l with HEJA elicitation, which was about 1.3-, 1.3-, 1.7-, and 2.1-fold than that using MJA, respectively. Early signal events in plant defense response, including oxidative burst and jasmonic acid (JA) biosynthesis, were also examined. Levels of H2O2 and NO in medium and L-phenylalanine ammonia lyase activity in cells were not affected by addition of MJA and HEJA. On the other hand, the JA content in cells was increased with external jasmonates elicitation, and it was inhibited with the addition of JA biosynthesis inhibitors. The results suggest that oxidative burst might not be involved in the jasmonates-elicited signal transduction pathway, and MJA and HEJA may induce the ginsenoside biosynthesis via induction of endogenous JA biosynthesis and key enzymes (such as UGRdGT) in the ginsenoside biosynthetic pathway of P. notoginseng cells. The information is useful for hyperproduction of plant-specific heterogeneous products.

Acetates↗
PubMed2006

Regulation of avilamycin biosynthesis in Streptomyces viridochromogenes: effects of glucose, ammonium ion, and inorganic phosphate.

Effects of glucose, ammonium ions and phosphate on avilamycin biosynthesis in Streptomyces viridochromogenes AS4.126 were investigated. Twenty grams per liter of glucose, 10 mmol/L ammonium ions, and 10 mmol/L phosphate in the basal medium stimulated avilamycin biosynthesis. When the concentrations of glucose, ammonium ions, and phosphate in the basal medium exceeded 20 g/L, 10 mmol/L, and 10 mmol/L, respectively, avilamycin biosynthesis greatly decreased. When 20 g/L glucose was added at 32 h, avilamycin yield decreased by 70.2%. Avilamycin biosynthesis hardly continued when 2-deoxy-glucose was added into the basal medium at 32 h. There was little influence on avilamycin biosynthesis with the addition of the 3-methyl-glucose (20 g/L) at 32 h. In the presence of excess (NH4)2SO4 (20 mmol/L), the activities of valine dehydrogenase and glucose-6-phosphate dehydrogenase were depressed 47.7 and 58.3%, respectively, of that of the control at 48 h. The activity of succinate dehydrogenase increased 49.5% compared to the control at 48 h. The intracellular adenosine triphosphate level and 6-phosphate glucose content of S. viridochromogenes were 128 and 129%, respectively, of that of the control at 48 h, with the addition of the 40 mmol/L of KH2PO4. As a result, high concentrations of glucose, ammonium ions, and inorganic phosphate all led to the absence of the precursors for avilamycin biosynthesis and affected antibiotic synthesis.

3-O-Methylglucose↗
PubMed1983

The effect of sucrose on the rate of de novo sucrose biosynthesis in leaf protoplasts from spinach, wheat and barley.

Protoplasts from the leaves of wheat, spinach, and barley were found to synthesize [14C]sucrose from 14CO2 at rates comparable with those of the parent tissue. CO2 fixation and sucrose biosynthesis ceased virtually immediately when the light was switched off. The effect of sucrose pretreatment on the rate of de novo sucrose biosynthesis was found to vary with leaf age and with plant species. Protoplasts from young wheat and spinach leaves showed an apparent stimulation of the rate of sucrose biosynthesis after sucrose pretreatment. In protoplasts from mature leaves of spinach, sucrose pretreatment produced inhibition. After sucrose pretreatment protoplasts from mature spinach leaves showed low rates of CO2 fixation, and sucrose biosynthesis compared with controls. Conversely, with protoplasts from mature leaves of wheat and barley, the rate of CO2 fixation was unchanged and there was little or no effect on the rate of sucrose biosynthesis after sucrose pretreatment. Preincubation with sucrose had no effect on the activity of sucrose-phosphate synthetase (EC 2.4.1.14), cytoplasmic fructose-1,6-bisphosphatase (EC 3.1.3.11), or UDPglucose pyrophosphorylase (EC 2.7.7.9) from spinach leaves. It was concluded that there is no direct feedback inhibition of sucrose on the sucrose biosynthetic pathway in leaves of spinach, wheat, and barley. The mechanism of inhibition of sucrose biosynthesis by sucrose in spinach remains to be elucidated.

Carbon Dioxide↗
PubMed1984

Growth inhibition by methionine analog inhibitors of S-adenosylmethionine biosynthesis in the absence of polyamine depletion.

Four methionine analog inhibitors of methionine adenosyltransferase, the enzyme which catalyzes S-adenosylmethionine biosynthesis, were tested in cultured L1210 cells for their effects on cell growth, leucine incorporation, S-adenosylmethionine (AdoMet) formation and polyamine biosynthesis. The IC50 values were as follows: selenomethionine, 0.13 mM; L-2-amino-4-methoxy-cis-but-3-enoic acid (L-cis-AMB), 0.4 mM; cycloleucine, 5 mM and 2-aminobicyclo[2.1.1]hexane-2-carboxylic acid, 5 mM. At IC50 levels, the analogs significantly reduced AdoMet pools by approximately 50% while not similarly affecting leucine incorporation or polyamine biosynthesis. In combination with inhibitors of polyamine biosynthesis, growth inhibition was greatly increased with methylglyoxal bis(guanylhydrazone), an inhibitor of AdoMet decarboxylase, but only slightly increased with alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase. Overall, the data indicate that the methionine analogs, and particularly L-cis-AMB, seem to inhibit cell growth by interference with AdoMet biosynthesis. Since polyamine biosynthesis is not affected, the antiproliferative effect may be mediated through perturbations of certain transmethylation reactions.

Adenosylmethionine Decarboxylase↗
PubMed1986

Rat lens prostaglandin biosynthesis during galactose-induced cataractogenesis.

The relationship between the development of galactose-induced cataractogenesis and rat lens microsomal prostaglandin (PG) biosynthesis was studied. Within 24 hr of the introduction of 50% galactose to the rat's diet, lens PGF2 alpha production fell dramatically to 31% of control. Following the initial depression of PGF2 alpha biosynthesis, the ability to generate PGF2 alpha in lens microsomes slightly recovered reaching 58- and 53% of controls at day 2 and day 5 on the sugar diet, respectively. Determination of microsomal PGF2 alpha biosynthesis at 9- and 21 days revealed a continued decline in PG synthesis with complete cessation of PGF2 alpha synthesis by day 36 (hypermature cataracts, +5). The decreased PGF2 alpha biosynthetic capacity was a result of decreased cyclo-oxygenase activity since: PGE2 production demonstrated a similar time course for inhibition; and lens microsomes from control and galactose fed rats revealed no difference in the PGs produced from PGH2 endoperoxide. Neither galactose (1 mM) nor galactitol (1 mM), when added to control microsomal preparations inhibited PG biosynthesis, eliminating the possibility of a direct effect of the sugar, or its metabolite, on cyclo-oxygenase activity. While PG biosynthesis was rapidly inhibited by the galactose feeding no changes were observed in basal lens cyclic AMP levels measured during the first 5 days of the feedings. These results demonstrate that depressed PG biosynthesis is an early consequence of galactose feeding.

Animals↗
PubMed1976

Role of hydroxyl radical scavengers dimethyl sulfoxide, alcohols and methional in the inhibition of prostaglandin biosynthesis.

Prostaglandin biosynthesis from eicosa-8, 11, 14-trienoic acid in microsomes from bovine seminal vesicles is inhibited by relatively high concentrations of hydroxyl radical scavengers: dimethyl sulfoxide, n- and t-butanol, and methional. Methional is a more effective scavenger than t-butanol and dimethyl sulfoxide, two compounds which are more miscible with water than methional. The synthesis of both PGE and PGF is inhibited with incubation systems that promote PGE formation and with incubation systems that promote PGF formation. Furthermore, dimethyl sulfoxide and methional inhibit arachidonic acid-induced platelet aggregation, a reaction involving endoperoxide biosynthesis. The water soluble alcohol, ethanol, stimulates PGF biosynthesis when it is added in the same concentration range as t-butanol. Thus hydroxyl radical scavengers inhibit biosynthesis when their effective concentrations are high and stimulate biosynthesis when their effective concentrations are low. The results of this study and other studies where low concentrations of hydroxyl radical scavengers stimulate both prostaglandin biosynthesis and lipid peroxidation are consistent with a mechanism involving the hydroxyl radical both in the generation of singlet oxygen and the elimination of hydrogen peroxide.

8,11,14-Eicosatrienoic Acid↗
PubMedDate not supplied

A model for intracellular calcium signaling and the coordinate regulation of hormone biosynthesis, receptors and secretion.

A two-state model for the stimulus-induced nongraded response of a single cell is formulated. Individual metestrus gonadotropes stimulated with LHRH operate as a simple switch: either on or off. At a given concentration of stimulus some gonadotropes switch on, while others do not switch on, secretion. The probability of a gonadotrope being in the secretory state is enhanced with each increment of LHRH concentration. Individual gonadotropes in a secretory state are envisioned to decrease their number of LHRH receptors and to switch off LH biosynthesis. On the other hand, individual gonadotropes that are not in a secretory state are thought to increase their number of LHRH receptors and to switch on LH biosynthesis. The group of individuals in the population that have thresholds falling in the range of a given stimulus initiate secretion. And, the group of individuals in the population that have thresholds that fall above the range of a given stimulus do not initiate secretion. More remarkable is evidence that the cells that are protected from hormone secretion nevertheless respond with a set of intracellular signals and this provides a new perspective of how they switch on hormone biosynthesis and up-regulate the LHRH receptors. These changes are envisioned to reduce the threshold of an individual cell and accordingly to enhance the probability that the cell responds in the secretory state with the next stimulus. This scheme would appear to lead to automatic cycles of secretion and biosynthesis since an individual cell can occupy only one of two states at any time and occupancy of either state promotes change to the other. This may provide a solution to the problem of how an endocrine gland might reconcile differences in the time-course of hormone secretion which occurs rapidly and hormone biosynthesis that requires a longer period of time. Parenthetically, the model may also be adapted to the case where the vast majority of individuals in the population are generally subthreshold in relation to the physiological stimulus: such an adaption leads to interesting ways of viewing the mammalian reproductive cycle and the regulation of the preovulatory LH surge. A two-state model of the internal Ca2+ store is outlined here to stimulate thought on how the intracellular signals of each binary state may switch a variety of cellular responses either on or off. The model provides a new perspective on the coordinate regulation of hormone biosynthesis, receptors, and secretion that may be useful in the final reconciliation of population studies with insights about individual cells.

Animals↗
PubMed1994

Signal transduction in the inhibition of juvenile hormone biosynthesis by allatostatins: roles of diacylglycerol and calcium.

The effects of pharmacological agents that interfere with the 1,4,5-inositol trisphosphate (IP3)/diacylglycerol (DAG) pathway on juvenile hormone (JH) biosynthesis by corpora allata (CA) of the cockroach Diploptera punctata have been investigated. These effects were assessed in the presence of the inhibitory neuropeptides, allatostatins, with a view to elucidating the pathway for signal transduction in the inhibition of JH biosynthesis. Treatment of CA with inhibitors of DAG kinase to elevate the concentration of DAG within the CA cells, resulted in a significant, dose-dependent decrease in JH biosynthesis. Simultaneous treatment of glands with both DAG kinase inhibitors and allatostatins further enhanced this effect, suggesting that DAG is an intermediate in the allatostatin-induced inhibition of JH production. The inhibitory actions of the phorbol ester activator of PKC, PDBu, or of allatostatin on JH biosynthesis were partially blocked by pre-incubating the CA with PKC inhibitors. Treatment of CA with the calcium-mobilizing drug thapsigargin resulted in a significant stimulation in JH biosynthesis in glands from mated females producing JH at high rates. Thapsigargin was also able to reverse the effect of allatostatins in high-activity mated CA. This suggests an involvement of the other product of phosphoinositide hydrolysis, IP3, in the modulation of JH biosynthesis at specific developmental times and in glands showing specific levels of activity.

Animals↗
PubMed1982

Correlation of the biosynthesis of prostaglandin and cyclic AMP in monolayer cultures of rabbit articular chondrocytes.

We have utilized ionophores to test whether stimulation of chondrocyte prostaglandin biosynthesis is accompanied by an increase in cyclic nucleotide levels in these cells. Radioimmunoassay of prostaglandin E2, 6-oxo-prostaglandin F1 alpha (the stable metabolite of prostaglandin I2) and prostaglandin F2 alpha showed that synthesis of each was stimulated by the divalent-cation ionophore, A23187 after short-term incubation (1-7 min) in serum-free medium. No stimulation of thromboxane B2 was detected. Two monovalent ionophores, lasalocid and monensin failed to stimulate prostaglandin biosynthesis after short-term incubation. Ionophore A23187-stimulated prostaglandin biosynthesis was variably and partially inhibited by sodium meclofenamate, indomethacin and aspirin, but not by sodium salicylate. Ionophore A23187-stimulated prostaglandin biosynthesis was accompanied by a 7.5-fold increase in cyclic AMP levels after 15 min. Sodium meclofenamate, indomethacin and aspirin which inhibited prostaglandin E2 biosynthesis also reduced cyclic AMP levels. Exogenous prostaglandin E2 (1 microgram/ml) stimulated cyclic AMP biosynthesis, which was not inhibited by aspirin. These results indicated that prostaglandins can be considered as one of the local effectors controlling cyclic AMP production in articular cartilage.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Action of PBAN and related peptides on pheromone biosynthesis in isolated pheromone glands of the redbanded leafroller moth, Argyrotaenia velutinana.

Isolated pheromone glands from the redbanded leafroller moth, Argyrotaenia velutinana, were utilized to demonstrate the action of pheromone biosynthesis activating neuropeptide (PBAN) and bursa pheromonotropic peptide plus several other related peptides on pheromone biosynthesis. All peptides belonging to the PBAN family and the bursa peptide stimulated pheromone biosynthesis as measured by pheromone titer and incorporation of radiolabeled acetate. These peptides required the presence of extracellular Ca2+ for expression of full activity and several inorganic Ca2+ channel blockers inhibited the stimulation of pheromone biosynthesis. The Ca2+ ionophore A23187 alone stimulated pheromone biosynthesis as did a cAMP analogue. Stimulation by the cAMP analogue in the absence of extracellular Ca2+ was observed. Maximum pheromone titers were observed in 16 hr gland incubations; however, 2-6 hr incubations were required if pheromone biosynthesis was measured by incorporation of radiolabeled acetate. Radiolabeled glucose incorporation was not increased in the presence of PBAN. These results are discussed in the context of how the pheromone biosynthetic pathway is stimulated by these peptides.

Analysis of Variance↗
PubMed2004

Effect of L-fucose and fucose-rich polysaccharides on elastin biosynthesis, in vivo and in vitro.

With increasing age elastic fibres in human skin are progressively lysed and skin elasticity is also decreasing. Still there is an age-dependent increase of elastic fibre surface density, mostly due to an alteration of the fibres. The present experiments were undertaken to explore if L-fucose and fucose-rich polysaccharides (FROP-s) could influence elastin biosynthesis. We show here, that topical application of a fucose-containing preparation to the skin of hairless rats increased after 4 weeks the elastic fibre surface density by about 40%, shown by quantitative morphology. Using human skin fibroblasts in explant cultures, the addition of L-fucose or of FROP-3 increased the biosynthesis of immunoprecipitable tropoelastin by about 40%. No increase was found however of desmosine-isodesmosine in skin explant cultures after 72 h of incubation. The effect of L-fucose and FROP-3 on the biosynthesis of collagen and non-collagen proteins excreted by the skin explant cultures was also investigated. L-fucose, but not FROP-3, decreased collagen biosynthesis but both increased non-collagen protein biosynthesis. These results show that L-fucose and FROP-3 stimulate tropoelastin biosynthesis in vitro, and elastic fibre formation in vivo. This stimulation concerns also several non-collagen proteins secreted by skin explant cultures. Elastic fibre formation necessitates the simultaneous synthesis of several microfibrillar glycoproteins as well as of tropoelastin. The increased elastic fibre density in the in vivo experiments suggests that this is indeed achieved by L-fucose and FROP-3, further demonstrating their efficiency in the control of age-dependent modifications of connective tissues in general and of skin in particular.

Administration, Cutaneous↗
PubMed2005

Inhibition of sphingolipid biosynthesis decreases phosphorylated ERK2 in LLC-PK1 cells.

Fumonisin B(1) (FB(1)) is a fungal toxin produced by Fusarium verticillioides that inhibits ceramide synthase (CS), a key enzyme in the de novo sphingolipid biosynthesis pathway. In LLC-PK(1) cells, FB(1) inhibits cell proliferation and induces apoptosis, which can be prevented by inhibitors of serine palmitoyltransferase (SPT). Inhibition of SPT prevents the FB(1)-induced accumulation of free sphinganine, a precursor of ceramide biosynthesis. However, not all of the effects of FB(1) in LLC-PK(1) cells can be explained solely by the increase in free sphingoid bases. The downstream signaling pathways that are affected by FB(1)-induced disruption of sphingolipid biosynthesis are not well understood. This study determined, in LLC-PK(1) cells, changes in p42 MAP kinase (phosphorylated ERK2 [pERK2]) phosphorylation in response to various inhibitors of key enzymes of the de novo sphingolipid biosynthesis pathway (CS, SPT, and glucosylceramide synthase [GlcCer synthase]). The results show that inhibition of any of the three enzymes caused a similar decrease in the extent of phosphorylation of ERK2 with no reduction in total ERK2. The co-treatment of FB(1) (CS inhibitor) with SPT inhibitors or the GlcCer synthase inhibitor had no effect on the FB(1)-induced reduction in pERK2 phosphorylation, indicating that FB(1)-mediated changes in phosphorylation of pERK2 was independent of increases in free sphinganine or its metabolites or a reduction in ceramide. Nonetheless, the decrease in pERK2 phosphorylation was dependent on inhibition of de novo sphingolipid biosynthesis. Decreased pERK2 activity could contribute to the physiological effects of FB(1) in LLC-PK(1) cells that are not due to alteration in pathways modulated by free sphingoid bases and their metabolites but are sensitive to inhibition of glycosphingolipid biosynthesis.

Acyltransferases↗
PubMed2004

A morph-specific daily cycle in the rate of JH biosynthesis underlies a morph-specific daily cycle in the hemolymph JH titer in a wing-polymorphic cricket.

A previous study documented a high amplitude, morph-specific daily cycle in the hemolymph JH titer in the wing-polymorphic cricket, Gryllus firmus. The JH titer rose and fell 10-20 fold in the flight-capable [LW(f), long-winged] morph during the late-photophase-early scotophase, while it was relatively constant during that time in the flightless (SW, short-winged) morph. In the present study we documented a dramatic morph-specific daily cycle in the in vitro rate of juvenile hormone (JH) biosynthesis that was tightly correlated with the hemolymph JH titer on days 5-7 of adulthood. Biosynthetic rates rose and fell 1-2 fold between the late photophase-early scotophase on each of days 5-6 and 6-7 of adulthood in the LW(f) morph, while biosynthetic rates were relatively constant during this period in the flightless, short-winged morph (SW), except for a slight dip in the rate of biosynthesis late in the photophase on these days. Similar morph-specific patterns of JH biosynthesis were observed whether rates were measured on corpora allata attached to corpora cardiaca in males or females, or on corpora allata alone. Hemolymph juvenile hormone esterase activity was significantly higher in the LW(f) vs. the SW morph during the beginning of scotophase, when the JH titer is decreasing rapidly in the LW(f) morph. Results indicate that the morph-specific daily cycle in the JH titer in G. firmus is primarily regulated by a morph-specific daily cycle in the rate of JH biosynthesis and to a lesser degree by hemolymph JH esterase activity. This is the first documentation of a diurnal cycle in the rate of JH biosynthesis in any insect, or a daily cycle in the rate of JH biosynthesis that is correlated with a specific morph in a polymorphic species. Results have important implications for the endocrine regulation of dispersal polymorphism, circadian rhythms of insect hormone titers and their regulators, and general studies of the JH titer and its regulation in insects.

Animals↗
PubMed1998

Synergistic interactions of bradykinin, thrombin, interleukin 1 and tumor necrosis factor on prostanoid biosynthesis in human periodontal-ligament cells.

Prostaglandins are involved in force-induced orthodontic tooth movement. Bradykinin (BK) and thrombin are known to cause a significant time- and concentration-dependent burst of prostanoid biosynthesis in cultured human periodontal-ligament (PDL) cells. The aim now was to investigate interactive effects between interleukin 1 alpha, -beta (IL-1 alpha, -1 beta), tumour necrosis factor-alpha,-beta (TNF-alpha, -beta) and BK or thrombin on prostaglandin biosynthesis in human PDL cells. IL-1 alpha and -1 beta produced time- and concentration-dependent stimulation of prostanoid biosynthesis [prostaglandin (PG)E2 and 6-keto-PGF1alpha]. Synergistic stimulation of prostanoid biosynthesis was demonstrated when BK or thrombin were added together with IL-1 alpha or -1 beta. BK and IL-1 beta both significantly stimulated the release of [3H]arachidonic acid. No synergistic effect on [3H]arachidonic acid release was seen when BK and IL-1 beta were added simultaneously. These data suggest that the synergistic effect of BK and IL-1 beta on prostanoid biosynthesis is not due to interactions at the receptor level nor to enhanced release of arachidonic acid, but may be due to increased activity of cyclo-oxygenase. Also, TNF-alpha and -beta produced a concentration-dependent stimulation of PGE2 formation in cultured human PDL cells. Synergistic effects of BK and thrombin were demonstrated when PGE2 production was stimulated in combination with TNF-beta. In addition, a synergistic effect on the PGE2 response to IL-1 alpha or -1 beta was demonstrated when added in combination with TNF-alpha. These experiments demonstrate synergistic interactions between BK, thrombin, IL-1 and TNF on prostaglandin biosynthesis in cultured human PDL cells. The findings suggest that inflammatory mediators may act in concert in stimulating prostanoid production in response to pro-inflammatory stimuli. As an inflammatory reaction is seen in the periodontal ligament when teeth are orthodontically treated, this synergistic interaction may be of importance in force-induced tooth movement.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Cloning of conserved genes from Zymomonas mobilis and Bradyrhizobium japonicum that function in the biosynthesis of hopanoid lipids.

The squalene-hopene cyclase (SHC) is the only enzyme involved in the biosynthesis of hopanoid lipids that has been characterized on the genetic level. To investigate if additional genes involved in hopanoid biosynthesis are clustered with the shc gene, we cloned and analyzed the nucleotide sequences located immediately upstream of the shc genes from Zymomonas mobilis and Bradyrhizobium japonicum. In Z. mobilis, five open reading frames (ORFs, designated as hpnA-E) were detected in a close arrangement with the shc gene. In B. japonicum, three similarly arranged ORFs (corresponding to hpnC-E from Z. mobilis) were found. The deduced amino acid sequences of hpnC-E showed significant similarity (58-62%) in both bacteria. Similarities to enzymes of other terpenoid biosynthesis pathways (carotenoid and steroid biosynthesis) suggest that these ORFs encode proteins involved in the biosynthesis of hopanoids and their intermediates. Expression of hpnC to hpnE from Z. mobilis as well as expression of hpnC from B. japonicum in Escherichia coli led to the formation of the hopanoid precursor squalene. This indicates that hpnC encodes a squalene synthase. The two additional ORFs (hpnA and hpnB) in Z. mobilis showed similarities to enzymes involved in the transfer and modification of sugars, indicating that they may code for enzymes involved in the biosynthesis of the complex, sugar-containing side chains of hopanoids.

Amino Acid Sequence↗
PubMed1999

Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis.

Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10(-7) M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P < 0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [3H]acetate into cholesterol) by up to 90% (P < 0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM's cholesterol synthesis by up to 70% (P < 0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10(-7) M Ang II for 18 h at 37 degrees C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10(-5) M), an AT1 blocker, but not PD 123319 (10(-5) M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.

Angiotensin II↗
PubMed2001

Tn10 insertional mutations of Bacillus subtilis that block the biosynthesis of bacilysin.

Transposon mutagenesis was employed to isolate the gene(s) related with the biosynthesis of dipeptide antibiotic in Bacillus subtilis PY79 (a prototrophic derivative of the standard 168 strain). The blocked mutants were phenotypically selected from the transposon library by bioassay and the complete loss of biosynthetic ability was verified through ESI-mass spectrometry analysis. Four different bacilysin nonproducer mutants (Bac(-)::Tn10(ori-spc)) were isolated from the transposon library. The genes involved in bacilysin biosynthesis were identified as thyA (thymidilate synthetase), ybgG (unknown; similar to homocysteine methyl transferase) and oppA (oligopeptide permease), respectively. The other blocked gene was yvgW (unknown; similar to heavy metal-transporting ATPase); however, backcross studies did not verify its involvement in bacilysin biosynthesis. This gene, on the other hand, appeared to be necessary for efficient sporulation and transformation. Opp involvement was significant as it suggested that bacilysin biosynthesis is under or a component of the quorum sensing pathway which has been shown to be responsible for the establishment of sporulation, competence development and onset of surfactin biosynthesis. For verification, it was necessary to check the involvement of peptide pheromones (PhrA or PhrC) internalized by the Opp system and response regulator ComA as the essential components of this global control. phrA, phrC and comA deleted mutants of PY79 were thus constructed and the latter two genes were shown to be essential for bacilysin biosynthesis.

ATP-Binding Cassette Transporters↗
PubMed2001

The effects of dexamethasone on insulin release and biosynthesis are dependent on the dose and duration of treatment.

Complex results concerning the effect of glucocorticoids on insulin secretion have been reported. The aim of this study is to clarify the direct effects of glucocorticoids on pancreatic islets and to determine whether the effect of glucocorticoids on insulin biosynthesis or release is dependent on the dose and duration of treatment with glucocorticoid. Studies on insulin secretion and biosynthesis were performed with different concentrations (0, 1, 10, 100 nmol/l) and durations (1 and 6 h) of treatment with dexamethasone (dexa) in rat pancreatic islets. (1) One nmol/l dexa had no inhibitory effect on insulin secretion and biosynthesis. Ten and 100 nmol/l had an inhibitory effect on insulin secretion, which was mainly due to suppression of the first phase of insulin secretion. (2) Insulin content was significantly increased regardless of the concentration in 1-h treated islets. However, insulin content was markedly diminished with 100 nmol/l dexa in 6-h treated islets. (3) The preproinsulin mRNA expression of 6-h treated islets was suppressed in a dose-dependent manner. Our data revealed that, in the condition of short-term and low-dose glucocorticoid exposure, insulin secretion and biosynthesis are not affected. The secretory process of insulin seems to be the initial step of the inhibitory action of glucocorticoid. Both insulin release and biosynthesis are inhibited by chronic exposure to high dose dexamethasone. It can be concluded that glucocorticoid might be involved in the multisteps of insulin release and biosynthesis.

Animals↗