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Biomedical subjects

M A Wells

Publications and source records attributed to M A Wells.

At least 19 recordsLinked to original sources

Reevaluation of the role of early trypsin activity in the transcriptional activation of the late trypsin gene in the mosquito Aedes aegypti.

In the female mosquito Aedes aegypti, trypsin expression is largely biphasic. Early trypsin synthesis, which is regulated at the translational level relative to feeding, peaks in the first few hours post-blood meal. Late trypsin expression is regulated at the transcriptional level, and peaks 18-24h post-blood meal. It was proposed that early trypsin activity released unknown factors during digestion of a meal that caused activation of transcription of the late trypsin gene. This connection between early trypsin activity and late trypsin expression was dependent on the fact that feeding a single trypsin inhibitor, soybean trypsin inhibitor (STI), which blocked early trypsin activity, also blocked late trypsin expression. We show in this study that feeding different trypsin inhibitors which effectively blocked early trypsin activity did not result in reduced late trypsin expression. We also found that a different lot of STI failed to cause inhibition of late trypsin transcription, although it was effective in inhibiting early trypsin activity. In addition, using RNAi methodology to reduce the level of early trypsin expression had no effect on the level of late trypsin expression. We conclude that early trypsin activity is not necessary for the transcriptional activation of late trypsin and that the previous results were due to the effect of a cytotoxic agent present in some, but not all preparations of STI.

Aedes↗

The role of hemolymph proline as a nitrogen sink during blood meal digestion by the mosquito Aedes aegypti.

Mosquitoes utilize the amino acids derived from blood meal protein to produce egg proteins. But the amino acids can also be used to produce egg lipid or can be oxidized for energy production. These latter two processes result in the release of nitrogen as toxic ammonia. Therefore, amino acids must be processed in such a way that amino acid nitrogen can be incorporated into non-toxic waste products. Proline is the predominant amino acid in the hemolymph of the adult female mosquito Aedes aegypti. After feeding on albumin meal, hemolymph proline levels increased five-fold over unfed levels, reached maximal levels in the first hours after feeding and remained high through oviposition. Hemolymph proline levels increased as the concentration of protein in the meal increased. When starved of sugar for 24 h prior to feeding on an albumin meal, hemolymph proline levels increased four-fold over the proline levels of non-starved mosquitoes. Proline levels after feeding on a protein deficient in essential amino acids, pike parvalbumin, increased to twice the levels of albumin fed mosquitoes. Based on these observations, we propose that mosquitoes utilize proline as a temporary nitrogen sink to store ammonia arising from deamination of blood meal amino acid.

Aedes↗

Proline can be utilized as an energy substrate during flight of Aedes aegypti females.

In order to determine whether proline can be utilized as fuel during flight of Aedes aegypti, proline, alanine, and glutamine concentrations were monitored at 0, 30 and 60 min after flight using sugar-fed males and females, and blood meal-fed females. In sugar-fed and blood meal-fed females, flight lead to a significant decrease in proline and a significant increase in glutamine concentration in both hemolymph and thorax. Only during flight after a blood meal was a significant increase in the alanine concentration observed in hemolymph. After flight, the proline alanine and glutamine levels in the hemolymph and thorax from males did not change significantly. In addition, activities of enzymes related to amino acid metabolism were assayed in homogenates of cephalothorax and thorax from both sexes, and in fat body and midgut from females. In both sexes, the activities of all the enzymes studied were significantly higher in thorax than in cephalothorax. The levels of the enzymes involved in proline oxidation were higher in thorax than in fat body and midgut. These results suggest that proline can be used as an energy substrate for flight muscle of Ae. aegypti females. However, the elevation in glutamine levels observed in hemolymph and thorax after flight has not been reported in other insects that fuel flight using proline and may suggest an additional mechanism for shuttling ammonia between flight muscle and fat body is present in mosquitoes.

Aedes↗

Transfer of cholesterol and diacylglycerol from lipophorin to Bombyx mori ovarioles in vitro: role of the lipid transfer particle.

The objective of this study was to characterize the transfer of diacylglycerol (DAG) and cholesterol from larval Bombyx mori lipophorin to ovarioles. Transfer studies were carried out by incubating pupal ovarioles (5-day) with [(3)H]-cholesterol and [(3)H]-DAG-labeled lipophorin under different conditions. Transfer of both cholesterol and DAG exhibited hyperbolic dependency on lipophorin concentration with apparent Km values of 0.83 +/- 0.17 mg/ml and 0.74 +/- 0.16 mg/ml, respectively. Pretreatment of ovarioles with anti-lipid transfer particle (LTP) IgG significantly inhibited transfer of labeled DAG to ovarioles (75%) and not cholesterol. Injection of B. mori pupae (day 4) with anti-LTP IgG significantly affected the weight (65%), number of eggs (49%), amount of lipid (74%), and protein (65%) of the adult ovaries. Matured eggs had a very faint yellow color and deformed shape compared to controls. The inhibitory effect demonstrates the active role LTP plays in growth of ovaries, development, and oogenesis. The effect on vitellogenin shortage on egg development and maturation was determined by implanting ovaries in male recipients that lack vitellogenin. An 80% decline in egg production was observed. However, the mature eggs were normal in shape, color, and lipid content. Thus, restricting lipid or protein delivery to developing ovaries would dramatically affect choriogenesis.

Animals↗

Role of lipid transfer particle in delivery of diacylglycerol from midgut to lipophorin in larval Manduca sexta.

The present work analyzed the function of lipid transfer particle (LTP) in the process of exporting diacylglycerol from larval Manduca sexta midgut cells to lipophorin. When midgut sacs, which had been prelabeled in vivo with [(3)H]oleic acid, were incubated in vitro with a lipophorin-containing medium, a significant amount of radiolabeled diacylglycerol was transferred to lipophorin. Negligible amounts of diacylglycerol were released into lipophorin-free medium. In contrast, lipid-labeled lipophorin did not transfer diacylglycerol to the midgut sacs. The transfer of diacylglycerol from the midgut sac to lipophorin was blocked by preincubation of midgut sacs with antibody against LTP. Diacylglycerol transfer was restored to control values by the addition of purified LTP to midgut sacs that had been treated with antibody against LTP. Under these conditions the amount of diacylglycerol transferred was a function of the LTP concentration. These are the first results showing that LTP is required to export diacylglycerol from the midgut to lipophorin.

Animals↗

Neuroendocrine factors affecting the steady-state levels of early trypsin mRNA in Aedes aegypti.

Transcription of the early trypsin gene occurs in the midgut after adult emergence under control of juvenile hormone (JH). We tested the hypothesis that factors that affect the steady-state levels of early trypsin mRNA do so by influencing the levels of JH. We investigated the effect of ingesting different meals on early trypsin mRNA levels as well as on JH levels. We also studied how early trypsin mRNA levels changed when the midgut was isolated from different components of the neuroendocrine system by abdominal ligation and decapitation. Early trypsin transcripts levels are high in unfed females; feeding different meals had three distinct effects on the changes of steady-state levels of early trypsin mRNA: (1) blood and protein meals caused the level to decrease drastically and remained low for at least 24 h; (2) amino acid meals caused a transient decrease in the mRNA level, but it returned to high levels after 12-18 h; and (3) sugar, latex and saline meals had no effect on the early trypsin mRNA steady-state levels. The changes in JH levels after ingesting blood and amino acid meals show profiles resembling the changes in early trypsin mRNA levels for the corresponding meal. Decapitation at 1, 2 and 3 days after emergence does not affect the steady-state levels of early trypsin in unfed females. In contrast, 24 h after feeding, transcript levels were significantly higher in decapitated females when compared with non-decapitated fed females. We propose that the changes in the steady-state levels of early trypsin mRNA observed after the ingestion of different meals, ligations and decapitations are generated by changes in the levels of juvenile hormone.

Journal Article↗

Lipid storage and mobilization in insects: current status and future directions.

In this paper we review the current status of research on fatty acid absorption and conversion to diacylglycerol in the midgut. We further discuss how diacylglycerol may leave the midgut and associate with lipophorin in hemolymph. We review the present understanding of the role of the lipid transfer particle and lipophorin receptors in lipid delivery between lipophorin and tissues. Finally, we discuss recent studies on the mobilization of diacylglycerol from the fat body in response to adipokinetic hormone. Several suggestions for exciting areas of future research are described.

Absorption↗

Fat body fructose-2,6-bisphosphate content and phosphorylase activity correlate with changes in hemolymph glucose concentration during fasting and re-feeding in larval Manduca sexta.

Fasting of second-day fifth instar larval Manduca sexta leads to a rapid decrease in hemolymph glucose concentration from 3.39+/-0.29 to 0.33+/-0.06 mM in 1 h, along with a decrease in the fructose-2,6-bisphosphate content in the fat body (from 5.92+/-0.31 to 2.80+/-0.47 nmol fructose-2,6-bisphosphate/g fat body in 3 h) and activation of fat body glycogen phosphorylase (from 16% to 55-65% phosphorylase a). During re-feeding an increase in the glucose level in the hemolymph was observed (from 0.36+/-0.05 to 3.91+/-0.36 mM in 3 h), along with an increase in the fructose-2,6-bisphosphate level in the fat body (from 2.88+/-0.47 to 6.66+/-0.42 nmol fructose-2,6-bisphosphate/g fat body in 3 h) and inactivation of fat body glycogen phosphorylase (from 56% to 16% phosphorylase a). These data are consistent with the hypothesis that a decrease in hemolymph glucose both activates fat body glycogen phosphorylase and causes a decrease in fat body fructose-2,6-bisphosphate content. Both of these changes would favor conversion of stored glucose to trehalose in the fat body. When second-day larvae were decapitated, the changes in hemolymph glucose and fat body fructose-2,6-bisphosphate were very similar to those observed in fasting whole insects. These data are consistent with a direct role for glucose in controlling carbohydrate metabolism in Manduca sexta.

Animals↗

Fat metabolism in insects.

The study of fat metabolism in insects has received considerable attention over the years. Although by no means complete, there is a growing body of information about dietary lipid requirements, and the absolute requirement for sterol is of particular note. In this review we (a) summarize the state of understanding of the dietary requirements for the major lipids and (b) describe in detail the insect lipid transport system. Insects digest and absorb lipids similarly to vertebrates, but with some important differences. The hallmark of fat metabolism in insects centers on the lipid transport system. The major lipid transported is diacylglycerol, and it is carried by a high-density lipoprotein called lipophorin. Lipophorin is a reusable shuttle that picks up lipid from the gut and delivers it to tissues for storage or utilization without using the endocytic processes common to vertebrate cells. The mechanisms by which this occurs are not completely understood and offer fruitful areas for future research.

Animals↗

Diacylglycerol transport in the insect fat body: evidence of involvement of lipid droplets and the cytosolic fraction.

In this report we show the existence of a distinct pool of fat body diacylglycerol (DG) that can be distinguished from the bulk DG. This is a dynamic pool of DG that uses FA entering the fat body from the hemolymph, whereas the bulk DG uses the fatty acids stored in the fat body fat droplets. Using a dual labeling technique, it was possible to compare the effect of hormone-stimulated DG synthesis and secretion on the distribution of radiolabeled FA among the lipids of the dynamic pool (short-term radiolabeling), with the hormonal effect on the total complement of fat body lipids (long-term radiolabeling). We observed that, whereas DG represents 2% to 3% of the fat body lipid mass, about 20% of the short-term radiolabeled lipids are represented by DG. Stimulation of lipolysis produces a fast decrease in the fraction of short-term radiolabeled DG, whereas there is an increase in the mass of fat body DG. The subcellular distribution of bulk DG showed that its majority (62%) was in the fat cake whereas only 2.9% was in the cytosol. On lipolysis stimulation, the largest changes in specific activities of newly synthesized DG were detected in the cytosol and the fat cake, suggesting that newly synthesized DG localized in the lipid droplets and the cytosol is preferentially mobilized.

Animals↗

Ectonucleotide diphosphohydrolase activities in hemocytes of larval Manduca sexta.

In this work, we describe the ability of living hemocytes from an insect (Manduca sexta, Lepidoptera) to hydrolyze extracellular ATP. In these intact cells, there was a low level of ATP hydrolysis in the absence of any divalent metal (8.24 +/- 0.94 nmol of Pi/h x 10(6) cells). The ATP hydrolysis was stimulated by MgCl2 and the Mg2+-dependent ecto-ATPase activity was 15.93 +/- 1.74 nmol of Pi/h x 10(6) cells. Both activities were linear with cell density and with time for at least 90 min. The addition of MgCl2 to extracellular medium increased the ecto-ATPase activity in a dose-dependent manner. At 5 mM ATP, half-maximal stimulation of ATP hydrolysis was obtained with 0.33 mM MgCl2. This stimulatory activity was not observed when Ca2+ replaced Mg2+. The apparent Km values for ATP-4 and Mg-ATP2- were 0.059 and 0.097 mM, respectively. The Mg2+-independent ATPase activity was unaffected by pH in the range between 6.6 and 7.4, in which the cells were viable. However, the Mg2+-dependent ATPase activity was enhanced by an increase of pH. These ecto-ATPase activities were insensitive to inhibitors of other ATPase and phosphatase activities, such as oligomycin, sodium azide, bafilomycin A1, ouabain, furosemide, vanadate, sodium fluoride, tartrate, and levamizole. To confirm the observed hydrolytic activities as those of an ecto-ATPase, we used an impermeant inhibitor, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), as well as suramin, an antagonist of P2-purinoreceptors and inhibitor of some ecto-ATPases. These two reagents inhibited the Mg2+-independent and the Mg2+-dependent ATPase activities to different extents. Interestingly, lipopolysaccharide, a component of cell walls of gram-negative bacteria that increase hemocyte aggregation and phagocytosis, increased the Mg2+-dependent ecto-ATPase activity in a dose-dependent manner but did not modify the Mg2+-independent ecto-ATPase activity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

cDNA and deduced amino acid sequences of apolipophorin-IIIs from Bombyx mori and Bombyx mandarina.

The cDNA sequence for apolipophorin-III from two strains of Bombyx mori (N4 and P50) and the Japanese and Chinese strains of Bombyx mandarina were determined. Both the cDNA and deduced amino acid sequences of the four apolipophorin-IIIs were highly similar (95-98%). The four Bombyx sequences also showed significant similarity to the sequence of apolipophorin-III from another lepidopteran, Manduca sexta (83-84%), particularly in the five amphipathic alpha-helices that are proposed to play a critical role in the binding of apolipophorin-III to lipophorin. In the coding region, the nucleotide sequences for the Chinese strain of B. mandarina and the P50 strain of B. mori were identical, supporting the suggestion that P50 is the current strain most closely related to the original domesticated strain. The N4 strain of B. mori is more closely related to these two strains than is the Japanese strain of B. mandarina, suggesting that Japanese strain of B. mandarina separated from the Chinese strain of B. mandarina before domestication of B. mori. Arch.

Amino Acid Sequence↗

Characterization of lipophorin binding to the midgut of larval Manduca sexta.

Lipophorin binding to the midgut of Manduca sexta larvae was characterized in a midgut membrane preparation, using iodinated larval high-density lipophorin ((125)I-HDLp-L). The iodination procedure did not change the affinity of the preparation for lipophorin. In the presence of increasing concentrations of membrane protein, corresponding increases in lipophorin binding were observed. The time-course of lipophorin binding to the membranes was affected by the lipophorin concentration in the medium, and at a low lipoprotein concentration, a longer time was required for equilibrium to be reached. The specific binding of lipophorin to the midgut membrane was a saturable process with a K(d) = 1.5+/-0.2x10(-7) M and a maximal binding capacity = 127+/-17 ng lipophorin/microg of membrane protein. Binding did not depend on calcium, was maximal around pH 5.5, was strongly inhibited by an increase in the ionic strength, and abolished by suramin. However, suramin did not completely displace lipophorin that was previously bound to the membrane preparation. The lipid content of the lipophorin did not significantly affect the affinity of the membrane preparation for lipoprotein.

Animals↗

Developmental changes in the response of larval Manduca sexta fat body glycogen phosphorylase to starvation, stress and octopamine.

Fasting or starvation of 1(st)- and 2(nd)-day fifth instar Manduca sexta larvae leads to rapid activation of fat body glycogen phosphorylase. Under feeding conditions, 21-29% of the phosphorylase was found in the active form. However, after only one hour of starvation, the active form increased to 55-65%. In larvae on the 3(rd)-day there was a slower increase in the activation, requiring three hours of starvation to reach a maximum of 60-65%. No activation was observed in 4(th)-day larvae after three hours of starvation. When 1(st)- or 2(nd)-day larvae were decapitated, the time-course of activation of glycogen phosphorylase was very similar to that observed in intact insects. However, activation of glycogen phosphorylase following decapitation was only observed in 1(st)- and 2(nd)-day larvae. In 2(nd)-day larvae, octopamine promoted activation of glycogen phosphorylase and 100-pmol of octopamine promoted maximum activation. Higher amounts of injected octopamine caused a decrease in activation. The injection of 100 pmol of octopamine caused a 50-55% activation of phosphorylase within 30 minutes. The simultaneous injection of the alpha-adrenergic receptor antagonist phentolamine with octopamine blocked the octopamine effect in 1(st)- and 2(nd)-day feeding larvae. However, the activation of glycogen phosphorylase observed in ligated/decapitated larvae on the 1(st)- and 2(nd)-day was not abolished by injection of phentolamine. All of these data suggest that factors other than adipokinetic hormone and octopamine may be involved in the activation of glycogen phosphorylase during fasting or starvation in the early part of the fifth larval stage of M. sexta.

Animals↗

Allosteric effectors and trehalose protect larval Manduca sexta fat body glycogen phosphorylase B against thermal denaturation.

In this paper we assessed the ability of modulators of the activity of glycogen phosphorylase b from the fat body of larval Manduca sexta to stabilize the enzyme against thermal denaturation. This approach has allowed us to distinguish between modulators that stabilize the enzyme, presumably through some conformational effect, from those that do not affect thermal stability. For example, 5'-AMP and 5'-IMP are both positive modulators of the enzyme and the K(m)s for AMP and IMP were similar, 0.71 and 1.09 mM, respectively. However, the V(max) for AMP (123 nmol/mg/min) was 10 times higher than the value found for IMP (12.5 nmol/mg/min) and AMP increased the thermal stability of glycogen phosphorylase b, however IMP did not increase the enzyme's thermal stability. Indeed, IMP decreased both the allosteric activation of the enzyme by AMP and the thermal protection conferred by AMP. The allosteric inhibitors ADP and ATP, which in vertebrate phosphorylase bind to the same site as AMP, both increased the thermal stability of the enzyme, however with less efficiency than AMP. Inorganic phosphate increased thermal stability, but glycogen and amylose did not. Glycerol, at 600 mM, protected the enzyme against thermal inactivation, whereas sorbitol at the same concentration did not show any effect. Among the polyols tested, trehalose was the most effective in conferring thermal stability. In fact, in the presence of 20 mM AMP and 600 mM trehalose, 90% of the enzyme activity remained after 20 min at 60 degrees C.

Allosteric Regulation↗

Metabolic pathways for diacylglycerol biosynthesis and release in the midgut of larval Manduca sexta.

The pathway for the synthesis of diacylglycerol in larval Manduca sexta midgut was studied. Fifth instar larvae were fed with [9, 10-(3)H]-oleic acid-labeled triolein and the incorporation of the label into lipid intermediates was analyzed as a function of time. The results showed that the triacylglycerol was hydrolyzed to fatty acids and glycerol in the midgut lumen. In midgut tissue, the labeled fatty acids were rapidly incorporated into phosphatidic acid, diacylglycerol and triacylglycerol, but no significant labeling of monoacylglycerol was observed. Dual-labeling experiments were performed in order to characterize the kinetics of diacylglycerol biosynthesis in the midgut, its incorporation into hemolymph lipophorin and its clearance from hemolymph. The results were best described by a model in which the rate-limiting step in diacylglycerol biosynthesis was the uptake of fatty acid from the lumen of the midgut. Once in the cell the fatty acid was rapidly incorporated in phosphatidic acid and diacylglycerol. Diacylglycerol was converted to triacylglycerol or exported into hemolymph. The interconversion of diacylglycerol and triacylglycerol was fairly rapid, suggesting that triacylglycerol serves as a reservoir from which diacylglycerol can be produced. This mechanism permits the cell to maintain a low steady-state concentration of diacylglycerol and yet efficiently absorb fatty acids from the lumen of the midgut.

Animals↗

Recombinant juvenile hormone esterase, an effective tool for modifying juvenile hormone-dependent expression of the early trypsin gene in mosquitoes.

The study of the changes in the steady-state levels of the early trypsin (ET) messenger RNA (mRNA) was used as a sensitive assay for measuring the effects of recombinant juvenile hormone esterase (rJHE) on juvenile hormone (JH)-dependent gene expression in mosquitoes. ET is a female-specific protease present in the midgut of the yellow fever mosquito Aedes aegypti during the first few hours after ingestion of a blood meal. Transcription of the early trypsin gene is part of the normal postemergence maturation of the midgut in the adult female, and it is regulated by JH. JHE was cloned from Heliothis virescens and expressed in a baculovirus vector. Injection of rJHE into mosquitoes resulted in an increase of JHE activity in the haemolymph. Injection of rJHE into newly emerged adult females delayed the normal increase in steady-state levels of ET mRNA observed in controls. Topically applied methoprene (a JH analogue) reversed the effect of rJHE. Injection of increasing concentrations of rJHE into 3-day-old unfed females resulted in a dose-dependent decrease in the steady-state levels of ET mRNA after 24 h. The effect of rJHE was transient, once the enzyme was cleared (72 h after injection), the steady-state levels of ET mRNA were restored. The injection of rJHE is an effective tool for modifying JH-dependent expression of the early trypsin gene in mosquitoes.

Administration, Topical↗

alpha-cyclodextrin extracts diacylglycerol from insect high density lipoproteins.

alpha-Cyclodextrins are water-soluble cyclic hexamers of glucose units with hydrophobic cavities capable of solubilizing lipophiles. Incubating alpha-cyclodextrin with high density lipophorin from Manduca sexta or Bombyx mori resulted in a cloudy, turbid solution. Centrifugation separated a pale yellowish precipitate. Thin-layer chromatography analysis of the lipid extract of the precipitate showed that the major lipid was diacylglycerol, while KBr density gradient analysis of the supernatant demonstrated the presence of a lipid-depleted very high density lipophorin. Transfer of diacylglycerol from lipophorin to cyclodextrin was specific to alpha-cyclodextrin and was not observed with beta- or gamma-cyclodextrins. pH had no effect on diacylglycerol transfer to alpha-cyclodextrin. However, the transfer was strongly dependent on the concentration of alpha-cyclodextrin and temperature. Increasing the concentration of alpha-cyclodextrin in the incubation mixture was associated with the formation of increasingly higher density lipophorins. Thus, at 20, 30, and 40 mm alpha-cyclodextrin, the density of B. mori lipophorin increased from 1.107 g/ml to 1.123, 1. 148, and 1.181 g/ml, respectively. At concentrations greater than 40 mm, alpha-cyclodextrin had no further effect on the density of lipophorin. alpha-Cyclodextrin removed at most 83;-87% of the diacylglycerol present in lipophorin. Temperature played an important role in altering the amount of diacylglycerols transferred to alpha-cyclodextrin. At 30 mm alpha-cyclodextrin, the amount of diacylglycerol transferred at different temperatures was 50% at 4 degrees C, 41% at 15 degrees C, 20% at 28 degrees C, and less than 3% at 37 degrees C. We propose that diacylglycerol transfers to alpha-cyclodextrin via an aqueous diffusion pathway and that the driving force for the transfer is the formation of an insoluble alpha-cyclodextrin-diacylglycerol complex.

Animals↗