Action of ecdysoids,juvenoids, and non-hormonal agents on termination of pupal diapause in the flesh fly

Pupal diapause in Sarcophaga crassipalpis can be immediately terminated with high doses of ecdysterone or 5,β-hydroxyecdysterone. Within a range of lower doses diapause is not immediately terminated, but the duration of diapause is shortened. Injection of small doses at 3-day intervals is more effective than a single application of the same total amount. 5,β-hydroxy-ecdysterone is more effective than ecdysterone. The juvenoid isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate does not cause immediate termination of diapause but diapause is shortened. Simultaneous application of ecdysterone and the juvenoid synergistically produce a shorter duration of diapause than either hormone applied separately. Topical application of acetone and several other organic compounds can cause an immediate break of diapause. Neckligated pupae, however, do not respond to acetone treatment. Temperature shocks caused by brief exposure to high or low temperatures are ineffective.Although high doses of ecdysoids cause immediate termination of diapause, subsequent adult morphogenesis is protracted in direct proportion to the dose of ecdysoid. With the highest doses many flies fail to complete adult morphogenesis. Flies receiving high doses of ecdysoid are characterized by developmental abnormalities such as underdeveloped antennae, compound eyes, and mouthparts. By contrast, adultoids produced with juvenoids are characterized by abdominal abnormalities.     

Preparation and preliminary biological screening of cholic acid-juvenoid conjugates

Steroidal compounds have been utilized as carriers and for modification of physico-chemical properties of model biologically active secondary alcohols - juvenoids. Juvenoids are juvenile hormone analogues - environmentally safe insecticides, possessing significant biological activity towards different arthropods groups in focus on insect pest species. Structure modification of juvenoids plays important role to control the rate of liberation and decomposition of juvenoid in digestive system and can also play important role in the mode of action towards selected insect. This study presents an approach to the synthesis of steroidal monomers and dimers carrying one and two molecules of a juvenoid in their structures. The prepared compounds were tested for their inhibition activity on reproduction of the blowfly Neobellieria (Sarcophaga) bullata. These steroid-juvenoid conjugates showed promising possibilities in synthesis of new unique biochemical insecticides. Preliminary biological test results of prepared compounds are presented.     

Cross-resistance to a juvenile hormone analogue in wild strains of the housefly

A wild organophosphate-resistant strain of houseflies has an eightfold resistance at LD₅₀ and sixfold resistance at LD₉₀ to a juvenile hormone analogue, isopropyl 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate. Insecticide resistance in this strain developed after several years using Nexion (bromophos-ethyl). Resistance to both organophosphates and to the juvenoid is caused by factor(s) on chromosome II. In both cases, the effects are synergized by TBTP and sesamex at levels of 1.25 and 2.0 g/fly, respectively. Two other wild organophosphate-resistant strains acquired resistance after prolonged field applications of Metation E 50 (fenitrothion). The factors of resistance to the juvenoid were 2.5 and 1. Lethal effects of juvenoids are caused by specific disturbances of the process of pupal-adult transformation during metamorphosis, which may necessarily be expressed by integumental defects. The degree of morphological effects in the integument caused by the juvenoid in susceptible and resistant strains was analyzed and compared.

---

Zusammenfassung Eine nahezu achtfache Resistenz gegenüber einem Analog des Juvenilhormons (Isopropyl 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoat) wurde bei einem organophosphat-resistenten Wildstamm der Stubenfliege gefunden. Die Resistenz gegenüber Insektiziden hat sich bei diesem Stamm nach mehrjähriger Anwendung von Nexion (Bromophos-äthyl) zur Bekämpfung entwickelt. Die Resistenz gegenüber dem Organophosphat und dem Juvenoid wird verursacht durch Faktoren am Chromosom II. In beiden Fällen wirkte TBTP und Sesamex (1,25 bzw. 2,0 g/Fliege) synergistisch. Die beiden anderen untersuchten organophosphat-resistenten Wildstämme erwarben die Resistenz nach längerer Anwendung von Metation E 50 (Fenitrothion) zur Bekämpfung im Freien. Die Resistenzfaktoren gegenüber dem Juvenoid waren 2,5 bzw. 1. Lethale Effekte von Juvenoiden werden durch spezifische Störungen des Prozesses während der Puppe/Adult-Metamorphose verursacht. Der Grad der durch das Juvenoid verursachten morphologischen Wirkungen am Integument wurde bei anfälligen und resistenten Stämmen analysiert und verglichen.

     

Effects of insect growth regulators on the tobacco cutworm, Spodoptera litura: Rectal prolapse

Prolapse of the rectum was observed when ZR-515 (isopropyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) was applied to the 6th instar larva of the tobacco cutworm, Spodoptera litura. It was induced by an administration of ZR-515 in the middle of the 6th instar larval stage, and either by a dose higher than required for the induction of larval-pupal intermediates or by a dose lower than the dose that produces extra larvae. Larvae with a rectal prolapse appeared only on the 3rd day after treatment. These larvae did not survive for more than 1 to 2 days because the prolapsed rectum ruptured, leading to haemorrhage.Rectal prolapse was also induced by other two IGRs, ZR-512 (ethyl 3,7,11-trimethyl-2,4-dodecadienoate) and ZR-619 (ethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienethiolate).     

Effects of the anti hormone-hormone mimic ETB on the induction of insect juvenile hormone esterase in Trichoplusia ni.

Juvenile hormone (JH) esterases can be artificially induced to appear in the hemolymph of last instar larvae of the lepidopterous insect $\text{Trichoplusia}$$\text{ni}$ (Noctuidae) by topical treatment with JH I, JH II, or dihomo branched juvenoids. ETB (ethyl-4-[2-(t-butylcarbonyloxy) butoxy] benzoate; ZR-2646) at high doses is a weak inducer of JH esterase (JHE). However, at doses of ETB that induce only low levels of JHE activity, ETB will block the JHE induction caused by the dihomo juvenoid epofenonane and at higher doses will reduce the induction caused by JH I or JH II. ETB is not a JHE inhibitor; rather, it appears to be acting as a JH agonist/antagonist in normal larvae and in isolated abdomens. These effects of ETB on JHE induction may illustrate a new mode of action of anti-JH's.     

Critical Sensitivity of the Ovary of <Emphasis Type="Italic">Aedes aegypti</Emphasis> Adults to Sterilization by Juvenile Hormone Mimics

STERILIZATION of adult insects with juvenile hormone mimics has been reported several times^1–5, but only once for adult mosquitoes and no details were given². I report here on the sterilizing effect of three juvenile hormone mimics on female Aedes aegypti. They were (i) mixed geometric isomers of methyl 10,11-epoxy-3,7,11-trimethyl-2,6-tridecadienoate (CJH2), one of two substances with high juvenile hormone activity isolated from Cecropia oil⁶; (ii) mixed geometric isomers of farnesyl methyl ether (FME) and (iii) 2 cis/trans, 6 trans farnesenic acid ethyl ester (FAE). All three compounds were first tested on fifth instar Rhodnius prolixus using Wiggles-worth's method⁷. The doses to give a score of ten were as follows: CJH2 1.3µg; FME 1.4 µg; FAE 31.7 µg.     

Cross communication between signaling pathways: juvenoid hormones modulate ecdysteroid activity in a crustacean

Methyl farnesoate is a juvenoid hormone that regulates a variety of processes in crustaceans including male sex determination among daphnids (Branchiopoda, Cladocera). The synthetic juvenoids pyriproxyfen and fenoxycarb mimic the action of methyl farnesoate in daphnids. In the present study we tested the hypothesis that juvenoids also can regulate ecdysteroid activity in a crustacean (Daphnia magna). Methyl farnesoate, pyriproxyfen, and fenoxycarb all disrupted ecdysteroid-regulated aspects of embryo development in daphnids. Exposure of ecdysteroid-responsive cells to 20-hydroxyecdysone reduced cell proliferation and increased mRNA levels of the ecdysone receptor and its partner protein ultraspiracle. Co-treatment of cells with the juvenoid pyriproxyfen attenuated all of these ecdysteroid mediated responses. While juvenoids functioned as anti-ecdysteroids in both intact embryos and in cultured cells, 20-hydroxyecdysone showed no evidence of acting as an anti-juvenoid. The combined effects of pyroproxyfen with the ecdysteroid synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone were evaluated in an effort to discern whether the action of the juvenoids were additive with those of know anti-ecdysteroids. The anti-ecdysteroid effects of pyriproxyfen were non-additive with those of either anti-ecdysteroid. Rather, joint effects conformed to a model of synergy. These results demonstrated that juvenoids elicit anti-ecdysteroidal activity in a crustacean through a unique mechanism of action. A model involving receptor partner deprivation is proposed that explains the synergistic interactions observed.     

Morphogenetic and physiological effects of a juvenile hormone analogue on the light brown apple moth,Epiphyas postvittana (Lepidoptera: Tortricidae)

Abstract

The juvenile hormone analogue ZR-619—ethyl 11-methoxy-3,7,11-trimethyl-(2E,4E-dodecadienethiolate) —produced morphological and physiological effects when fed via artificial diet to larvae of Epiphyas postvittana (Walker). Morphological effects included changes in larval head and antennal structures after instar V (supernumerary instars); deformation of pupal and adult structures, particularly in genitalia and wings; and development of individuals with varying mixtures of larval and pupal structures. Physiological effects included prolongation of larval life, increase in larval weight, increase in larval instars, and decrease in fecundity. Effects were directly related to dosage concentrations.     

Ethyl (E)-3,5-ethano-7,11-dimethyl-2,4-dodecadienoate,A new insect growth regulator with potent juvenile hormone activity

A number of analogs of ethyl (2E,4E)-3,7,11-trimethyl-2,4-dodecadienoate were prepared and bioassayed for juvenile hormone activity on the yellow-fever mosquito (Aedes aegypti), the greater wax moth (Galleria mellonella), the yellow mealworm (Tenebrio molitor), the house fly (Musca domestica), and the tobacco budworm (Heliothis virescens). The analog ethyl (E)-3,5-ethanol-7,11-dimethyl-2,4-dodecadienoate (VI), containing a cyclopentene ring, showed remarkable potency on the above insect species. Since this compound possesses a fixed 3-s-trans-diene conformation it may provide some insight into the active conformation of bound 2,4-dienoate analogs.     

A Network Pharmacology Study of Chinese Medicine QiShenYiQi to Reveal Its Underlying Multi-Compound,Multi-Target,Multi-Pathway Mode of Action

Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine, QiShenYiQi (QSYQ), on myocardial infarction. QSYQ is composed of Astragalus membranaceus (Huangqi), Salvia miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and Dalbergia odorifera (Jiangxiang). Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched in ArrayTrack. 55 potential targets of QSYQ were identified, of which 14 were confirmed in CVD-related literatures with experimental supporting evidences. Furthermore, three sesquiterpene components of QSYQ, Trans-nerolidol, (3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol and (3S,6R,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol from Dalbergia odorifera T. Chen, were validated experimentally in this study. Their anti-inflammatory effects and potential targets including extracellular signal-regulated kinase-1/2, peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 were identified. Finally, through a three-level compound-target-pathway network with experimental analysis, our study depicts a complex MOA of QSYQ on myocardial infarction.     

Development of superfluous soldiers induced by juvenile hormone analogues in the termite,Reticulitermes lucifugus santonensis

Summary The synthetic juvenile hormone (JH): 17% alltrans+83%trans, trans, cis-methyl 10-epoxy-3,7,11-trimethyl-2,6 tridecadienoate and juvenile hormone analogues (JHA): methyl 10-chloro-3,7,11-trimethyl-2 dodecenoate and ethyl 10-epoxy-3,7,11-trimethyl-2,6-dodecadienoate administered on filter paper to small groups of the European subterranean termiteReticulitermes lucifugus santonensis Feyt. caused differentiation of larvae and pseudergates into pre-soldiers and/or pseudergate-soldier intercastes. In contrast to the proportion of one soldier to 100–300 other individuals in normal colonies, the effect of the compounds tested that showed JH activity was to induce the development of a large number of superfluous soldiers in quantities that even exceeded the number of other kinds of individuals. Such a disturbance in the caste ratio leads to increased mortality.

---

Zusammenfassung Das synthetische Juvenilhormon (JH): 17% alltrans+83%trans, trans, cis-Methyl 10-epoxy-3,7,11-trimethyl-2,6 tridecadienoate und die Juvenilhormonanaloge (JHA): Methyl 10-chloro-3,7,11-trimethyl-2 dodecenoate und Ethyl 10-epoxy-3,7,11-trimethyl-2,6-dodecadienoate, die auf Filterpapier kleinen Termitengruppen der europäischen ErdtermitenartReticulitermes lucifugus santonensis Feyt. zugeführt wurden, verursachten eine Differenzierung von Larven und Pseudergaten in Vorsoldaten und/oder Interkasten Pseudergate-Soldat. Zum Unterschied vom Verhältnis ein Soldat zu 100 bis 300 anderen Individuen in normalen Kolonien erscheint unter der Einwirkung der getesteten juvenilhormonwirksamen Stoffe eine grosse Menge überzähliger Soldaten, deren Anzahl jene der übrigen Individuen sogar übersteigen kann. Die Gleichgewichtstörung zwischen den Kasten hat eine höhere Absterberate der Termiten zur Folge.

---

Résumé L'hormone juvénile synthétique: 17% alltrans+83%trans, trans, cis-méthyle 10-epoxy-3,7,11-triméthyle-2,6 tridecadienoate et l'analogue de l'hormone juvénile: méthyle 10-chloro-3,7,11-triméthyle-2 dodecenoate et éthyle 10-epoxy-3,7,11-triméthyle-2,6-dodecadienoate, qui ont été administrés amenés sur papier filtre à de petits groupes de termitesReticulitermes lucifugus santonensis Feyt., ont causé une différenciation de larves et de pseudergates en présoldats et/ou intermédiaires pseudergate-soldat. A la différence du rapport de 1 soldat à 100–300 autres individus dans des colonies normales, on assiste sous l'effet de la substance testée avec effet d'hormone juvénile à l'apparition d'un grand nombre de soldats en surplus, dont le nombre peut même dépasser celui des autres individus. Le trouble de l'équilibre entre les castes conduit à un taux de mortalité supérieur des termites.

---

---

Dedicated to Prof.K. Gösswald at the occasion of his 65th birthday.     

Pupariation in flies: A tool for monitoring effects of drugs,venoms, and other neurotoxic compounds

A complex Sarcophaga bullata pupariation assay was used to evaluate the neurotropic effects of several drugs, venoms, and insecticides. The assay consists of tests for (1) immediate effects on the intact larva, (2) effects on ligated (ie, isolated from the central nervous system) larval abdomens, (3) morphogenetic effects on the puparium, and (4) effects on stereotyped pupariation behavior. The latter are monitored barographically by recording changes in hemocoelic pressure. Of 62 compounds screened, 18 showed morphogenetic activity at a threshold dose of 5 μg or less, 11 at a dose of 50 μg, four at a dose of 100 μg, and 29 showed no morphogenetic activity. From a comparison of the putative pharmacological actions of the tested compounds with their morphogenetic effects, certain generalizations can be made: Agents that paralyze neuromuscular systems at the peripheral level (eg, tetrodotoxin), or suppress or modify basic motor patterns centrally (eg, veratrine sulphate), cause retention of larval morphological characters in the puparium. Compounds that stimulate convulsive contractions of segmental musculature (mostly cholinergic drugs like eserine sulphate, nicotine, organophosphate insecticides) cause retention of larval segmentation on longitudinally contracted puparia. Five compounds (venom of the scorpion, Leirus quinquestriatus, pyrethrins, protoveratrine A, and kainic and quisqualic acids) stimulate musculature of the denervated abdomen. Barographic monitoring of changes in pupariation behavior appears to be a most sensitive and informative test. It reveals great differences in the ways in which compounds producing seemingly identical morphogenetic effects affect and modify behavior, thus making pharmacological classification more accurate.     

Specific Features of Haller's Organ Regeneration in the Tick Haemaphysalis longicornis (Acari,Ixodidae) in the Presence of Methoprene and Retinoic Acid

The results of experiments on regeneration of the Haller's sensory organ in the metastriate ixodid tick Haemaphysalis longicornisNeumann in the presence of the juvenoid methoprene and retinoic acid and of studies of its structural changes by SEM confirmed the similarity of prostriate and metastriate ixodids as concerns the juvenalizing effect of the above morphogens on regenerative processes during nymphal-imaginal metamorphosis. However, the metastriate ticks (Haemaphysalis and earlier studied Hyalomma) are well behind the prostriate ticks (Ixodes) as concerns the extent of changes induced by juvenoids and retinoids in the sensillar sets of Haller's organ regenerates.     

Acyclic diterpenes from Croton kerrii

Croton kerrii; Euphorbiaceae; acyclic diterpenes; anti-reserpine ulcer; (E,E,Z)-11- hydroxymethyl-3,7,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol; (E,E,E)-11-formyl-3,7,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol.     

Circadian control of the cellular response to β-ecdysone in Drosophila lebanonensis

Drosophila lebanonensis displays a strict circadian rhythm with regard to the puparium formation and the occurrence of ecdysone-specific puffs in the salivary gland chromosomes. In normal development these puffs occur 3–4 hours before puparium formation. Injection of β-ecdysone at periods before ecdysone puffs are present, induces in all instances their appearance within 30 minutes, irrespective of the phase of the circadian oscillation at the time of injection. In spite of the appearance of the hormone specific puffs following β-ecdysone injection, puparium formation did not occur 3–4 hours after the puffs became active. Depending upon the time of injection within the circadian cycle, puparium formation occurred 5–6 hours after injection (when injection was performed close to a “gate” period), or occurred during the next “gate” of the circadian oscillation.     

Morphogenetic derangements in the reproductive system of Bracon hebetor, a beneficial parasitoid, bred on juvenoid treated host (Corcyra cephalonica) larvae

Effect of juvenoids (hydroprene and methoprene) on the ecto-parasite B. hebetor was investigated by rearing them upon the juvenoid treated ultimate instar host larvae of C. cephalonica. Emerged adultoid wasps of either sexes obtained from treated series showed anatomical deformities in the reproductive systems. Ill-developed ovaries with reduced length, terminally free ovarioles and abnormal testicular growth showing non-fusion of lobes were the important abnormal features. Data on measurements of male reproductive system, e.g., width (transverse axis) of testis, length of common vas deferens plus ejaculatory duct and length of accessory gland showed significant difference (P < 0.05) from control.     

Effect of juvenile hormone on the autonomic nervous system

The effects of juvenoids on the autonomic nervous system, which controls certain physiological functions by means of special extracardiac pulsations in hemolymph pressure, have been studied in pupae of the mealworm, Tenebrio molitor. Prolonged tensiometric monitoring of the hemolymph pressure changes revealed that the extra-pupal development that had been caused by juvenoids evoked unusual reappearance of prepupal pattern of extracardiac pulsations. By contrast, the specific pharate adult types of the pulsations completely disappeared. The functioning of the autonomic nervous system was aberrant or incomplete during an unsuccessful extra-pupal ecdysis. It is suggested that malfunction of the autonomic nervous system in the extra-pupal instars may be the reason for the ecdysial failures associated with the use of juvenoids.     

Some effects of a cyclic and an acyclic juvenoid onAphidoletes aphidimyza [Dipt.: Cecidomyiidae]

Ethyl 4(4′-benzylphenoxy)-3methyl-2 butenoate (cpdI) and ethyl (2E, 4E)-3, 7, 11 trimethyl-2, 4-dodecadienoate (cpdII) proved to affect the hatch and embryonic development of the eggs of the aphids' predatorAphidoletes aphidimyza. The median effective concentrations of these compounds were 0.42 and 0.0029% respectively. The juvenoids inhibited the development of treated 4 days old larvae, L₄, to the adult stage. The median effective concentrations were 0.1 and 0.0011% for cpdI and cpdII respectively. The selective effects of the two juvenoids againstMyzus persicae and its predatorA. aphidimyza are discussed.     

Structure,haemolymph titre,and regulatory effects of juvenile homone during ovarian maturation in Leucophaea maderae

Juvenile hormone (JH) synthesized and secreted in vitro by the corpora allata of mated adult Leucophaea maderae females was determined to be JH III (methyl-10,11-epoxy-3,7,11-trimethyl-2,6-dodecadienoate).The haemolymph titre of JH was determined during maturation of the terminal oöcytes in the first reproductive cycle of L. maderae. In virgin females, JH is not detectable in the haemolymph during the first eight days following adult emergence; however, by 10 days after emergence, trace quantities of JH are apparent. Mating stimuli induce a dramatic increase in the concentration of haemolymph JH, with a peak occurring approximately 12 days after mating; thereafter, the JH concentration declines until it has reached an undetectable level 19 days after mating, at the time of chorion deposition.During ovarian maturation, changes in the rates of synthesis of vitellogenin by the fat body and DNA by the ovary correlate closely with the haemolymph titre of JH. However, no such correlation exists between the JH titre and the extensive ovarian protein synthesis that occurs in L. maderae coincident with chorion formation.The effects of JH I and JH III on both vitellogenin synthesis and ovarain DNA synthesis are statistically similar.