Search

Accurate control of innate behaviors associated with developmental transitions requires functional integration of hormonal and neural signals. Insect molting is regulated by a set of neuropeptides, which trigger periodic pulses in ecdysteroid hormone titers and coordinate shedding of the old cuticle during ecdysis. In the current study, we demonstrate that crustacean cardioactive peptide (CCAP), a structurally conserved neuropeptide described to induce the ecdysis motor program, also exhibits a previously unknown prothoracicostatic activity to regulate ecdysteroid production in the desert locust, Schistocerca gregaria. We identified the locust genes encoding the CCAP precursor and three G protein-coupled receptors that are activated by CCAP with EC50 values in the (sub)nanomolar range. Spatiotemporal expression profiles of the receptors revealed expression in the prothoracic glands, the endocrine organs where ecdysteroidogenesis occurs. RNAi-mediated knockdown of CCAP precursor or receptors resulted in significantly elevated transcript levels of several Halloween genes, which encode ecdysteroid biosynthesis enzymes, and in elevated ecdysteroid levels one day prior to ecdysis. Moreover, prothoracic gland explants exhibited decreased secretion of ecdysteroids in the presence of CCAP. Our results unequivocally identify CCAP as the first prothoracicostatic peptide discovered in a hemimetabolan species and reveal the existence of an intricate interplay between CCAP signaling and ecdysteroidogenesis. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:22 issue:24 ispartof: location:Switzerland status: published

Nutrient uptake and digestion are essential for optimal growth and development. In insects, these processes are regulated by the gut-brain axis, which is a neurohumoral communication system for maintaining gut homeostasis. The insect gut is a complex organ consisting of three distinct structures, denominated foregut, midgut and hindgut, each with their specific specializations. These specializations are tightly regulated by the interplay of several neuropeptides: a versatile group of signalling molecules involved in a multitude of processes including gut physiology. Neuropeptides take part in the regulation of gut processes ranging from digestive enzyme release to muscle activity and satiety. Some neuropeptide mimetics are a promising strategy for ecological pest management. This review focuses on a selection of neuropeptides that are well-known for their role in gut physiology, and neuropeptides for which the mode of action is yet to be unravelled.

Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and ThyX, only ThyX is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against ThyX. We exploited the NADPH oxidation to NADP+ step, catalyzed by ThyX, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z'=0.77) and identification of selective ThyX inhibitors. The most potent compound is a tight-binding inhibitor with an IC50 of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of ThyX mechanism and substrate and cofactor binding order. publisher: Elsevier articletitle: Discovery of a new Mycobacterium tuberculosis thymidylate synthase X inhibitor with a unique inhibition profile journaltitle: Biochemical Pharmacology articlelink: http://dx.doi.org/10.1016/j.bcp.2017.03.017 content_type: article copyright: © 2017 Published by Elsevier Inc. ispartof: Biochemical Pharmacology vol:135 pages:69-78 ispartof: location:England status: published