Insecticide accommodation and resistance are limiting factors to the much-needed increase in agricultural production. Various physiological and cellular modifications, such as the changes of ...insecticide molecular targets, have been linked to these events. Thus, a previous study demonstrated that the imidacloprid accommodation set up by the cockroach Periplaneta americana after an exposure to a sublethal dose of this insecticide involves functional alterations of two nicotinic acetylcholine receptor (nAChR) subtypes. As RNA interference (RNAi) is one of the most promising strategies for controlling pest insects, we evaluated, in this study, the use of RNAi that targets the β1 nAChR subunit to counteract the imidacloprid accommodation phenomenon in cockroaches. Interestingly, we showed that ingestion of dsRNA-β1 increased the sensitivity to imidacloprid of accommodated cockroaches. Thus, we have demonstrated for the first time that RNAi that targets an nAChR subunit can counteract the accommodation mechanism to insecticide targeting nAChRs set up by an insect.
Neonicotinoids are the most important class of insecticides used as pest management tools during several decades. Exposition of insect to sublethal dose of insecticide induces physiological and ...cellular changes that could contribute to the adaptation of the insects in order to loss their sensitivity to insecticides. The aim of our study is to demonstrate that a subchronic exposure to a sublethal dose of a neonicotinoid imidacloprid is sufficient to induce molecular changes leading to a loss of imidacloprid sensitivity. We report that in the cockroach, Periplaneta americana, subchronic exposure to a sublethal dose of imidacloprid induced weak changes in detoxification enzyme activity and a significant decrease of the nicotinic acetylcholine α2 mRNA. This molecular effect is correlated to a decrease of imidacloprid sensitivity of cockroaches. Using RNA interference, we shown the key role of nicotinic acetylcholine α2 subunit in imidacloprid sensitivity. Thus, quantitative changes in insecticide targets lead to decreased sensitivity to insecticides. This parameter needs to be considered in order to develop sustainable insect resistance management strategies.
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•Exposure to a sublethal dose of imidacloprid induces acclimation of cockroaches.•This acclimation persists overtime in absence of imidacloprid exposure.•Acclimation results in decreased sensitivity of cockroaches to imidacloprid.•Decrease of α2 nAChR subunit expression contributes to this phenomenon.
Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF), especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor ...erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype (α-smooth muscle actin and collagen I expression, proliferation, migration, and contraction) were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane (SFN), an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions (transforming growth factor β TGF-β).
Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and myofibroblastic dedifferentiation in IPF fibroblasts. SFN inhibited TGF-β profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated.
Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.
In the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1
) and the sodium channel (kdr
) genes confer resistance to organophosphate/carbamate and pyrethroid ...insecticides, respectively. The mechanisms of compensation that recover the functional alterations associated with these mutations and their role in the modulation of insecticide efficacy are unknown. Using multidisciplinary approaches adapted to neurons isolated from resistant Anopheles gambiae AcerKis and KdrKis strains together with larval bioassays, we demonstrate that nAChRs, and the intracellular calcium concentration represent the key components of an adaptation strategy ensuring neuronal functions maintenance. In AcerKis neurons, the increased effect of acetylcholine related to the reduced acetylcholinesterase activity is compensated by expressing higher density of nAChRs permeable to calcium. In KdrKis neurons, changes in the biophysical properties of the L1014F mutant sodium channel, leading to enhance overlap between activation and inactivation relationships, diminish the resting membrane potential and reduce the fraction of calcium channels available involved in acetylcholine release. Together with the lower intracellular basal calcium concentration observed, these factors increase nAChRs sensitivity to maintain the effect of low concentration of acetylcholine. These results explain the opposite effects of the insecticide clothianidin observed in AcerKis and KdrKis neurons in vitro and in vivo.
The effective control of insect pests is based on the use of insecticides. Most of these compounds act on molecular targets in the insect nervous system. However, the largescale deployment of ...insecticide treatment has led to the development of resistance, which decreases insecticide efficacy. Although the resistance mechanisms are largely studied today, this review aims to point out new insights on the less-known cellular and molecular factors involved in the modulation of the sensitivity of the targets to insecticides. This review will focus on the phosphorylation/dephosphorylation process, the post-transcriptional events such as editing and alternative splicing and the influence of the association with auxiliary proteins of the receptors and/or ion channels targeted by insecticides. In addition, the involvement of calcium-dependent signaling pathways in the modulation of the sensitivity of the target to insecticides will also be considered and discussed. Finally, this review will insist on different strategies proposed to optimize the efficacy of insecticide treatment while reducing doses to decrease side effects on environment and on non-target organisms by combining two different chemical insecticides or a given active ingredient associated with biological and/or chemical synergistic agents. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity".
•Subchronic exposure to imidacloprid changes neuronal nicotinic receptor properties.•Treatment differentially alters biophysical properties of nicotinic receptor subtypes.•Pattern expression of ...nicotinic receptor subtypes are modified.•Insects develop adaptive mechanisms in response to imidacloprid subchronic exposure.
Neonicotinoids are the most important class of insecticides used in agriculture over the last decade. They act as selective agonists of insect nicotinic acetylcholine receptors (nAChRs). The emergence of insect resistance to these insecticides is one of the major problems, which limit the use of neonicotinoids. The aim of our study is to better understand physiological changes appearing after subchronic exposure to sublethal doses of insecticide using complementary approaches that include toxicology, electrophysiology, molecular biology and calcium imaging. We used cockroach neurosecretory cells identified as dorsal unpaired median (DUM) neurons, known to express two α-bungarotoxin-insensitive (α-bgt-insensitive) nAChR subtypes, nAChR1 and nAChR2, which differ in their sensitivity to imidacloprid. Although nAChR1 is sensitive to imidacloprid, nAChR2 is insensitive to this insecticide. In this study, we demonstrate that subchronic exposure to sublethal dose of imidacloprid differentially changes physiological and molecular properties of nAChR1 and nAChR2. Our findings reported that this treatment decreased the sensitivity of nAChR1 to imidacloprid, reduced current density flowing through this nAChR subtype but did not affect its subunit composition (α3, α8 and β1). Subchronic exposure to sublethal dose of imidacloprid also affected nAChR2 functions. However, these effects were different from those reported on nAChR1. We observed changes in nAChR2 conformational state, which could be related to modification of the subunit composition (α1, α2 and β1). Finally, the subchronic exposure affecting both nAChR1 and nAChR2 seemed to be linked to the elevation of the steady-state resting intracellular calcium level. In conclusion, under subchronic exposure to sublethal dose of imidacloprid, cockroaches are capable of triggering adaptive mechanisms by reducing the participation of imidacloprid-sensitive nAChR1 and by optimizing functional properties of nAChR2, which is insensitive to this insecticide.
Particulate matter (PM) from atmospheric pollution can easily deposit in the lungs and induce recruitment of inflammatory cells, a source of inflammatory cytokines, oxidants, and matrix ...metalloproteases (MMPs), which are important players in lung structural homeostasis. In many large cities, the subway system is a potent source of PM emission, but little is known about the biological effects of PM from this source. We performed a comprehensive study to evaluate the biological effects of PM sampled at two sites (RER and Metro) in the Paris subway system. Murine macrophages (RAW 264.7) and C57Bl/6 mice, respectively, were exposed to 0.01–10 µg/cm2 and 5–100 µg/mouse subway PM or reference materials carbon black (CB), titanium dioxide (TiO2), or diesel exhaust particles (DEPs). We analyzed cell viability, production of cellular and lung proinflammatory cytokines tumor necrosis factor α (TNFα), macrophage inflammatory protein (MIP-2), KC (the murin analog of interleukin-8), and granulocyte macrophage-colony stimulating factor (GM-CSF), and mRNA or protein expression of MMP-2, -9, and -12 and heme oxygenase-1 (HO-1). Deferoxamine and polymixin B were used to evaluate the roles of iron and endotoxin, respectively. Noncytotoxic concentrations of subway PM (but not CB, TiO2, or DEPs) induced a time- and dose-dependent increase in TNFα and MIP-2 production by RAW 264.7 cells, in a manner involving, at least in part, PM iron content (34% inhibition of TNF production 8 h after stimulation of RAW 264.7 cells with 10 µg/cm2 RER particles pretreated with deferoxamine). Similar increased cytokine production was transiently observed in vivo in mice and was accompanied by an increased neutrophil cellularity of bronchoalveolar lavage (84.83 ± 0.98% of polymorphonuclear neutrophils for RER-treated mice after 24 h vs 7.33 ± 0.99% for vehicle-treated animals). Subway PM induced an increased expression of MMP-12 and HO-1 both in vitro and in vivo. PM from the Paris subway system has transient biological effects. Further studies are needed to better understand the pathophysiological implications of these findings.
We experimentally investigated the influence of developmental plasticity of ultraviolet (UV) visual sensitivity on predation efficiency of the larval smooth newt, Lissotriton vulgaris. We quantified ...expression of SWS1 opsin gene (UV-sensitive protein of photoreceptor cells) in the retinas of individuals who had developed in the presence (UV+) or absence (UV−) of UV light (developmental treatments), and tested their predation efficiency under UV+ and UV− light (testing treatments). We found that both SWS1 opsin expression and predation efficiency were significantly reduced in the UV− developmental group. Larvae in the UV− testing environment displayed consistently lower predation efficiency regardless of their developmental treatment. These results prove for the first time, we believe, functional UV vision and developmental plasticity of UV sensitivity in an amphibian at the larval stage. They also demonstrate that UV wavelengths enhance predation efficiency and suggest that the magnitude of the behavioural response depends on retinal properties induced by the developmental lighting environment.
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