Mechanism Of Desensitization Research Articles

Time-Dependent Odorant Sensitivity Modulation in Insects.

Simple SummaryInsects, including blood-feeding female mosquitoes, can transmit deadly diseases, such as malaria, encephalitis, dengue, and yellow fever. Insects use olfaction to locate food sources, mates, and hosts. The nature of odorant plumes poses a challenge for insects in locating odorant sources in the environment. In order to modulate the system for the detection of fresh stimuli or changes in odorant concentrations, the olfaction system desensitizes to different concentrations and durations of stimuli. Without this ability, the chemotaxis behaviors of insects are defective. Thus, understanding how insects adjust their olfactory response dynamics to parse the chemical language of the external environment is not only a basic biology question but also has far-reaching implications for repellents and pest control. Insects use olfaction to detect ecologically relevant chemicals in their environment. To maintain useful responses over a variety of stimuli, olfactory receptor neurons are desensitized to prolonged or high concentrations of stimuli. Depending on the timescale, the desensitization is classified as short-term, which typically spans a few seconds; or long-term, which spans from minutes to hours. Compared with the well-studied mechanisms of desensitization in vertebrate olfactory neurons, the mechanisms underlying invertebrate olfactory sensitivity regulation remain poorly understood. Recently, using a large-scale functional screen, a conserved critical receptor phosphorylation site has been identified in the model insect Drosophila melanogaster, providing new insight into the molecular basis of desensitization in insects. Here, we summarize the progress in this area and provide perspectives on future directions to determine the molecular mechanisms that orchestrate the desensitization in insect olfaction.

Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.

Signalling of the calcitonin-like receptor (CLR) is multifaceted, due to its interaction with receptor activity modifying proteins (RAMPs), and three endogenous peptide agonists. Previous studies have focused on the bias of G protein signalling mediated by the receptor and receptor internalisation of the CLR-RAMP complex has been assumed to follow the same pattern as other Class B1 G Protein-Coupled Receptors (GPCRs). Here we sought to measure desensitisation of the three CLR-RAMP complexes in response to the three peptide agonists, through the measurement of β-arrestin recruitment and internalisation. We then delved further into the mechanism of desensitisation through modulation of β-arrestin activity and the expression of GPCR kinases (GRKs), a key component of homologous GPCR desensitisation. First, we have shown that CLR-RAMP1 is capable of potently recruiting β-arrestin1 and 2, subsequently undergoing rapid endocytosis, and that CLR-RAMP2 and -RAMP3 also utilise these pathways, although to a lesser extent. Following this we have shown that agonist-dependent internalisation of CLR is β-arrestin dependent, but not required for full agonism. Overexpression of GRK2-6 was then found to decrease receptor signalling, due to an agonist-independent reduction in surface expression of the CLR-RAMP complex. These results represent the first systematic analysis of the importance of β-arrestins and GRKs in CLR-RAMP signal transduction and pave the way for further investigation regarding other Class B1 GPCRs.

Covid-induced nasal desensitization mechanism and physiology

Covid-induced nasal desensitization mechanism and physiology

Structural mechanism of muscle nicotinic receptor desensitization and block by curare.

Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three-dimensional structure how agonists and antagonists alter nicotinic acetylcholine receptor conformation. We used the muscle-type receptor from the Torpedo ray to first define the structure of the receptor in a resting, activatable state. We then determined the receptor structure bound to the agonist carbachol, which stabilizes an asymmetric, closed channel desensitized state. We find conformational changes in a peripheral membrane helix are tied to recovery from desensitization. To probe mechanisms of antagonism, we obtained receptor structures with the active component of curare, a poison arrow toxin and precursor to modern muscle relaxants. d-Tubocurarine stabilizes the receptor in a desensitized-like state in the presence and absence of agonist. These findings define the transitions between resting and desensitized states and reveal divergent means by which antagonists block channel activity of the muscle-type nicotinic receptor.

Desensitization to drugs in children

Better knowledge and understanding about drug desensitization is required in the pediatric population, since there is little literature available about it and the most pediatric desensitization protocols have been adapted from adult instructions.Aiming to soften this issue and foster the future studies, this article presents a recent review about mechanisms of desensitization, diagnostic tools, and up to date management of drug hypersensitivity reactions in children. Bringing up an overview of pediatric hypersensitivity reactions to chemotherapy, biologic agents, antibiotics, nonsteroidal anti-inflammatory drugs, and vaccines.

Desensitization for the prevention of drug hypersensitivity reactions.

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca2+ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal antiinflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Studies on Cashew and Shrimp-Oral Immunotherapy-Induced Changes in Allergen-Reactive CD4+ T Cells

Oral Immunotherapy (OIT) is a promising intervention for food allergic individuals and has been FDA-approved to treat peanut allergy. Various hitherto studies have probed the clinical efficacy and immune mechanism of OIT-induced desensitization to peanut, milk, and egg, although immunomodulatory effects of cashew and shrimp-OIT have not been investigated. Thus, we examined pre- vs. post-OIT PBMCs from 38 cashew (n=33) or shrimp (n=5) OIT treated participants.

State-dependent binding of DHA uncovers a mechanism for desensitization of pLGICs

Pentameric ligand-gated ion channels (pLGICs) are essential to ultra-fast synaptic transmission. Dysfunction of these channels is associated with a host of debilitating neurological disorders, including congenital myasthenias and Alzheimer’s dementia. Initial studies on pLGICs noted membrane lipid composition to be integral to proper channel function, with certain lipid species causing complete inactivity. Free fatty acid (FFA) lipid species are important to proper neuronal development and FFA levels in synaptic membranes are altered in pathologic states, such as stroke.

Investigation on thermal characteristics and desensitization mechanism of improved step ladder-structured nitrocellulose

Nitrocellulose, or cellulose nitrate, has received considerable interest due to its various applications, such as propellants, coating agents and gas generators. However, its high mechanical sensitivity caused many accidents during its storage and usage in ammunition. In this work, two kinds of insensitive step ladder-structured nitrocellulose (LNC) with different nitrogen contents were synthesized. The products were characterized by FT-IR, Raman, XRD, SEM, elemental analysis, TGA, DSC, accelerating rate calorimeter analysis (ARC), and drop weight test to study their molecular structure, thermal characteristics and desensitization performance. Compared with raw nitrocellulose, LNC has a sharper exothermic peak in the DSC and ARC curves. The H50 values of the two kinds of LNC increased from 25.76 to 30.01 cm for low nitrogen content and from 18.02 to 21.84 cm for high nitrogen content, respectively. The results show that the ladder-structure of LNC which provides regular molecular arrangement and a soft buffer made with polyethylene glycol could affect the energy releasing process of LNC and reduce the sensitivity of LNC. Insensitive LNC provides an alternative to be used as a binder in insensitive propellants formulation.

Dermatan sulfate and chondroitin sulfate from Lophius litulon alleviate the allergy sensitized by major royal jelly protein 1.

The objective of the present study was to explore the desensitization effect of dermatan sulfate (DS) and chondroitin sulfate (CS) from Lophius litulon (Ll) on mice sensitized by major royal jelly protein 1 (MRJP1). First, the affinity between six glycosaminoglycans and the MRJP1 polyclonal antibody was measured by the ELISA method. Lophius litulon dermatan sulfate (Ll DS) and Lophius litulon chondroitin sulfate (Ll CS) were selected due to their highest binding affinity. Second, the molecular docking method was used to explore the interaction between Ll DS and MRJP1 and Ll CS and MRJP1. The results showed that Ll DS and Ll CS combined with MRJP1 successfully, which meant a potential function of relieving the MRJP1-caused allergy. Finally, the MRJP1-sensitized mice model was established and confirmed that Ll DS and Ll CS had the desensitization ability to relieve MRJP1-induced allergic symptoms. To validate the conclusion, the relief of allergic symptoms in mice was observed. The production of total IgE, MRJP1-specific IgE and histamine was measured. The desensitization mechanism was further studied by measuring cytokines (IL-4 and IFN-γ) from splenocytes stimulated with MRJP1 in vitro. Based on in vivo and in vitro experiments, it was confirmed that Ll DS and Ll CS have the ability to alleviate MRJP1-induced allergic symptoms, which proposes a potential candidate material against IgE-mediated food allergy.

Тревожные расстройства в клинической практике - современный взгляд на проблему терапии

Clinically significant anxiety occurs in 5-7% of the general population and in 25% or more of patients seen by general practitioners. The lifetime incidence of anxiety disorders can be over 30%. Anxiety in adolescence and young adulthood often later develops into depression. The line between a “normal” response to a threat and a pathological anxiety disorder is often very blurred and there may be a continuum from personal distress to mental disorder. The real clinical situation is that most people with anxiety do not have their diagnosis. Only about a quarter (27.6%) of people who meet DSM-V, criteria for anxiety disorder receive treatment. The aim of the study was to optimize the treatment of anxiety disorders using the drug Mexidol®, taking into account modern data of epidemiology and neurobiology. Material and methods. This review is based on relevant publications obtained through selective searches in PubMed from 2010 to 2020 (58 references). The search was conducted for the following words: anxiety disorders, terminology, Mexidol®. The presence of at least one of these keywords served as a criterion for inclusion in this review. Results and discussion. Recently, there have been changes in the classification of anxiety disorders terminology. In ICD-10, disorders that were previously defined as neuroses are now located systemically in the headings F40 - F42: panic disorder, agoraphobia, social phobia; specific isolated phobias; general anxiety disorder, obsessive thoughts, compulsive actions and others. Estimates are widely spread across countries, with the highest prevalence in low-income countries (5.0%), lower in middle-income countries (2.8%), and lowest in high-income countries (1.6%). Mixed anxiety-depressive disorders are also one of the manifestations of chronic cerebral ischemia (CCI). In order to optimize treatment and to consider development of psychosomatic pathology in patients with anxiety disorders, Mexidol® is widely used. It has a vegetotropic, anti-stress, anxiolytic and other effects. Mexidol® creates a mechanism for biological desensitization of recurring neurotic, anxious experiences, stabilizes the parameters of the neuropsychiatric status. Conclusions. Our clinical and research experience shows that the management of patients with anxiety disorders can be optimized with the use of Mexidol®. Against the background of sequential drug therapy in most studies, a regression of affective disorders was noted (a decrease in the severity of anxiety, depressive manifestations, and asthenic syndrome). Keywords: anxiety disorders, terminology features, Mexidol®.

Assessing Artemisia arborescens essential oil compositions, antimicrobial, cytotoxic, anti-inflammatory, and neuroprotective effects gathered from two geographic locations in Palestine

Artemisia arborescens essential oil (EO), collected from two Palestinian regions, Bethlehem and Jenin, were extracted by hydro-distillation and examined for their chemical compositions, cytotoxic, antimicrobial, cyclooxygenase (COX) enzyme inhibitory effects, and their influence on neuronal (AMPA) receptors. The EO sample from Bethlehem A. arborescens had just 13 molecules, which accounted 100% of the total EO. Meanwhile, 18 molecules that accounted for 100% of the total EO were determined in the Jenin A. arborescens sample. β-thujone (89.64%), camphor (5.34%), and β-pinene (2.01%) were the major molecules in the Bethlehem EO sample, while β-thujone (79.16%), camphor (6.58%), and sabinene (3.44%) were the dominating components in the Jenin EO sample. Moreover, both EOs have antimicrobial effects against all of the examined microorganisms. The EO from Jenin has slightly higher cytotoxic potential against cervical adenocarcinoma (HeLa) cancer cells than the EO from Bethlehem, which has IC50 of 0.326 and 0.467 mg/mL, respectively. The COX inhibitory IC50 calculations showed that A. arborescens EO from Jenin has high potency against COX-1 (1.8 µg/mL). At the same time, the EO from Bethlehem was slightly more potent against COX-2 (IC50 =81.7 µg/mL). Both EOs show significant impacts on the different AMPAR types, yet Jenin EO shows more significant inhibition on amplitude, desensitization, and deactivation mechanisms generated by the receptors. Both EOs may be effective in reducing overexcitation of AMPARs and reducing the effects of ischemia. These results support the possible therapeutic application of A. arborescens EO from both regions to prevent and treat certain pathogenic infections, cancers, inflammations, and neurodegenerative diseases.

P032 STUDIES ON CASHEW AND SHRIMP-ORAL IMMUNOTHERAPY-INDUCED CHANGES IN ALLERGEN-REACTIVE CD4+ T CELLS

Oral Immunotherapy (OIT) is a promising intervention for food allergic individuals, and has been FDA-approved to treat peanut allergy. Various hitherto studies have probed the clinical efficacy and immune mechanism of OIT-induced desensitization to peanut, milk, and egg, although immunomodulatory effects of cashew and shrimp-OIT have not been investigated. Thus, we examined pre- vs. post-OIT PBMCs from 38 cashew (n=33)- or shrimp (n=5)-OIT treated participants.

A010 MASS CYTOMETRY ANALYSIS REVEALS DAMPENING OF TH2 PHENOTYPE AMONG PEANUT-REACTIVE CD4+ T CELLS FOLLOWING PEANUT-OIT

Oral Immunotherapy (OIT) is a promising intervention to treat food allergies. OIT induces desensitization, defined as lack of clinical reactivity to previously offending food allergen, while under active therapy. We sought to understand the immune mechanism of desensitization among study participants successfully desensitized to peanut following peanut OIT.

Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L

AMPA receptors (AMPARs) mediate the majority of excitatory neurotransmission. Their surface expression, trafficking, gating, and pharmacology are regulated by auxiliary subunits. Of the two types of TARP auxiliary subunits, type I TARPs assume activating roles, while type II TARPs serve suppressive functions. We present cryo-EM structures of GluA2 AMPAR in complex with type II TARP γ5, which reduces steady-state currents, increases single-channel conductance, and slows recovery from desensitization. Regulation of AMPAR function depends on its ligand-binding domain (LBD) interaction with the γ5 head domain. GluA2-γ5 complex shows maximum stoichiometry of two TARPs per AMPAR tetramer, being different from type I TARPs but reminiscent of the auxiliary subunit GSG1L. Desensitization of both GluA2-GSG1L and GluA2-γ5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-γ5 but not GluA2-GSG1L LBD dimers remain two-fold symmetric. Different structural architectures and desensitization mechanisms of complexes with auxiliary subunits endow AMPARs with broad functional capabilities.

Desensitization of human breast progenitors by a transient exposure to pregnancy levels of estrogen

Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.

Mechanisms of differential desensitization of metabotropic glutamate receptors.

G protein-coupled receptors (GPCRs) interact with intracellular transducers to control both signal initiation and desensitization, but the distinct mechanisms that control the regulation of different GPCR subtypes are unclear. Here we use fluorescence imaging and electrophysiology to examine the metabotropic glutamate receptor (mGluR) family. We find distinct properties across subtypes in both rapid desensitization and internalization, with striking differences between the group II mGluRs. mGluR3, but not mGluR2, undergoes glutamate-dependent rapid desensitization, internalization, trafficking, and recycling. We map differences between mGluRs to variable Ser/Thr-rich sequences in the C-terminal domain (CTD) that control interaction with both GPCR kinases and β-arrestins. Finally, we identify a cancer-associated mutation, G848E, within the mGluR3 CTD that enhances β-arrestin coupling and internalization, enabling an analysis of mGluR3 β-arrestin-coupling properties and revealing biased variants. Together, this work provides a framework for understanding the distinct regulation and functional roles of mGluR subtypes.

Mechanistic diversity involved in the desensitization of G protein-coupled receptors.

The desensitization of G protein-coupled receptors (GPCRs), which involves rapid loss of responsiveness due to repeated or chronic exposure to agonists, can occur through various mechanisms at different levels of signaling pathways. In this review, the mechanisms of GPCR desensitization are classified according to their occurrence at the receptor level and downstream to the receptor. The desensitization at the receptor level occurs in a phosphorylation-dependent manner, wherein the activated receptors are phosphorylated by GPCR kinases (GRKs), thereby increasing their affinities for arrestins. Arrestins bind to receptors through the cavity on the cytoplasmic region of heptahelical domains and interfere with the binding and activation of G-protein. Diverse mechanisms are involved in the desensitization that occurs downstream of the receptor. Some of these include the sequestration of G proteins, such as Gq and Gi/o by GRK2/3 and deubiquitinated arrestins, respectively. Mechanistically, GRK2/3 attenuates GPCR signaling by sequestering the Gα subunits of the Gq family and Gβγ via regulators of G protein signaling and pleckstrin homology domains, respectively. Moreover, studies on Gi/o-coupled D2-like receptors have reported that arrestins are deubiquitinated under desensitization condition and form a stable complex with Gβγ, thereby preventing them from coupling with Gα and the receptor, eventually leading to receptor signaling inhibition. Notably, the desensitization mechanism that involves arrestin deubiquitination is interesting; however, this is a new mechanism and needs to be explored further.

Transcriptomic and Gene Set Enrichment Analysis of Peanut stimulated CD4+ T cells during Peanut Oral Immunotherapy

Early studies suggest that oral immunotherapy (OIT) decreases Th2 cytokine production, a possible mechanism for desensitization. However, data remains limited on the differences between individuals who develop transient desensitization (TD) versus sustained unresponsiveness (SU), a longer-lasting protection after OIT.

The Importance of Drug Desensitization in Cancer

Drug hypersensitivity reactions (HSRs) to antineoplastic agents have increased in the 21st century with the emergence of new therapeutic agents. Rapid drug desensitization (RDD) to chemotherapeutic agents and monoclonal antibodies (mAbs) has emerged as a safe and effective strategy for those patients who develop HSRs to their necessary medication, given their limited therapeutic options. Drug desensitization (DS) induces a temporary tolerance to the drug, allowing the patient with an HSR to safely receive an uninterrupted course of medication. The knowledge of the recently described new phenotypes, within HSRs, with their corresponding endotypes and biomarkers, provides a better diagnostic approach and more accurate risk stratification for a more secure and effective desensitization protocol. In addition, premedication can be tailored according to the phenotype, endotype and biomarkers of the reaction. Any desensitization should always be carried out with maximum safety in mind and adapted to the care organization of each allergy department. Desensitization is a temporary process, once the medication is discontinued the patient's hypersensitivity to the medication returns. Objective: The aim of this review is to briefly summarize updated information on the mechanisms of desensitization, indications, contraindications, risk stratification and treatment of reactions during desensitization to chemotherapeutic drugs and mAbs. Also to emphasize the importance of maintaining the first-line of treatment in cancer patients, thus improving the patient's life expectancy and quality of life.