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Frontiers in Pharmacology 2018There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane...
There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients.
PubMed: 30416447
DOI: 10.3389/fphar.2018.01221 -
Frontiers in Sociology 2023Queer Theory is a radically deconstructionist perspective within the humanities and social sciences. Since its initial emergence in the late 1980s and early 1990s in the...
Queer Theory is a radically deconstructionist perspective within the humanities and social sciences. Since its initial emergence in the late 1980s and early 1990s in the field of sexualities studies, Queer Theory has increasingly been used to challenges normative notions of self, identity, temporality and the nature of being, more broadly. Whilst Queer Theory has been utilized, to some extent, in gerontology and aging studies, this article makes an original contribution to this endeavor, assessing the potentiality and problems with queer(y)ing three aspects of aging: chronology; cognition; and frailty and vulnerability. To achieve this, the article draws on ideas from some key Queer theorical writers, existing studies of queer aging and illustrates theoretical points with qualitative data collected from two LGBTQ+ projects to illustrate. The article also considers problems with Queer Theory in challenging normativities associated with aging. It is concluded that despite problems, Queer Theory remains an important and valuable theoretical approach for disturbing and challenging many of the norms and understandings that shape and constrain older LGBTQ+ people's lives, in particular, and therefore have importance for how we think and understand aging and later life sociologically.
PubMed: 37841802
DOI: 10.3389/fsoc.2023.1228993 -
Neuropsychopharmacology : Official... Jan 2020Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its...
Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK's acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability.
Topics: Animals; Excitatory Postsynaptic Potentials; Female; Glutamic Acid; Hippocampus; Ketamine; Male; Organ Culture Techniques; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Transmission
PubMed: 31216563
DOI: 10.1038/s41386-019-0443-3 -
American Journal of Respiratory and... Apr 2020Enhancing non-CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic...
Enhancing non-CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Potentiating the activity of TMEM16A with ETX001 increased the Ca-activated Cl channel activity and anion secretion in human bronchial epithelial (HBE) cells from patients with CF without impacting calcium signaling. ETX001 rapidly increased fluid secretion and airway surface liquid height in CF-HBE cells under both static conditions and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases.
Topics: Administration, Inhalation; Animals; Anoctamin-1; Bronchi; Calcium Signaling; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Membrane Transport Modulators; Mucociliary Clearance; Mucus; Patch-Clamp Techniques; Respiration; Respiratory Mucosa; Sheep; Trachea
PubMed: 31898911
DOI: 10.1164/rccm.201908-1641OC -
Journal of Autism and Developmental... Oct 2014Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior.... (Randomized Controlled Trial)
Randomized Controlled Trial
Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We investigated the relationship between social avoidance and emotion-potentiated startle, a probe of amygdala activation, in children and adolescents with FXS, developmental disability without FXS (DD), and typical development. Individuals with FXS or DD demonstrated significantly reduced potentiation to fearful faces than a typically developing control group (p < .05). However, among individuals with FXS, social avoidance correlated positively with fearful-face potentiation (p < .05). This suggests that general intellectual disability blunts amygdalar response, but differential amygdala responsiveness to social stimuli contributes to phenotypic variability among individuals with FXS.
Topics: Acoustic Stimulation; Adolescent; Adult; Amygdala; Anxiety; Child; Child, Preschool; Emotions; Facial Expression; Fear; Female; Fragile X Syndrome; Humans; Male; Photic Stimulation; Reflex, Startle; Young Adult
PubMed: 24816942
DOI: 10.1007/s10803-014-2125-7 -
Journal of Neurophysiology Feb 2018Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect...
Endocannabinoids, such as 2-arachidonoyl glycerol (2-AG) and anandamide, can elicit long-term depression of both excitatory and inhibitory synapses. This latter effect will result in disinhibition and would therefore be expected to produce an increase in neural circuit output. However, there have been no examples directly linking endocannabinoid-mediated disinhibition to a change in a functional neurobehavioral circuit. The present study uses the well-characterized central nervous system of the medicinal leech, Hirudo verbana, to examine the functional/behavioral relevance of endocannabinoid modulation of an identified afferent synapse. Bath application of 2-AG potentiates synaptic transmission by pressure-sensitive sensory neurons (P cells) as well as the magnitude of the defensive shortening reflex elicited by P-cell stimulation. This potentiation requires activation of TRPV-like channels. Endocannabinoid/TRPV signaling was found to produce sensitization of the shortening reflex elicited by either direct stimulation of nearby nociceptive afferents (N cells) or noxious stimulation applied to skin several segments away. In both cases, heterosynaptic potentiation of P-cell synapses was observed in parallel with an increase in the magnitude of elicited shortening and both synaptic and behavioral effects were blocked by pharmacological inhibition of 2-AG synthesis or TRPV-like channel activation. Serotonin (5-HT) is known to play a critical role in sensitization in Hirudo and other animals, and the 5-HT receptor antagonist ritanserin also blocked behavioral sensitization and the accompanying synaptic potentiation. These findings suggest a novel, endocannabinoid-mediated contribution to behavioral sensitization that may interact with known 5-HT-dependent modulatory processes. NEW & NOTEWORTHY There is considerable interest in the analgesic potential of cannabinoids. However, there is evidence that the cannabinoid system can have both pro- and antinociceptive effects. This study examines how an endogenous cannabinoid transmitter can potentiate nonnociceptive synapses and enhance their capacity to elicit a nocifensive behavioral response.
Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Endocannabinoids; Glycerides; Leeches; Muscle Contraction; Neuronal Plasticity; Nociception; Polyunsaturated Alkamides; Reflex; Synapses; TRPV Cation Channels
PubMed: 29118192
DOI: 10.1152/jn.00092.2017 -
The Journal of Biological Chemistry Jun 2018The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and...
The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, leucine-rich repeat-containing, G protein-coupled receptors 4, 5, and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation. Here, we show that RSPO1-4 have differential dependence on LGRs in potentiating Wnt/β-catenin signaling and that RSPO2 can enhance this pathway without any LGR. LGR4 knockout (LGR4KO) in HEK293 cells completely abrogated the Wnt/β-catenin signaling response to RSPO1 and RSPO4 and strongly impaired the response to RSPO3. RSPO2, however, retained robust activity albeit with decreased potency. Complete rescue of RSPO1-4 activity in LGR4KO cells required the seven-transmembrane domain of LGR4. Furthermore, an RSPO2 mutant with normal binding affinity to ZNRF3 but no or little binding to LGR4 or LGR5 still potentiated Wnt/β-catenin signaling , supported the growth of intestinal organoids , and stimulated intestinal crypt growth Mechanistically, RSPO2 could increase Wnt receptor levels in the absence of any LGR without affecting ZNRF3 endocytosis and stability. These findings suggest that RSPO1-4 use distinct mechanisms in regulating Wnt and other signaling pathways, which have important implications for understanding the pleiotropic functions of RSPOs and LGRs in both normal and cancer development.
Topics: Animals; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Organoids; Receptors, G-Protein-Coupled; Signal Transduction; Thrombospondins; Wnt Proteins; beta Catenin
PubMed: 29752411
DOI: 10.1074/jbc.RA118.002743 -
Biological & Pharmaceutical Bulletin 2022Homomeric or heteromeric connexin (Cx) hemichannels-composed gap junction (GJ) intercellular channel can mediate direct cell-to-cell communication. Accumulating studies...
Homomeric or heteromeric connexin (Cx) hemichannels-composed gap junction (GJ) intercellular channel can mediate direct cell-to-cell communication. Accumulating studies indicate that GJs potentiate the cytotoxicity of antitumor drugs in malignant cells. Methylselenocysteine (MSC), a selenium compound from garlic, has been reported to modulate the activity of antineoplastic drugs, but the underlying mechanism remains unclear. This study investigates the efficacy of MSC on chemotherapeutic drugs-induced cytotoxicity and the relationship between this effect and the regulation of GJ function by MSC. Firstly, a doxycycline-regulated HeLa cell line expressing heteromeric Cx26/Cx32 was used as a tool. Etoposide, but not cisplatin or 5-fluorouracil, showed remarkable cytotoxicity in high-density (with GJ formation) cultures than in low-density (without GJ formation) in transformed HeLa cells. And cell density had no effect on etoposide-mediated cytotoxicity in the absence of Cx expression. MSC substantially enhanced etoposide-induced cytotoxicity, and this effect was only detected in the presence of functional GJs. Subsequently, MSC potentiated structural Cx expression as evidenced by increased dye coupling, but no alteration in Cx mRNA expression level in either transformed or primary cancer cell lines. Finally, a redox mechanism involving glutathione (GSH) was found to be related to the posttranscriptional modulation of Cx expression by MSC in HeLa cells. In conclusion, we provide the novel finding that MSC increases etoposide-mediated cytotoxicity by enhancing GJ activity, due to elevated Cx expression through a GSH-dependent posttranscriptional mechanism. More generally, the study highlights potential benefit of the combination of GJ modulators and chemotherapeutic agents in anticancer treatment.
Topics: Connexins; Etoposide; Gap Junctions; HeLa Cells; Humans; Selenocysteine
PubMed: 35370271
DOI: 10.1248/bpb.b21-00893 -
Acupuncture points injection mitigates chronic pain through transient receptor potential V1 in mice.Iranian Journal of Basic Medical... Apr 2022Tissue injury in peripheral sites can result in long-term potentiation in nociceptive neurons and surrounding glial cells, potentially resulting in the development of...
OBJECTIVES
Tissue injury in peripheral sites can result in long-term potentiation in nociceptive neurons and surrounding glial cells, potentially resulting in the development of chronic inflammatory pain (CIP). Acupoint injection (AI) is similar to Western phototherapy, which injects solutions at specific sites to mitigate chronic pain. AI has shown greater benefits compared with acupuncture. In this study, we examined the therapeutic effect and explored the underlying mechanisms of AI in mice CIP model.
MATERIALS AND METHODS
We injected thrice complete Freund's adjuvant (CFA) into the mouse's hind paw to induce CIP.
RESULTS
We found that, after two weeks, CFA injection significantly induced mechanical and thermal hyperalgesia which were attenuated by AI treatment. Transient receptor potential V1 (TRPV1) channels and associated molecules were all increased in CIP in mice dorsal root ganglion (DRG), spinal cord (SC), thalamus, and somatosensory cortex (SSC). The aforementioned molecules were mitigated in AI and Trpv1 knockout mice. Furthermore, Iba1-positive cells (microglial marker) were also potentiated and shared a similar tendency with TRPV1.
CONCLUSION
These findings suggest that AI can alleviate chronic pain by reducing TRPV1 overexpression in both neuronal and microglial cells. Our results suggest new potential therapeutic targets for AI in chronic pain.
PubMed: 35656078
DOI: 10.22038/IJBMS.2022.60121.13327 -
Physiological Reports Apr 2017We examined the effects of a submaximal voluntary elbow flexor contraction protocol on measures of corticospinal excitability and postactivation potentiation of evoked...
We examined the effects of a submaximal voluntary elbow flexor contraction protocol on measures of corticospinal excitability and postactivation potentiation of evoked muscle forces and if these measures were state-dependent (rest vs. voluntary muscle contraction). Participants completed four experimental sessions where they rested or performed a 5% maximum voluntary contraction (MVC) of the elbow flexors prior to, immediately, and 5 min following a submaximal contraction protocol. During rest or 5% MVC, transcranial magnetic stimulation, transmastoid electrical stimulation, electrical stimulation of biceps brachii motor point and Erb's point were elicited to induce motor-evoked potentials (MEPs), cervicomedullary MEPs (CMEPs), potentiated twitch (PT) force, and maximal muscle compound action potential (), respectively prior to, immediately, and 5 min postcontraction protocol. MEP amplitudes increased (215 and 165%M, ≤0.03) only at 1 and 6s postcontraction protocol, respectively during rest but not 5% MVC CMEP amplitudes decreased during rest and 5% MVC (range:21-58%, ≤0.04) for up to 81 sec postcontraction protocol. Peak twitch force increased immediately postcontraction protocol and remained elevated for 90 sec (range:122-147% increase, <0.05). There was a significant positive correlation between MEP and PT force during rest (=0.88, =0.01) and a negative correlation between CMEP and PT force during rest (=-0.85, <0.02 and 5% MVC (=-0.96, <0.01) immediately postcontraction protocol. In conclusion, the change in corticospinal and spinal excitability was state- and time-dependent whereas spinal excitability and postactivation potentiation were time-dependent following the contraction protocol. Changes in corticospinal excitability and postactivation potentiation correlated and were also state-dependent.
Topics: Adolescent; Adult; Brachial Plexus; Elbow Joint; Electric Stimulation; Electromyography; Evoked Potentials, Motor; Humans; Male; Muscle Contraction; Muscle, Skeletal; Pyramidal Tracts; Resistance Training; Spinal Cord; Transcranial Magnetic Stimulation; Young Adult
PubMed: 28455452
DOI: 10.14814/phy2.13265