Search Results (304)

Hearing loss is detrimental to human health, and currently, more than 1.5 billion people are affected by hearing loss. Active military personnel and construction workers are examples of individuals in the workplace who are exposed to loud noise and are at serious risk of hearing loss. While there is currently no therapy for hearing loss, evidence supports investigating the enhancement of the Medial Olivocochlear (MOC) system, an efferent pathway for hearing that serves as a gain-control for hearing loss protection. Selectively modulating the α9α10 nicotinic acetylcholine receptor (nAChRs) found within this pathway is promising for the development of a new drug class. In this review article, we present the most current findings related to the therapeutic targeting of α9α10 nAChRs for hearing loss. We discuss the loss- or gain-of-function of the receptor, evaluate the known modulators of the receptor, examine their clinical relevance, and discuss their chemical and physical properties. Investigation of this novel pathway may aid in the development of a therapeutic for hearing loss. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Background: Three-finger toxins (3FTxs) are a major axis of functional diversification in advanced snake venoms, with canonical paralytic activity mediated through muscle-type nicotinic acetylcholine receptors (nAChRs) and a broader set of non-nicotinic targets. This review integrates evidence bearing on coevolution between 3FTxs and target receptors, spanning toxin origin, diversification, receptor evolution, and ecological context. Methods: The synthesis draws on comparative genomic and transcriptomic studies of 3FTx gene-family evolution, codon-model analyses of selection, structural characterisation of toxin–receptor interfaces, and functional assays (including receptor-mimicking peptide binding) that link sequence variation to binding and toxicity. Results: Across lineages, 3FTx diversification is repeatedly structured by strong constraint on the disulphide-rich scaffold with accelerated change concentrated in solvent-exposed loops, alongside birth–death dynamics and exon/segment-level innovation that expand binding specificity. On the receptor side, resistance-associated variation is most intensively characterised for the nAChR α₁ orthosteric site and includes convergent, mechanistically distinct solutions such as electrostatic repulsion and glycosylation-mediated steric interference. Within the predominantly elapid systems currently examined, integrative datasets indicate that prey-selective binding and geographically variable susceptibility can arise from modest substitutions at toxin–receptor interfaces, but they also reveal substantial taxonomic and target-specific biases. Conclusions: Current evidence supports adaptive diversification in both toxins and receptors, while broader evolutionary interpretations are limited by uneven sampling and the frequent lack of matched toxin and receptor variants analysed within a common evolutionary framework. Development of predictive models will require joint pipelines linking genomics, structure-informed evolutionary inference, scalable functional assays, and explicit ecological network context. Full article

Face wrinkles caused by skin aging can be classified into dynamic wrinkles, which are caused by repetitive contraction of facial expression muscles, and static wrinkles, which are related to extracellular matrix damage and collagen breakdown caused by ultraviolet and oxidative stress. These two mechanisms are closely related, and prolonged, repetitive muscle contractions act as mechanical stress that promotes extracellular matrix degradation within the dermis, accelerating wrinkle formation. In this study, we used phage display to develop a novel peptide, Medipep-6PN, that targets both muscle-type nicotinic acetylcholine receptor (muscle nAChR), a major cause of dynamic wrinkles, and matrix metalloproteinase-1 (MMP-1), a cause of static wrinkles. In this study, the kinetic analysis of Medipep-6PN using surface plasmon resonance analysis showed that the equilibrium dissociation constant (K_D) for muscle nAChR α1 was 9.56 × 10⁻⁶ M, and the K_D for MMP-1 was 1.25 × 10⁻⁶ M. Calcium imaging analysis in TE671 cells expressing the muscle nAChR pentamer determined that Medipep-6PN inhibited muscle nAChR channel activity in a concentration-dependent manner, and in particular, it was confirmed that about 80% of muscle nAChR channel activity was inhibited under 30 μM of Medipep-6PN. In addition, in an in vitro test performed to evaluate MMP-1 activity, Medipep-6PN inhibited MMP-1 activity in a concentration-dependent manner, and the IC₅₀ was 4.2 ppm. When measuring MMP-1 gene expression in UVB-induced human fibroblasts, 1 ppm of Medipep-6PN showed a 52.3% decrease compared to UVB irradiation alone. When measuring type I procollagen synthesis in human fibroblasts, Medipep-6PN increased procollagen Iα1 production in a concentration-dependent manner, and concentrations between 5 and 10 ppm of Medipep-6PN significantly increased collagen I production. No significant toxicity was observed in cytotoxicity tests, demonstrating its safety. Furthermore, in a clinical study evaluating wrinkle improvement efficacy in 25 adults over a four-week period, the Medipep-6PN group demonstrated statistically significant reductions in wrinkle depth (by 10.16%) and wrinkle volume (by 13.00%), demonstrating efficacy comparable to that of commercially available functional anti-wrinkle ingredients. In conclusion, this study demonstrates that Medipep-6PN, developed to target two mechanisms—the relaxation of muscle contraction and the inhibition of collagen degradation—is a functional peptide effective in improving skin wrinkles, confirmed through in vitro evaluation and clinical studies. Full article

Nicotine is the main substance responsible for the development of tobacco addiction. The α3β4 nicotinic acetylcholine receptors (nAChRs) are a potential key target for mitigating nicotine reward. Preliminary studies in our laboratory suggest that α-conotoxin [S9K]TxID serves as a selective and potent antagonist targeting α3β4 nAChRs, which may be beneficial in addressing nicotine addiction. However, the mechanisms of [S9K]TxID treatment in nicotine addiction are still to be determined. This study aimed to identify the differential metabolic profiles of [S9K]TxID treatment in nicotine addiction using an untargeted metabolomic profiling method. As demonstrated by behavioral experiments, [S9K]TxID effectively attenuated nicotine-induced conditioned place preference (CPP) expression without exerting inhibitory effects on the central nervous system (CNS). The results of untargeted metabolomics revealed that eight metabolites were significantly altered after [S9K]TxID treatment, particularly phenylalanine. [S9K]TxID also attenuated nicotine-induced metabolic disorders by regulating phenylalanine, tyrosine and tryptophan biosynthesis. In conclusion, our findings suggest that [S9K]TxID could be a potential therapeutic compound for nicotine addiction. Full article

Recently, we found that Lystar5 protein from coelomic cells of A. rubens starfish interacts with nicotinic acetylcholine receptors (nAChRs) and integrin α8-like protein. We hypothesized that Lystar5 mediates detachment of coelomic cells from the matrix and their migration. Skin wound healing in humans is based on keratinocytes migration and is regulated by nAChRs and integrins. Here, we revealed that Lystar5 stimulates migration of human skin HaCaT keratinocytes and peripheral blood monocytes. Using ELISA, we found that Lystar5 binds to the membrane fraction of coelomic cells with its loops I and II, which form an active site of Lystar5 and resemble its pro-migratory activity. In keratinocytes and monocytes, Lystar5 and the peptides mimicking its loops I and II bound with α3, α4, and β2 nAChR and α5, αV, and β1 integrin subunits, which form molecular complexes. In keratinocytes, Lystar5 and its mimetics promoted short-term E/N cadherin switch and upregulated expression of α5 and αV integrins, EGFR, and ICAM-1. In keratinocytes and monocytes, Lystar5 and its mimetics upregulated E-selectin secretion. The ability of Lystar5 and its mimetics to stimulate skin keratinocyte migration and immune cell infiltration may be considered promising for the development of new wound-healing agents. Full article

Parkinson’s disease (PD) involves motor and cognitive impairment that nicotinic acetylcholine receptors (nAChRs) such as the α7 subtype are responsible for regulating. The hippocampus, abundant in α7 nAChRs, was quantitatively evaluated for [¹²⁵I]α-bungarotoxin ([¹²⁵I]α-Bgtx) binding to α7 nAChRs in postmortem human PD (n = 26; 12 male, 14 female) and cognitively normal (CN) (n = 29; 14 male, 15 female) brain slices. Anti-ubiquitin and anti-α-synuclein immunostained adjacent slices were analyzed using QuPath. Autoradiographs of [¹²⁵I]α-Bgtx radioligand binding were analyzed in OptiQuant. Ubiquitin and α-synuclein distribution generally aligned with the distribution of α7 nAChRs detected by [¹²⁵I]α-Bgtx. Binding of [¹²⁵I]α-Bgtx in PD cases was significantly greater than CN with a 32% increase in gray matter binding. A weak positive correlation between age and [¹²⁵I]α-Bgtx binding was found in both PD and CN. In comparison to Alzheimer’s disease hippocampus, [¹²⁵I]α-Bgtx binding in PD gray matter was higher by 41%. Differences in nAChR expression imply unique roles depending on the neurodegenerative pathology. PD may experience an increase in α7 nAChRs as a compensatory mechanism to the loss in neurons, highlighting its neuroprotective capabilities. [¹²⁵I]α-Bgtx shows potential as a radioligand for α7 nAChRs to elucidate the complexities of PD pathology. Full article

Alpha7 nicotinic receptors (α7-nAChRs) are implicated in many neurological disorders, but how they fold and assemble is not well understood. Unlike native α7-nAChRs, α7-5HT3 chimeras fold efficiently in HEK cells and do not require chaperones RIC3 or TMEM35A (NACHO) for proper assembly. We investigated the effects of swapping 5HT3 and α7-receptor protein sequences on α7-5HT3R chimera surface expression in mammalian HEK293 or Bosc23 cells, or chimeric receptor function using Xenopus laevis oocytes with or without chaperones. α7-5HT3Rs, consisting of human α7-nAChRs with mouse 5HT3 transmembrane domains (TMs) express without chaperones as measured by cell surface alpha-bungarotoxin binding. However, when subunit TMs from α7-nAChRs and 5HT3Rs were mixed, chaperones were required. Substituting the SAP motif prior to the α7-nAChR “Latch” tail sequence for the 5HT3 C-terminal decreased expression relative to α7-nAChRs with chaperones. Chaperone effects on L264 and G265 mutations in M2 were also investigated. Some constructs that express well in HEK293 or Bosc23 cells are nonfunctional in oocytes with or without NACHO. Our data do not support direct binding of RIC3 or NACHO to the α7-nAChR TM4 (M4) region; instead, they emphasize the functional importance of the conserved SAP motif. Full article

Background: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder with limited treatment options. Emerging evidence reveals bidirectional crosstalk between gut and brain through inflammatory signaling, leading us to hypothesize that anti-neuroinflammatory agents may concurrently ameliorate intestinal inflammation. The scorpion venom-derived heat-resistant synthetic peptide (SVHRSP), a bioactive peptide initially identified in scorpion venom and subsequently synthesized by our laboratory, possesses neuroprotective, anti-inflammatory, and antioxidative activities. Its properties make SVHRSP a promising candidate for investigating the therapeutic potential of anti-neuroinflammatory strategies in mitigating intestinal inflammation. Methods: Using a chronic dextran sodium sulfate (DSS)-induced colitis model in wild-type and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, along with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, we assessed SVHRSP’s effects on inflammation, histopathology, gut permeability, oxidative stress markers, and α7nAChR-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Results: SVHRSP treatment significantly ameliorated colitis symptoms in wild-type mice by reducing inflammation, repairing histological damage, restoring gut barrier function, and attenuating oxidative stress, with these effects abolished in α7nAChR knockout mice. Mechanistically, SVHRSP activated JAK2/STAT3 signaling through α7nAChR engagement, suppressing proinflammatory cytokine production in macrophages. Conclusion: These results demonstrated that SVHRSP alleviated intestinal inflammation via α7nAChR-dependent JAK2/STAT3 activation. Combined with its known neuroprotective properties, our findings support the repurposing of this neuroactive peptide, SVHRSP, for treating intestinal inflammatory disorders. Full article

Neonicotinoid pesticides, including imidacloprid (IMI), are widely used in agriculture and as household insecticides. IMI displays strong affinity for insect nicotinic acetylcholine receptors (nAChRs); however, neonicotinoids still partially bind to mammalian nAChRs. Relatively little is known about how neonicotinoid exposure alters learning, memory or mood, even though nAChRs play a role in these mechanisms. We tested the hypothesis that developmental exposure to IMI impairs performance on memory tasks, and anxiety- and depressive-like behavior. We orally dosed pregnant CD-1 mice from gestation day 10 to birth with vehicle or IMI at 0.5 mg/kg/day or 5.7 mg/kg/day. When exposed animals were adults, we examined cognitive and emotional behaviors and we examined the effect of IMI on α7 and α4 nAChR subunit mRNA expression using qPCR. For both sexes, IMI exposure was associated with impaired striatal-dependent procedural learning task and hippocampal-dependent spatial learning but had no effect on hippocampal-dependent working memory. Males, but not females, displayed increased anxiety-like behavior, with low dose subjects displaying more pronounced effects, suggesting a non-linear dose response. In males, we found lower α7 subunit mRNA expression in the hippocampus and amygdala and lower α4 mRNA expression in the striatum compared to controls. Thus, exposure to IMI during a critical period is associated with disruptions to cognitive and anxiety-like behaviors. Additionally, in males, IMI exposure is associated with reduced expression of nAChR subunits in relevant brain regions. Full article

Highly degraded sterols belonging to the incisterol group have been identified in a large set of microorganisms. The leading product in the family is demethylincisterol A3 (DM-A3), isolated from various fungi and endowed with marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, essentially from fungi. An overview of these products, their bio-origin, chemical synthesis, and associated pharmacological properties is presented. The series includes diverse incisterol and demethylincisterol derivatives, chaxines, volemolide, different analogues (salimyxins, phellinignincisterols, daedatrin D, inonotoide F, aplykurodinone-1, dendrodoristerol), and a glycoside derivative (xyloneside), all bearing a tetracyclic incisterol framework. An analysis of the anticancer mechanism of the action of DM-A3 underlined the three main components of its activity associated with the (i) inhibition of β-catenin and the Wnt signaling pathway, (ii) inhibition of tyrosine phosphatase SHP2 (IC₅₀ = 6.75 µM) implicated in cancer cell survival and differentiation, and (iii) blockade of α7nAchR activation coupled with inhibition of acetylcholinesterase (IC₅₀ = 11.16 µM). A comprehensive picture of the DM-A3 mechanism of action is discussed, highlighting the uniqueness of the compound as a dual SHP2/AchE inhibitor able to attenuate an inflammatory response through the cholinergic anti-inflammatory pathway. The review shed light on this little-known category of incisterol-type natural products, with the objective of promoting further research into this neglected group of anticancer agents. Full article

In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer’s disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction. Full article

Marine sources contain compounds that act on a wide variety of systems, including ligand-gated ion channels. This review will focus on the effectors of nicotinic acetylcholine receptors (nAChRs), for which the diversity of ligands and modulators from marine sources is determined mainly by neurotoxic peptides (α-conotoxins) from mollusks of the Conus genus. These are very selective compounds that allow the study of the role of different nAChR subtypes in the cancer cells. They have analgesic or anti-inflammatory activities associated with cholinergic transmission and have shown analgesic effect in case of chemotherapy-induced neuropathic pain. Another class of marine compounds targeting nAChRs for which cytotoxicity for cancer cells was shown is represented by low molecular organic substances found mostly in dinoflagellates and marine sponges. Some of the compounds discussed in this review show promise for developing drugs that suppress cancer growth. Full article

Diverse neuronal nicotinic acetylcholine receptor (nAChR) subtypes are expressed in hippocampal interneurons. Single-cell analysis of mRNA expression previously revealed prominent co-expression of the α3 and β2 subunits within rat interneurons in the CA1 region. Although the α3 subunit (traditionally expressed together with β4) is usually associated with the peripheral nervous system, its significant co-expression with the β2 subunit in hippocampal interneurons suggests a distinct, potentially novel central nervous system nAChR subtype. We demonstrate that the human α3 and β2 subunits injected into Xenopus laevis oocytes can assemble into at least two functionally distinct subtypes of nAChRs based on different subunit stoichiometries. These subtypes exhibit similar reversal potentials but differ significantly in their desensitization kinetics and acetylcholine (ACh) affinities. The response obtained from a 1:5 α3:β2 mRNA injection ratio shows a higher affinity for ACh and significantly greater desensitization during prolonged ACh application compared to the response obtained from a 5:1 α3:β2 mRNA injection ratio. The identification of distinct functional α3β2 subtypes, characterized by differential desensitization kinetics and ACh affinity, could represent novel targets for the potential development of highly selective cognitive therapeutics for conditions such as Alzheimer’s disease, autism spectrum disorder, and attention deficit hyperactivity disorder, where hippocampal nAChRs are implicated. Full article

Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer’s disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington’s disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA’s structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFβ secretion. Heteronuclear NMR and ¹⁵N relaxation measurements reveal a classical β-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of α3β2-, high-, and low-sensitive variants of α4β2- (IC₅₀ ~50, 27, and 15 μM, respectively) but not α4β4-nAChRs, suggesting targeting of the β2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive α4β2-nAChR at α4/β2 and β2/β2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA’s loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA’s interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders. Full article