Search Results (602)

This study was designed to systematically identify novel umami peptides in lager beer, clarify their molecular interactions with the T1R1/T1R3 receptor, and determine their specific effects on multidimensional sensory attributes. The peptides were characterized by LC-MS/MS combined with de novo sequencing, and 906 valid sequences were obtained. Machine-learning models (UMPred-FRL, Tastepeptides-Meta, and Umami-MRNN) predicted 76 potential umami peptides. These candidates were docked to T1R1/T1R3 with the CDOCKER protocol, producing 57 successful complexes. Six representative peptides—KSTEL, DELIK, DIGISSK, IEKYSGA, DEVR, and PVPL—were selected for 100 ns molecular-dynamics simulations and MM/GBSA binding-energy calculations. All six peptides stably occupied the narrow cleft at the T1R1/T1R3 interface. Their binding free energies ranked as DEVR (−44.09 ± 5.47 kcal mol⁻¹) < KSTEL (−43.21 ± 3.45) < IEKYSGA (−39.60 ± 4.37) ≈ PVPL (−39.53 ± 2.52) < DELIK (−36.14 ± 3.11) < DIGISSK (−26.45 ± 4.52). Corresponding taste thresholds were 0.121, 0.217, 0.326, 0.406, 0.589, and 0.696 mmol L⁻¹ (DEVR < KSTEL < IEKYSGA < DELIK < PVPL < DIGISSK). TDA-based sensory validation with single-factor additions showed that KSTEL, DELIK, DEVR, and PVPL increased umami scores by ≈21%, ≈22%, ≈17%, and ≈11%, respectively, while DIGISSK and IEKYSGA produced marginal changes (≤2%). The short-chain peptides thus bound with high affinity to T1R1/T1R3 and improved core taste and mouthfeel but tended to amplify certain off-flavors, and the long-chain peptides caused detrimental impacts. Future formulation optimization should balance flavor enhancement and off-flavor suppression, providing a theoretical basis for targeted brewing of umami-oriented lager beer. Full article

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article

Central nervous system (CNS) insulin signaling is involved in a broad array of cardiometabolic physiology, including glucose and lipid metabolism, feeding, energy expenditure, and blood pressure regulation. A key role for hypothalamic neuroendocrine and autonomic centers in regulating insulin-associated cardiovascular and metabolic physiology has been highlighted. However, it is still unclear which CNS site(s) initiate insulin-dependent neural cascades. While some investigations have suggested that circulating insulin can access hypothalamic regions by crossing the blood-brain barrier, other studies point to a necessity of other brain areas upstream of the hypothalamus to initiate central insulin actions. In this context, accumulating evidence points to a possible involvement of the sensory circumventricular organs (CVOs), unique areas located outside of the blood-brain barrier, in insulin-dependent cardiometabolic homeostasis. Here, the multifaceted roles for the sensory CVOs in cardiovascular and metabolic regulation, with a special emphasis on insulin receptor pathways, are discussed. Full article

Sleep paralysis (SP), an REM parasomnia, can be characterized as one of the symptoms of narcolepsy. The SP phenomenon involves regaining meta-consciousness by the dreamer during REM, when the physiological atonia of skeletal muscles is accompanied by visual and auditory hallucinations that are perceived as vivid and distressing nightmares. Sensory impressions include personification of an unknown presence, strong chest pressure sensation, and intense fear resulting from subjective interaction with the unfolding nightmare. While the mechanism underlying skeletal muscle atonia is known, the physiology of hallucinations remains unclear. Their complex etiology involves interactions among various membrane receptor systems and neurotransmitters, which leads to altered neuronal functionality and disruptions in sensory perception. According to current knowledge, serotonergic activation of 5-hydroxytryptamine-receptor-2A (5-HT2A)-associated pathways plays a critical role in promoting hallucinogenesis during SP. Furthermore, they share similarities with psychedelic-substance-induced ones (i.e., LSD, psilocybin, and 2,5-dimethoxy-4-iodoamphetamine). These compounds also target the 5-HT2A receptor; however, their molecular mechanism varies from serotonin-induced ones. The current review discusses the intracellular signaling pathways responsible for promoting hallucinations in SP, highlighting the critical role of β-arrestin-2. We propose that the β-arrestin-2 signaling pathway does not directly induce hallucinations but creates a state of network susceptibility that facilitates their abrupt emergence in sensory areas. Understanding the molecular basis of serotonergic hallucinations and gaining better insight into 5-HT2A-receptor-dependent pathways may prove crucial in the treatment of multifactorial neuropsychiatric disorders associated with the dysfunctional activity of serotonin receptors. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

The flavor characteristics, perception, and molecular mechanisms of eight menthol isomers were investigated by sensory analysis combined with computational simulations. The sensory analysis results show significant differences in the odor profiles of the different menthol isomers. Among them, L-menthol shows a pleasant, sweet, and mint-like odor with a distinct freshness and no off-flavors, whereas the remaining seven isomers were interspersed with negative odors (musty, herbal, or earthy aromas). L-menthol and D-menthol had the lowest detection thresholds of 5.166 and 4.734 mg/L, respectively. The molecular docking results of the menthol isomers with olfactory receptors (Olfr874, OR8B8, and OR8B12) indicate that hydrogen bonding and hydrophobic interactions were the key binding forces. The binding energy ranged from −7.3 to −5.1 kcal/mol. Residues His-55 (Olfr874), Thr-56 (Olfr874), Leu-55 (OR8B8), Tyr-94 (OR8B8), Thr-57 (OR8B8), Phe-199 (OR8B12), and Ser-248 (OR8B12) with high frequencies particularly contributed to the recognition of menthol isomers. These findings contribute to a deeper understanding of the olfactory perception mechanism of menthol and provide data support for the development and precise application of minty odorants. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Deep learning has great potential in the field of functional peptide prediction. This study combines metagenomics and deep learning to efficiently discover potential umami peptides in fermented sausages. A candidate peptide library was generated using metagenomic data from fermented sausages, an integrated deep learning model was constructed for prediction, and SHAP (SHapley Additive exPlanations) interpretability analysis was performed to elucidate the key amino acid features and contributions of the model in predicting umami peptides, screening the top ten peptides with the highest predicted probability. Subsequently, molecular docking was performed to assess the binding stability of these peptides with the umami receptor T1R1/T1R3, selecting the three peptides DDSMAATGL, DGEEDASM, and DEEEVDI with the most stable binding for further study. Docking analysis revealed the important roles of the key receptor residues Glu301, Arg277, Lys328, and His71 in hydrogen bond formation. Molecular dynamics simulations validated the robust integrity of the peptide–receptor associations. Finally, sensory evaluation demonstrated that these three peptides possessed significant umami characteristics, with low umami thresholds (0.11, 0.37, and 0.44 mg/mL, respectively). This study, based on metagenomics and deep learning, provides a high-throughput strategy for the discovery and validation of functional peptides. Full article

Sweet taste plays a pivotal role in human dietary behavior and metabolic regulation. With the increasing incidence of metabolic disorders linked to excessive sugar intake, the development and accurate evaluation of new sweeteners have become critical topics in food science and public health. However, the structural diversity of sweeteners and their complex interactions with sweet taste receptors present major challenges for standardized sweetness detection. This review offers a comprehensive and up-to-date overview of sweet taste transmission mechanisms and current detection methods. It outlines the classification and sensory characteristics of both conventional and emerging sweeteners, and explains the multi-level signaling pathway from receptor binding to neural encoding. Key detection techniques, including sensory evaluation, electronic tongues, and biosensors, are systematically compared in terms of their working principles, application scope, and limitations. Special emphasis is placed on advanced biosensing technologies utilizing receptor–ligand interactions and nanomaterials for highly sensitive and specific detection. Furthermore, an intelligent detection framework integrating molecular recognition, multi-source data fusion, and artificial intelligence is proposed. This interdisciplinary approach provides new insights and technical solutions to support precise sweetness evaluation and the future development of healthier food systems. Full article

Sweet sensing is a fundamental sensory experience that plays a critical role not only in food preference, reward and dietary behaviour but also in glucose metabolism. Sweet taste receptors (STRs), composed of a heterodimer of taste receptor type 1 member 2 (T1R2) and member 3 (T1R3), are now recognised as being widely distributed throughout the body, including the gastrointestinal tract. Preclinical studies suggest these receptors are central to nutrient and glucose sensing, detecting energy availability and triggering metabolic and behavioural responses to maintain energy balance. Both internal and external factors tightly regulate their signalling pathways, and dysfunction within these systems may contribute to the development of metabolic disorders such as obesity and type 2 diabetes (T2D). Functional magnetic resonance imaging (fMRI) has provided valuable insights into the neural mechanisms underlying sweet sensing by mapping brain responses to both lingual/oral and gastrointestinal sweet stimuli. This review highlights key findings from fMRI studies and explores how these neural responses are modulated by metabolic state and individual characteristics such as body mass index, habitual intake and metabolic health. By integrating current evidence, this review advances our understanding of the complex interplay between sweet sensing, brain responses, and health and identifies key gaps and directions for future research in nutritional neuroscience. Full article

Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has been implicated in both neuronal plasticity and inflammatory processes, but its role in tendon pathology has not been explored. A rat supraspinatus tear model was employed to assess, in vivo, the expression of genes encoding netrin-1 (Ntn1) and its receptors (Unc5b and Neo1) at 0, 7, 14, 28, and 56 days post-injury (n = 10 per time point). Primary rat tenocytes isolated from rotator cuff tissue were treated in vitro with recombinant netrin-1, and transcriptional changes in genes encoding TNF-α (Tnfa), IL-6 (Il6), MMP-1 (Mmp1), and MMP-3 (Mmp3) were quantified by qRT-PCR. Separately, human iPSC-derived sensory neurons were exposed to netrin-1, and dose- and time-dependent effects on neurite outgrowth were measured at 4 and 14 days in culture. In injured tendons, Ntn1 mRNA increased significantly at day 14 (p = 0.010) and 28 (p = 0.042), Unc5b at day 7 (p = 0.002) and 14 (p < 0.001), and Neo1 at day 14 (p < 0.001) versus intact controls. Tenocyte exposure to 500 ng/mL netrin-1 induced transient upregulation of Tnfa (3 h, p = 0.023; 6 h, p = 0.009) and Il6 (3 h–24 h, all p < 0.013), as well as Mmp3 (3–24 h, p < 0.043) and Mmp1 (6 h–24 h, p < 0.024); no induction was observed at 50 ng/mL. In sensory neurons, 50 ng/mL of netrin-1 enhanced neurite extension at day 4 (p = 0.006) but not at 500 ng/mL or at day 14 for either dose. Netrin-1 and its receptors are upregulated in a rat rotator cuff tear model, and netrin-1 elicits distinct pro-inflammatory and matrix-remodeling responses in tenocytes while promoting early neurite growth in sensory neurons. These findings suggest netrin-1 as a key modulator of tendon inflammation, matrix turnover, and peripheral nerve plasticity following injury. Full article

Peripheral tissue injury initiates a multifaceted cascade of structural and molecular modifications within nociceptors, the primary sensory neurons tasked with detecting noxious stimuli. These alterations play a crucial role in the induction and maintenance of pain states, encompassing acute and chronic pain. Structural remodeling includes alterations in axonal architecture, dendritic morphology, and synaptic connectivity, collectively impacting nociceptor excitability and functional integration. Simultaneously, molecular adaptations comprise the regulation of ion channels, receptor expression, and intracellular signaling pathways, as well as transcriptional reprogramming that modulates nociceptive signaling. This review synthesizes current evidence regarding the cellular and molecular bases of injury-induced plasticity in nociceptors, identifying prospective targets for therapeutic intervention to counteract maladaptive sensitization. Elucidating these processes is critical for the advancement of pain treatment strategies and for enhancing clinical outcomes in individuals experiencing neuropathic pain secondary to tissue injury. Full article

TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. As a key player in nociceptive signaling pathways, TRPA1 has emerged as a promising therapeutic target for the development of novel analgesics. Crotalphine (CRP), a 14-amino acid peptide, has been demonstrated to specifically activate TRPA1 and elicit potent analgesic effects. Previous cryo-EM (cryo-electron microscopy) studies have elucidated the structural mechanisms of TRPA1 activation by small-molecule agonists, such as iodoacetamide (IA), through covalent modification of N-terminal cysteine residues. However, the molecular interactions between TRPA1 and peptide ligands, including crotalphine, remain unclear. Here, we present the cryo-EM structure of ligand-free human TRPA1 consistent with the literature, as well as TRPA1 complexed with crotalphine, with resolutions of 3.1 Å and 3.8 Å, respectively. Through a combination of single-particle cryo-EM studies, patch-clamp electrophysiology, and microscale thermophoresis (MST), we have identified the cysteine residue at position 621 (Cys621) within the TRPA1 ion channel as the primary binding site for crotalphine. Upon binding to the reactive pocket containing C621, crotalphine induces rotational and translational movements of the transmembrane domain. This allosteric modulation coordinately dilates both the upper and lower gates, facilitating ion permeation. Full article

Olfaction has been extensively studied in the yellow fever mosquito, Aedes aegypti. This species uses its sense of smell to find blood hosts and other resources, contributing to its impact as a vector for human pathogens. Two major families of protein-coding genes, the odorant receptors (Ors) and the ionotropic receptors (Irs), provide the mosquito with sensitivities to distinct classes of volatile compounds in the antennae. Individual tuning receptors in both families require co-receptors for functionality: Orco for all Ors, and Ir8a for many Irs, especially ones that are involved in carboxylic acid detection. In Drosophila melanogaster, disruptions of Orco or Ir8a impair receptor function, tuning receptor expression, and membrane localization, leading to general anosmia. We reasoned that Orco and Ir8a might also be important for coordinated chemosensory receptor expression in the antennal sensory neurons of Ae. aegypti. To test this, we performed RNAseq and differential expression analysis in wildtype versus Orco^−/− and Ir8a^−/− mutant adult female antennae. Our analyses revealed Or and Ir tuning receptors are broadly under-expressed in Orco^−/− mutants, while a subset of tuning Irs are under-expressed in Ir8a mutants. Other chemosensory and non-chemosensory genes are also dysregulated in these mutants. Furthermore, we identify differentially expressed transcription factors including homologs of the Drosophila melanogaster Mip120 gene. These data suggest a previously unknown pleiotropic role for the Orco and Ir8a co-receptors in the coordination of expression of chemosensory receptors within the antennae of Ae. aegypti by participating in a feedback loop involving amos and members of the MMB/dREAM complex. Full article

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article