Search Results (743)

It has long been accepted that breathing gases that are physiologically inert include helium (He), neon (Ne), nitrogen (N₂), argon (Ar), krypton (Kr), xenon (Xe), and hydrogen (H₂). The term “inert gas” has been used to describe them due to their unusually high chemical stability. However, as investigations have advanced, many have shown that inert gas can have specific biological impacts when exposed to high pressure or atmospheric pressure. Additionally, different inert gases have different effects on intracellular signal transduction, ion channels, and cell membrane receptors, which are linked to their anesthetic and cell protection effects in normal or pathological processes. Through a selective analysis of the representative literature, this study offers a concise overview of the state of research on the biological impacts of inert gas and their molecular mechanisms. Full article

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. 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

Animal venoms are complex biochemical secretions rich in highly potent and selective bioactive molecules, including peptides, enzymes, and small organic compounds. Once associated primarily with toxicity, these venoms are now recognized as a promising source of therapeutic agents for a wide range of medical conditions. This review provides a comprehensive analysis of the pharmacological potential of venom-derived compounds, highlighting their mechanisms of action, such as ion channel modulation, receptor targeting, and enzyme inhibition. Successful venom-derived drugs like captopril and ziconotide exemplify the translational potential of this biological arsenal. We discuss therapeutic applications in cardiovascular diseases, chronic pain, cancer, thrombosis, and infectious diseases, as well as emerging peptide candidates in clinical development. Technological advancements in omics, structural biology, and synthetic peptide engineering have significantly enhanced the discovery and optimization of venom-based therapeutics. Despite challenges related to stability, immunogenicity, and ecological sustainability, the integration of AI-driven drug discovery and personalized medicine is expected to accelerate progress in this field. By synthesizing current findings and future directions, this review underscores the transformative potential of animal venoms in modern pharmacotherapy and drug development. We also discuss current therapeutic limitations and how venom-derived compounds may address unmet needs in specific disorders. Full article

F₄-Neuroprostanes (F₄-NeuroPs), oxidative metabolites of docosahexaenoic acid, act as bioactive lipid mediators enhancing sperm motility and induce capacitation-like changes in vitro. Their biological action is proposed to involve sperm ion channels, in particular ryanodine receptors (RyRs), which regulate intracellular calcium homeostasis. We evaluated the effects of dantrolene, a RyR inhibitor, on motility and vitality of a selected spermatozoa at different concentrations (10, 30, 50, 100 μM). Then sperm motility, acrosome integrity, and RyR localization following co-incubation with dantrolene (D50 or D100 μM) and 4-/10-F_4t-NeuroPs (7 ng) were investigated. Acrosomal status was assessed using Pisum sativum agglutinin (PSA) staining and RyR localization by immunofluorescence. D50 was identified as the minimum effective dose to induce significant reductions in sperm motility. F₄-NeuroPs significantly increased rapid progressive motility versus controls. Co-incubation with F₄-NeuroPs + D50 reduced rapid motility and increased in situ and circular movement. The acrosome staining appeared altered or absent to different percentages, and RyR localization was also seen in the midpiece. These findings suggested that F₄-NeuroPs enhance sperm motility via RyR-mediated pathways, as confirmed by dantrolene inhibition. Accordingly, our results underscore the physiological relevance of RyRs in sperm function and suggest new insights into lipid-based mechanisms regulating sperm motility. Full article

Chronic visceral pain, a significant contributor to morbidity in the United States, affects millions and results in substantial economic costs. Despite its impact, the mechanisms underlying disorders of gut–brain interaction (DGBIs), such as irritable bowel syndrome (IBS), remain poorly understood. Visceral hypersensitivity, a hallmark of chronic visceral pain, involves an enhanced pain response in internal organs to normal stimuli. Various factors like inflammation, intestinal hyperpermeability, and epigenetic modifications influence its presentation. Emerging evidence suggests that persistent colonic stimuli, disrupted gut barriers, and altered non-coding RNA (ncRNA) expression contribute to the pathophysiology of visceral pain. Additionally, cross-sensitization of afferent pathways shared by pelvic organs underpins the overlap of chronic pelvic pain disorders, such as interstitial cystitis and IBS. Central sensitization and viscerosomatic convergence further exacerbate pain, with evidence showing IBS patients exhibit hypersensitivity to both visceral and somatic stimuli. The molecular mechanisms of visceral pain involve critical mediators such as cytokines, prostaglandins, and neuropeptides, alongside ion channels like transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channels (ASICs). These molecular insights indicate potential therapeutic targets and highlight the possible use of TRPV1 antagonists and ASIC inhibitors to mitigate visceral pain. This review explores the neurophysiological pathways of visceral pain, focusing on peripheral and central sensitization mechanisms, to advance the development of targeted treatments for chronic pain syndromes, particularly IBS and related disorders. Full article

Three-finger toxins (3FTxs) are the largest group of nonenzymatic toxins found in snake venoms. Among them, neurotoxins that target nicotinic acetylcholine receptors are the most well-studied ligands. In addition to the classical neurotoxins, several other new classes have been characterized for their structure, receptor subtype, and species selectivity. Here, we systematically analyzed over 700 amino acid sequences of three-finger neurotoxins that interact with nicotinic acetylcholine receptors. Based on the amino acid residue substitutions in the functional sites and structural features of various classes of neurotoxins, we have classified them into over 150 distinct subgroups. Currently, only a small number of typical examples representing these subgroups have been studied for their structure, function, and subtype selectivity. The functional site residues responsible for their interaction with specific receptor subtypes of several toxins are yet to be identified. The molecular details of each subgroup representative toxin with its target receptor will contribute towards the understanding of subtype- and/or interface-selectivity. Thus, this review will provide new impetus in the toxin research and pave the way for the design of potent, selective ligands for nicotinic acetylcholine receptors. Full article

Diabetes mellitus and atrial fibrillation (AF) frequently coexist, creating a complex bidirectional relationship that exacerbates cardiovascular risk and challenges clinical management. Diabetes fosters a profibrotic, pro-inflammatory, and proarrhythmic atrial substrate through a constellation of pathophysiologic mechanisms, including metabolic remodeling, oxidative stress, mitochondrial dysfunction, ion channel dysregulation, and autonomic imbalance, thereby promoting AF initiation and progression. Conventional rhythm control strategies remain less effective in diabetic individuals, underscoring the need for innovative, substrate-targeted interventions. In this context, sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising agents with pleiotropic antiarrhythmic properties, modulating fibrosis, inflammation, and mitochondrial integrity. Moreover, advances in anti-inflammatory, antifibrotic, and ion channel-modulating therapeutics, coupled with novel mitochondrial-targeted strategies, are reshaping the therapeutic landscape. Multi-omics approaches are further refining our understanding of diabetes-associated AF, facilitating precision medicine and biomarker-guided interventions. This review delineates the molecular nexus linking diabetes and AF, critically appraises emerging rhythm control strategies, and outlines translational avenues poised to advance individualized management in this high-risk population. 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

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation. Full article

Fatty acids (FAs) play a crucial role in human physiology, including energy production and serving as signaling molecules. However, a dysregulation in their balance can lead to multiple disorders, such as obesity and metabolic syndrome. These pathological conditions alter the balance between the heart’s energetic substrates, promoting an increased reliance on FAs and decreased cardiac efficiency. A therapeutic application of a non-psychotropic phytocannabinoid, cannabigerol (CBG), seems to be a promising target since it interacts with different receptors and ion channels, including cannabinoid receptors—CB₁ and CB₂, α2 adrenoceptor, or 5-hydroxytryptamine receptor. Therefore, in the current study, we evaluated a concentration-dependent effect of CBG (2.5 µM, 5 µM, and 10 µM) on H9c2 cardiomyocytes in lipid overload conditions. Gas–liquid chromatography and Western blotting techniques were used to determine the cellular lipid content and the level of selected proteins involved in FA metabolism, glucose transport, and the insulin signaling pathway. The glucose uptake assay was performed using a colorimetric method. Eighteen-hour CBG treatment in the highest concentration (10 µM) significantly diminished the accumulation of diacylglycerols (DAGs) and the saturation status of this lipid fraction. Moreover, the same concentration of CBG markedly decreased the level of FA transporters, namely fatty acid translocase (CD36) and plasma membrane fatty acid-binding protein (FABPpm), in the presence of palmitate (PA) in the culture medium. The results of our experiment suggest that CBG can significantly modulate lipid storage and composition in cardiomyocytes, thereby protecting against lipid-induced cellular dysfunction. 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

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg/kg on days 16 and 20 of the 21-day CUMS protocol—in hourly injections seven times to ensure sustained exposure. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety. Full article

This study investigated the effects of potassium magnesium sulfate (PMS) on intestinal dissociation and absorption rate, immune function, and expression of the NOD-like receptor thermal domain-associated protein 3 (NLRP3) inflammasome, aquaporins (AQPs), and potassium and magnesium ion channels in weaned piglets. Experiment 1 involved the assessment of the dissociation rate of PMS in pig digestive fluid and the absorption rate of PMS in the small intestine using an Ussing chamber in vitro. In Experiment 2, 216 healthy 21-day-old weaned piglets were selected and randomly assigned to six groups (0%, 0.15%, 0.30%, 0.45%, 0.60%, and 0.75% PMS), with each group 6 replicates of six piglets per replicate. The in vitro Ussing chamber results indicated that the absorption of K⁺ and Mg²⁺ in the jejunum and ileum was significantly higher than that in the duodenum (p < 0.05). The in vivo study demonstrated that the addition of PMS resulted in a linear increase in serum K⁺, IgG, and interleukin (IL)-2 levels while simultaneously reducing serum IL-1β levels (p < 0.05). Dietary PMS significantly elevated serum IL-10 and Mg²⁺ levels in feces (p < 0.05). Furthermore, supplementation with 0.60% or 0.75% PMS significantly downregulated the mRNA expression of NLRP3 in the jejunum (p < 0.05). Dietary PMS supplementation linearly reduced the mRNA expression levels of cysteine protease 1 (Caspase-1) and IL-1β in both the jejunum and colon as well as the mRNA expression levels of two-pore domain channel subfamily K member 5 (KCNK5) in these regions (p < 0.05). Notably, supplementation with 0.15% PMS significantly decreased the mRNA expression of transient receptor potential channel 6 (TRPM6) in the jejunum and significantly increased the expression of TRPM6 in the colon (p < 0.05). Dietary addition of 0.45% and 0.60% PMS significantly increased the mRNA expression of aquaporin 3 (AQP3) in the colon (p < 0.05), whereas 0.75% PMS significantly increased the mRNA expression of aquaporin 8 (AQP8) in both the jejunum and colon. Moreover, the expression levels of AQP3 and AQP8 were significantly negatively correlated with the diarrhea rate observed between days 29 and 42. In conclusion, dietary PMS supplementation improved immune function, inhibited the activation of intestinal NLRP3, and modulated the expression of water and ion channels in weaned piglets, thereby contributing to the maintenance of intestinal water and ion homeostasis, which could potentially alleviate post-weaning diarrhea in piglets. The recommended supplemental level of PMS in the corn-soybean basal diet for weaned piglets is 0.30%. Full article