Search Results (146)

Background/Objectives: One of the neurotoxic components from the sea trumpet polyps, Protopalythoa variabilis (Cnidaria, Anthozoa), is a 26-residue, V-shape helical peptide (PpVα). Its synthetic versions, i.e., the linear, the single-disulfide-bonded analog, and the chimeric peptide with a 6-residue stretch of the N-terminal native homologous peptide covalently linked to the linear sequence, were investigated for their activity on ion channels responsible for cellular excitability and synaptic transmission. Methods: Molecular docking analyses and dynamic simulations focused on the ability of PpVα peptides to bind ion channels selectively through interaction with critical residues at their binding sites. Results: Electrophysiological studies using the patch clamp technique with sympathetic bovine chromaffin cells from the adrenal medulla confirmed that PpVα analogs can block both sodium and calcium currents, which are responsible for initiating and propagating action potentials, respectively, and for neurotransmitter release. Additionally, the peptides displayed neuroprotective effects, attenuating cellular damage induced by veratridine, which interferes with sodium channel activity, and by oligomycin and rotenone (O/R), which affect mitochondrial function. Conclusions: The block of calcium and sodium channels and the neuroprotective effects against oxidative stress make the PpVα peptide scaffold an attractive template for developing agents that has significant clinical potential in several areas, such as the treatment of neurological diseases (epilepsy, multiple sclerosis, and neurodegenerative diseases), neuroprotection in acute events (stroke and traumatic brain or spinal cord injuries), the management of neuropathic pain, the prevention of ischemic damage, and psychiatric disorders (anxiety and bipolar disorder). Full article

Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer’s disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin. Full article

Scorpion venoms contain a wide range of toxins that interact with a variety of target molecules (ion channels, receptors and enzymes) associated with synaptic transmission, action potential propagation, cardiac function, hemostasis and other physiological systems. Scorpion toxins are also active towards bacteria, viruses, fungi and parasites. Such interactions make scorpion toxins useful lead molecules for developing compounds with biotechnological and therapeutic applications, and as tools for cell biology. In addition, scorpion toxins act as insectotoxins, with promising applications as insecticides. This review describes the range of scorpion toxins and discusses their usefulness for the development of insecticides and therapeutic drugs. Full article

Leaching mining of ion-adsorption rare earths degrades soil organic matter and hampers vegetation recovery. High-resolution UAV remote sensing enables large-scale monitoring of reclamation, yet vegetation detection accuracy is constrained by key challenges. Conventional three-channel detection struggles with terrain complexity, illumination variation, and shadow effects. Fixed UAV altitude and missing topographic data further cause resolution inconsistencies, posing major challenges for accurate vegetation detection in reclaimed land. To enhance multi-spectral vegetation detection, the model input is expanded from the traditional three channels to six channels, enabling full utilization of multi-spectral information. Furthermore, the Channel Attention and Global Pooling SPPF (CAGP-SPPF) module is introduced for multi-scale feature extraction, integrating global pooling and channel attention to capture multi-channel semantic information. In addition, the C2f_DynamicConv module replaces conventional convolutions in the neck network to strengthen high-dimensional feature transmission and reduce information loss, thereby improving detection accuracy. On the self-constructed reclaimed vegetation dataset, MRV-YOLO outperformed YOLOv8, with mAP@0.5 and mAP@0.5:0.95 increasing by 4.6% and 10.8%, respectively. Compared with RT-DETR, YOLOv3, YOLOv5, YOLOv6, YOLOv7, yolov7-tiny, YOLOv8-AS, YOLOv10, and YOLOv11, mAP@0.5 improved by 6.8%, 9.7%, 5.3%, 6.5%, 6.4%, 8.9%, 4.6%, 2.1%, and 5.4%, respectively. The results demonstrate that multichannel inputs incorporating near-infrared and dual red-edge bands significantly enhance detection accuracy for reclaimed vegetation in rare earth mining areas, providing technical support for ecological restoration monitoring. 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

Background/Objectives: Potassium (K⁺) channels are essential transmembrane proteins that regulate ion flow, playing a critical role in regulating action potentials and neuronal transmission. Although K⁺ channel openers (agonists, K⁺ Ag) are widely used in treating neurological and psychiatric disorders, their precise mechanisms of action remain unclear. Our study explored how K⁺ channel openers might influence the expression of voltage-gated K⁺ channels (Kv) in rat brain. Methods: Briefly, eight rats per group received intraperitoneal injections of diazoxide (Dia), chlorzoxazone (Chl), or flupirtine (Flu). Two hours post-injection, the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), dorsal hippocampus (dHIP), and ventral hippocampus (vHIP) were collected for mRNA expression analysis of various Kv. Results: Dia administration altered expression of Kcna6 in the NAc, dSTR, and vHIP, and Kcnq2 in the PFC, dSTR, and dHIP. The mRNA levels of Kcna2 and Kcna3 changed in the NAc, dHIP, and vHIP, while Kcna6 expression increased in the PFC, dHIP, and vHIP of rats treated with Chl. Injection of Flu resulted in altered expression for Kcna1 in the NAc, dSTR, and dHIP; Kcna3 in the PFC, NAc, dHIP, and vHIP; Kcna6 in the dSTR, dHIP, and vHIP; and Kcnq2 and Kcnq3 in the PFC, dHIP, and vHIP. We also found dose-dependent changes. Conclusions: To our knowledge, this is the first study to identify the effects of potassium channel openers on gene expression within the mesocorticolimbic and nigrostriatal dopaminergic systems. These findings reveal a novel molecular mechanism underlying the action of these drugs in the brain. Importantly, our results have broader implications for translational neuroscience, particularly in the context of repurposing FDA-approved drugs, such as diazoxide and chlorzoxazone, for the treatment of neurological disorders. Full article

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia. 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

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting nerve impulse transmission and leading to systemic physiological dysfunctions in the nervous, respiratory, cardiovascular, and digestive systems. Severe exposure can lead to paralysis, respiratory failure, and mortality. STX primarily enters the human body through the consumption of contaminated shellfish, posing a significant public health risk as the causative agent of paralytic shellfish poisoning (PSP). Beyond its acute toxicity, STX exerts cascading impacts on food safety, marine ecosystem integrity, and economic stability, particularly in regions affected by harmful algal blooms (HABs). Moreover, the complex molecular structure of STX—tricyclic skeleton and biguanide group—and its diverse analogs (more than 50 derivatives) have made it the focus of research on natural toxins. In this review, we traced the discovery history, chemical structure, molecular biosynthesis, biological enrichment mechanisms, and toxicological actions of STX. Moreover, we highlighted recent advancements in the potential for detection and treatment strategies of STX. By integrating multidisciplinary insights, this review aims to provide a holistic understanding of STX and to guide future research directions for its prevention, management, and potential applications. Full article

Recently, complementary and alternative medicine have been actively employed for patients experiencing symptoms unresponsive to Western medical treatments like drug therapy. Natural compounds, including polyphenols, carotenoids, and omega fatty acids, have demonstrated various beneficial biological actions for human health in several studies. Given their broad pharmacological activities and reduced toxicity, these compounds possess significant potential as resources for the development of natural analgesic drugs. Given recent studies showing that natural compounds can modulate neuronal excitability (including nociceptive sensory transmission through mechanoreceptors and voltage-gated ion channels) and inhibit the cyclooxygenase-2 cascade, these compounds hold promise as complementary and alternative medicine candidates, particularly as therapeutic agents for nociceptive and pathological pain. This review focuses on elucidating the mechanisms by which natural compounds modulate neuronal electrical signals—including generator potentials, action potentials, and postsynaptic potentials—in nociceptive pathway neurons, potentially leading to local and intravenous anesthetic effects, as well as inflammatory pain relief. Specifically, we discuss the contribution of natural compounds to the relief of nociceptive and/or pathological pain and their potential clinical application, drawing on our recent published in vivo studies. 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

Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (Na_V), calcium (Ca_V), and potassium (K_V) channels, play a pivotal role in modulating neuronal excitability and pain signal transmission following nerve injury. This review intends to provide a comprehensive analysis of the molecular and cellular mechanisms by which dysregulation in the expression, localization, and function of specific Na_V channel subtypes (mainly Na_V1.7 and Na_V1.8) and their auxiliary subunits contributes to aberrant neuronal activation, the generation of ectopic discharges, and sensitization in neuropathic pain. Likewise, special emphasis is placed on the crucial role of Ca_V channels, particularly Ca_V2.2 and the auxiliary subunit Ca_Vα₂δ, whose overexpression increases calcium influx, neurotransmitter release, and neuronal hyperexcitability, thus maintaining persistent pain states. Furthermore, K_V channels (particularly K_V7 channels) function as brakes on neuronal excitability, and their dysregulation facilitates the development and maintenance of neuropathic pain. Therefore, targeting specific K_V channel subtypes to restore their function is also a promising therapeutic strategy for alleviating neuropathic pain symptoms. On the other hand, recent advances in the development of small molecules as selective modulators or inhibitors targeting voltage-gated ion channels are also discussed. These agents have improved efficacy and safety profiles in preclinical and clinical studies by attenuating pathophysiological channel activity and restoring neuronal function. This review seeks to contribute to guiding future research and drug development toward more effective mechanism-based treatments by discussing the molecular mechanisms underlying neuropathic pain and highlighting translational therapeutic opportunities. Full article

The SCN9A gene, a critical regulator of pain perception, encodes the voltage-gated sodium channel Nav1.7, a key mediator of pain signal transmission. This study conducts a multimodal assessment of SCN9A, integrating genetic variation, structural architecture, and molecular dynamics to elucidate its role in pain regulation. Using advanced computational methods, I-TASSER simulations generated structural decoys of the SCN9A homology domain, producing an ensemble of conformational states. SPICKER clustering identified five representative models with a C-score of −3.19 and TM-score of 0.36 ± 0.12, reflecting moderate structural similarity to experimental templates while highlighting deviations that may underpin functional divergence. Validation via ProSA-web supported model reliability, yielding a Z-score of −1.63, consistent with native-like structures. Central to the analysis was the R1150W non-synonymous variant, a potential pathogenic variant. Structural modeling revealed localized stability in the mutant conformation but disrupted hydrogen bonding and altered charge distribution. Its pathogenicity was underscored by a high MetaRNN score (0.7978498) and proximity to evolutionarily conserved regions, suggesting functional importance. Notably, the variant lies within the Sodium-Ion-Transport-Associated Domain, where perturbations could impair ion conductance and channel gating—mechanisms critical for neuronal excitability. These findings illuminate how SCN9A variants disrupt pain signaling, linking genetic anomalies to molecular dysfunction. While computational insights advance mechanistic understanding, experimental validation is essential to confirm the variant’s impact on Nav1.7 dynamics and cellular physiology. By refining SCN9A’s molecular blueprint and highlighting its therapeutic potential as a target for precision analgesics, this work provides a roadmap for mitigating pain-related disorders through channel-specific modulation. Integrating structural bioinformatics with functional genomics, this study deciphers SCN9A’s role in pain biology, laying the groundwork for novel strategies to manage pathological pain. Full article

In the presence of cellular mutations and impaired mechanisms of energy transmission to the attached cells and tissues, excess energy is available to upregulate some of the mechanotransduction pathways that maintain cell and tissue structure and function. The ability to transfer applied energy through integrin-mediated pathways, cell ion channels, cell membrane, cytoskeleton–nucleoskeleton connections, cell junctions, and cell–extracellular matrix attachments provides an equilibrium for energy storage, transmission, and dissipation in tissues. Disruption in energy storage, transmission, or dissipation via genetic mutations blocks mechanical communication between cells and tissues and impairs the mechanical energy equilibrium that exists between cells and tissues. This results in local structural changes through altered regulatory pathways, which produce cell clustering, collagen encapsulation, and an epithelial–mesenchymal transition (EMT), leading to increased cellular motility along newly reorganized collagen fibers (fibrosis). The goal of this review is to postulate how changes in energy transfer between cells and the extracellular matrix may alter local energy equilibrium and mechanotransduction pathways. The changes along with cellular mutations lead to cell and ECM changes reported in cancer, which is postulated to modify mechanical equilibria between cells and their ECM. This leads to uncontrolled cancer cellular proliferation and collagen remodeling. Full article

This study aimed to develop a novel Transdermal Energy Transmission System (TETS) device that addresses the driveline complications faced by patients with advanced heart failure (HF). Our TETS device utilizes a two-channel configuration with a very-low duty cycle and a pulsed RF power transmission technique, along with elliptically shaped flexible coil inductive coupling elements. We integrated a battery charging controller module into the TETS, enabling it to recharge an implanted Lithium-Ion (Li-Ion) battery that powers low-power-rated Circulatory Assist Devices, or left ventricular assist devices (LVADs). Benchtop measurements demonstrated that the TETS delivered energy from the implanted coils to the battery charging module, at a charging rate of up to 2900 J/h, presented an average temperature increase (ΔT) of 3 °C. We conducted in vivo measurements using four porcine models followed by histopathological analysis of the skin tissue in the implanted coils areas. The thermal profile analysis from the in vivo measurements and the calculated charging rates from the current and voltage waveforms, in porcine models, indicated that the charging rate and temperature varied for each model. The maximum energy charging rate observed was 2200 J/h, with an average ΔT of 3 °C. The exposed skin tissue histopathological analysis results showed no evidence of tissue thermal damage in the in vivo measurements. These results demonstrate the feasibility of our developed TETS device for wireless driving implanted low-power-rated LVADs and Li-Ion charging. Full article