Modulation Of Channels Research Articles

The irreversible, towards fatalic neuropathy: from the genesis of diabetes.

Diabetic neuropathy is the most prevalent diabetes-associated complication that negatively impacts the quality of life of the patients. The extensive complications of diabetic peoples in the world are the leading cause of neuropathic pain, and over-activation of different biochemical signalling process induces the pathogenic progression and are also corresponding the epidemic painful symptom of diabetic neuropathy. The main prevalent abnormality is neuropathy, which further causing distal symmetric polyneuropathy and focal neuropathy. The exact pathological complication of diabetes associated neuropathic algesia is still unclear, but the alteration in micro-angiopathy associated nerve fibre loss, hyper polyol formation, MAPK signalling, WNT signalling, tau-derived insulin signalling processes are well known. Furthermore, the post-translational modification of different ion channels, oxidative and nitrosative stress, brain plasticity and microvascular changes can contributes the development of neuropathic pain. However, in the current review we discussed about these pathogenic development of neuropathic pain from the genesis of diabetes, and how diabetes affects the physiological and psychological health, and quality of life of the patients. Furthermore, the treatment of diabetic neuropathy with conventional monotherapy and emerging therapy are discussed. In addition, the treatment with phytochemical constituents their mechanisms and clinical evidences are also reported. The future investigation is required on pathological alteration occurs in neuropathic individuals, and on molecular mechanisms as well as the adverse effect of phytochemicals to determine all aspects of neuropathic algesia including effective treatments, which will prevents the sympathetic pain in patients.

Nanomaterial‐Mediated Modulation of TRPV1 Ion Channels for Biomedical Applications

AbstractTransient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inflammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, offering high spatiotemporal resolution and specificity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic fields to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non‐invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction. In this review, recent advances are highlighted in nanomaterial‐mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for effective TRPV1 modulation, and the required material properties are covered. Moreover, biomedical applications are discussed, including neurostimulation, neurological disorder therapies, cancer therapies, metabolic disease treatments, and cardiovascular disease interventions. Future research directions and challenges in this field are also proposed.

An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying K+ Channel 4 Variant to Identify Small Molecule Modulators

Primary aldosteronism is characterised by the excessive production of aldosterone, which is a key regulator of salt metabolism, and is the most common cause of secondary hypertension. Studies have investigated the association between primary aldosteronism and genetic alterations, with pathogenic mutations being identified. This includes a glycine-to-arginine substitution at position 151 (G151R) of the G protein-activated inward rectifier potassium (K+) channel 4 (GIRK4), which is encoded by the KCNJ5 gene. Mutations in GIRK4 have been found to reduce the selectivity for K+ ions, resulting in membrane depolarisation, the activation of voltage-gated Ca2+ channels, and an increase in aldosterone secretion. As a result, there is an interest in identifying and exploring the mechanisms of action of small molecule modulators of wildtype (WT) and mutant channels. In order to investigate the potential modulation of homotetrameric GIRK4WT and GIRK4G151R channels, homology models were generated. Molecular dynamics (MD) simulations were performed, followed by a cluster analysis to extract starting structures for molecular docking. The central cavity has been previously identified as a binding site for small molecules, including natural compounds. The OliveNetTM database, which consists of over 600 compounds from Olea europaea, was subsequently screened against the central cavity. The binding affinities and interactions of the docked ligands against the GIRK4WT and GIRK4G151R channels were then examined. Based on the results, luteolin-7-O-rutinoside, pheophorbide a, and corosolic acid were identified as potential lead compounds. The modulatory activity of olive-derived compounds against the WT and mutated forms of the GIRK4 channel can be evaluated further in vitro.

Dapagliflozin and Sirtuin-1 interaction and mechanism for ameliorating atrial fibrillation in a streptozotocin-induced rodent diabetic model.

The incidence of atrial fibrillation (AF) increases with age and is particularly high in individuals with diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), such as dapagliflozin, show promise in treating heart failure (HF) and reducing the risk of AF. Sirtuin 1 (SIRT1), a key enzyme in metabolic regulation, may be influenced by SGLT2i and play a role in the development of AF. This study investigates the relationship between dapagliflozin therapy and atrial tachyarrhythmia in diabetic cardiomyopathy, with a focus on the role of SIRT1. A streptozotocin (STZ)-induced diabetes mellitus (DM) rat model was used to assess AF across four groups: sham, STZ, STZ with dapagliflozin, and STZ with dapagliflozin + sirtinol (a SIRT1 inhibitor). Additionally, HL-1 cardiomyocytes were cultured under high glucose (HG) conditions and treated with dapagliflozin, with or without sirtinol. In the rat model, dapagliflozin improved atrial fibrosis and reduced AF inducibility and duration-effects that were partially reversed by sirtinol. These findings suggest that dapagliflozin may alleviate cardiac fibrosis and atrial arrhythmia by modulating SIRT1. In HL-1 cells under HG conditions, dapagliflozin reduced apoptosis, restored autophagy and mitophagy, and improved calcium channel activity. However, sirtinol negated these protective effects. Dapagliflozin helped normalize autophagy, mitophagy, and calcium handling, while sirtinol diminished its protective effects, highlighting the key role of SIRT1 in regulating calcium handling under HG conditions. Overall, SIRT1 plays a protective role in diabetic cardiomyopathy by reducing apoptosis, regulating autophagy and mitophagy, and modulating calcium channel activity. Dapagliflozin reduces AF duration and inducibility in the STZ model, likely through SIRT1 upregulation and calcium channel modulation.

Bionanoparticles with In Situ Nitric Oxide Release for Precise Modulation of ER-TRPV1 Ion Channels in Multimodal Killing of Glioblastoma.

Glioblastoma (GBM) with highly immunosuppressive tumor microenvironment is a significant factor contributing to its treatment resistance and low survival rate. The activation of the transient receptor potential vanilloid 1 (TRPV1) ion channel, which is overexpressed on the endoplasmic reticulum (ER) of GBM cells, governs the control of multi-organelle stress pathway branches to inhibit GBM expansion. Precise modulation of ER-TRPV1 is considered an effective strategy for inhibition of GBM. As an effective intracellular and extracellular second messenger, nitric oxide (•NO) activates the TRPV1 ion channel through nitrosylation of cysteine residues. However, the short lifespan and limited effective range of •NO makes it challenging to achieve precise regulation of ER-TRPV1. Herein, a biomimetic upconversion nanoassembly (M-UCN-T) is constructed, which encapsulates an organic •NO donor and is coated with homologous tumor-targeting cell membrane and ER-targeting peptide. In response to near-infrared light and glutathione, M-UCN-T releases •NO in situ to activate the ER-TRPV1 ion channels. This study developed a •NO-targeted release nanoplatform with stepwise targeting functions, which allow for the precise modulation of ER-TPRV1 in GBM through in situ release of •NO. This approach induces multi-organelle stress signaling pathways, ultimately resulting in multi-modal killing of tumor cells.

The Role of Ion-Transporting Proteins on Crosstalk Between the Skeletal Muscle and Central Nervous Systems Elicited by Physical Exercise.

A paradigm shift in the understanding of bidirectional interactions between peripheral and central nervous systems is essential for development of rehabilitation and preventive interventions based on physical exercise. Although a causal relationship has not been completely established, modulation of voltage-dependent ion channels (Ca2+, Cl-, K+, Na+, lactate-, H+) in skeletal and neuronal cells provides opportunities to maintain force production during exercise and reduce the risk of disease. However, there are caveats to consider when interpreting the effects of physical exercise on this bidirectional axis, since exercise protocol details (e.g., duration and intensity) have variable effects on this crosstalk. Therefore, an integrative perspective of the skeletal muscle and brain's communication pathway is discussed, and the role of physical exercise on such communication highway is explained in this review.

Pharmacological Targeting of Sodium and Calcium Channels as a Therapeutic Approach for Chronic Pain Relief

Background: It is determined that chronic pain is a common, worsening health issue that reduces patient’s quality of life and is a huge strain on health systems. Sodium and calcium channels are key for the process of transferring pain signals. Pharmacological targeting of these ion channels has been identified as a potential and efficient long-term therapy of chronic pain in the absence of non-specific side effects of traditional analgesics.Objectives: In a clinical trial, to determine the effectiveness of the drugs, selective sodium and calcium channel blockers in the management of chronic pain symptoms by comparing patients’ pain scores and the number of effectively treated patients over time.Study design: A Double-blind, randomized, controlled trialPlace and duration of the Study: Department of Biochemistry, Saidu Medical College, Saidu Sharif Swat KP – Pakistan from March 2022 to March 2023.Methodology: The effect of sodium and calcium channel blockers was examined in a double-blind, randomized comparison study of 150 patients in a chronic pain clinic. Subjects rated their pain using an anchored pain intensity scale at baseline, two weeks, and four weeks. In analyzing the results, the use of mean, standard deviation and P-value were used whereby the P value used to test hypotheses in an experiment is the probability of obtaining the observed results. Hypothesis derived parameters included; the primary end point being pain score reduction, and the secondary end points including functional changes and side effects respectively.Results: In 150 patients these three groups recognized 23 percent achieving reasonable pain heading for sodium and calcium channel blockers who achieved extra pain cut off the placebo mean pain heading of 7.3 ±1.5 SD reducing to mean pain heading of 3.8 ±1.2 SD in the same patients. Actual placebo group demonstrate a slight improvement (mean change from 7.4 to 6.8). Analysis of the data by the G * Power software showed that the effect size was highly statistically significant, with a p-value = < 0.001. Hundred percent increase in the functional scores for the treatment group, but the adverse effects were reported to be less and were comparable with that of the placebo group. These results suggest that selective sodium and calcium channel blockade can attenuate neuropathic pain.Conclusion: This class of drugs has a substantial potential and does not trigger such severe side effects as constant use of traditional analgesics does for relieving chronic pain. The present work provides evidence that ion channel modulation can be used for chronic pain management, which should be further investigated and considered for implementation into therapeutic pain paradigms.Conclusion: Results indicate that G6PD deficiency is a leading cause of neonatal jaundice, particularly in populations at higher risk due to genetic factors. Early diagnosis and treatment significantly improve outcomes, though complications such as kernicterus remain a risk in severe cases.

Unintended consequences of modifying coastal river systems

Coastal infrastructure projects, particularly the modification of coastal river channels, are becoming increasingly significant to economic activities worldwide as a response to climate-driven changes and urbanization. The benefits of channel modification projects can be realized quickly, but the altered movement of sediments in the river channel can lead to unintended geomorphic changes years or decades later. An example of this is the closure of the San Bernard River mouth, located on the central coast of Texas, which was clogged with sediments by the 1990s as a result of two major projects in the area: the diversion of the Brazos River channel (1929) and the construction of the Gulf Intracoastal Waterway (GIWW) (1940s). The objective of this study was to a) document the delayed geomorphic response to the projects using a GIS analysis of historical maps and aerial imagery, and b) provide a snapshot of altered flow pathways in the area using measurements collected in situ. Results showed that the GIWW was the main conduit for river flow as it bisects the San Bernard River 2 km inland of its river mouth, reducing discharge in the terminal limb of the river. Due to reduced flow, the river mouth became clogged with wave-transported sediment supplied by the still-adjusting Brazos River which had been diverted to within 6 km of the San Bernard River. With a limited connection to the sea, altered sediment and flow pathways have led to numerous hazards and costly corrective dredging projects surpassing $12 million to date. Optimizing the cost-effectiveness of channel modification projects requires considering their long-term impact as managers continue to adapt to ever-changing coastal zones.

VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction

Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.

OFDM system based on parametric DFT transform

This study introduces a specific type of orthogonal frequency division multiplexing (OFDM) system that relies on the parametric discrete Fourier transform (DFT-alpha), where alpha is a parameter randomly selected within the range [-2pi, 0]. We investigate the performance of the proposed system across various channel types and modulation formats, including binary phase shift keying (BPSK), 16 quadratic amplitude modulation (QAM), analyzing aspects such as bit-error rate (BER), peak-to-average power ratio (PAPR), and computational complexity. This work considers the most interesting special case of the one-parameter DFT, which is the DFT-π/6 . The simulated results confirm the suggested OFDM system’s ability to minimize the computational complexity of the conventional OFDM system, standing as the primary contribution of the current study, while maintaining the performance identical. Therefore, the parametric DFT-OFDM system would be a good alternative to the classical DFT-OFDM. The findings suggest that parametric DFT based OFDM holds significant potential for high-speed optical wireless communication systems.

Opto-chemogenetic inhibition of L-type CaV1 channels in neurons through a membrane-assisted molecular linkage

Genetically encoded inhibitors of CaV1 channels that operate via C-terminus-mediated inhibition (CMI) have been actively pursued. Here, we advance the design of CMI peptides by proposing a membrane-anchoring tag that is sufficient to link the inhibitory modules to the target channel as well as chemical and optogenetic modes of system control. We designed and implemented the constitutive and inducible CMI modules with appropriate dynamic ranges for the short and long variants of CaV1.3, both naturally occurring in neurons. Upon optical (near-infrared-responsive nanoparticles) and/or chemical (rapamycin) induction of FRB/FKBP binding, the designed peptides translocated onto the membrane via FRB-Ras, where the physical linkage requirement for CMI could be satisfied. The peptides robustly produced acute, potent, and specific inhibitions on both recombinant and neuronal CaV1 activities, including Ca2+ influx-neuritogenesis coupling. Validated through opto-chemogenetic induction, this prototype demonstrates Ca2+ channel modulation via membrane-assisted molecular linkage, promising broad applicability to diverse membrane proteins.

Transcriptomic imputation identifies tissue-specific genes associated with cervical myelopathy

BACKGROUND CONTEXTDegenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology. PURPOSETo determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy. STUDY DESIGNRetrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank. METHODSIn a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature. RESULTSWe identified 16 genes significantly associated with DCM across 5 different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention. CONCLUSIONSThe inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects. CLINICAL SIGNIFICANCEUnderstanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM.

Fluorescence-Based HTS Assays for Ion Channel Modulation in Drug Discovery Pipelines.

Ion channels represent a druggable family of transmembrane pore-forming proteins with important (patho)physiological functions. While electrophysiological measurement (manual patch clamp) remains the only direct method for detection of ion currents, it is a labor-intensive technique. Although automated patch clamp instruments have become available to date, their high costs limit their use to large pharma companies or commercial screening facilities. Therefore, fluorescence-based assays are particularly important for initial screening of compound libraries. Despite their numerous disadvantages, they are highly amenable to high-throughput screening and in many cases, no sophisticated instrumentation or materials are required. These features predispose them for implementation in early phases of drug discovery pipelines (hit identification), even in an academic environment. This review summarizes the advantages and pitfalls of individual methodological approaches for identification of ion channel modulators employing fluorescent probes (i. e., membrane potential and ion flux assays) with emphasis on practical aspects of their adaptation to high-throughput format.

Molecular mapping of KCNE4-dependent regulation of Kv1.3.

The voltage-gated potassium channel Kv1.3 plays a crucial role in the immune system response. In leukocytes, the channel is coexpressed with the dominant negative regulatory subunit KCNE4, which associates with Kv1.3 to trigger intracellular retention and accelerating C-type inactivation of the channel. Previous research has demonstrated that the main association between these proteins occurs through both C-termini. However, these data fail to fully elucidate the KCNE4-dependent modulation of channel kinetics. In the present study, we analyzed the contribution of each KCNE4 domain to the modulation of Kv1.3. Our results further confirmed that the C-terminus of KCNE4 is the main determinant involved in the association-triggered intracellular retention of the channel. Moreover, interactions throughout the transmembrane region were also observed. Both the C-terminus and, especially, the transmembrane domain of KCNE4 accentuated the C-type inactivation of Kv1.3. Our data provide, for the first time, the molecular effects that a KCNE peptide, such as KCNE4, exerts on a Shaker channel, such as Kv1.3. Our results pave the way for understanding the molecular mechanisms underlying potassium channel modulation and suggest that KCNE4 participates in the conformational rearrangement of the Kv1.3 architecture, altering the C-type inactivation of the channel.

CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors. Intriguingly, these synaptic perturbations coexisted with increased non-synaptically driven activity, as characterized by inhibition of NMDA and AMPA receptors on micro-electrode arrays. Single-cell electrophysiology and gene expression analysis corroborated this increased intrinsic excitability through reduced potassium channel function and expression. Moreover, we observed partial mitigation of the CACNA1A+/- network phenotype by 4-aminopyridine, a therapeutic intervention for episodic ataxia type 2. Positive modulation of KCa2 channels could reverse the CACNA1A+/- network electrophysiological phenotype. In summary, our study pioneers the characterization of a human induced pluripotent stem cell-derived neuronal model for CACNA1A haploinsufficiency, and has unveiled novel mechanistic insights. Beyond showcasing synaptic deficits, this neuronal model exhibited increased intrinsic excitability mediated by diminished potassium channel function, underscoring its potential as a therapeutic discovery platform with predictive validity.

Structural Basis for Voltage Gating and Dalfampridine Binding in the Shaker Potassium Channel.

The generation and propagation of action potentials in neurons depend on the coordinated activation of voltage-dependent sodium and potassium channels. Potassium channels of the Shaker family regulate neuronal excitability through voltage-dependent opening and closing of their ion conduction pore. This family of channels is an important therapeutic target, particularly in multiple sclerosis where the inhibitor dalfampridine (4-aminopyridine) is used to improve nerve conduction. The molecular details of how the voltage sensor domain drives opening of the pore domain has been limited by the lack of closed-state structures, also impairing the search for novel drugs. Using AlphaFold2-based conformational sampling methods we identify a structural model for the closed Shaker potassium channel where movement of the voltage sensor drives the opening trough interactions between the S4-S5 linker and S6 helix. We show experimentally that breakage of a backbone hydrogen bond is a critical part of the activation pathway. Through docking we identify a hydrophobic cavity formed by the pore domain helices that binds dalfampridine in the closed state. Our results demonstrate how voltage sensor movement drives pore opening and provide a structural framework for developing new therapeutic agents targeting the closed state. We anticipate this work will enable structure-based drug design efforts focused on state-dependent modulation of voltage-gated ion channels for the treatment of neurological disorders.

Advances in deep learning-based intelligent receivers

Abstract. This paper presents a summary of the progress of deep learning in the research of intelligent receivers and predicts its future development direction. First, the background of the era of intelligent receivers is introduced. With the rapid development of communication technology, intelligent receivers show insufficient flexibility, low accuracy, and spectral efficiency in detecting current radio signals. This is a challenge that is difficult to overcome in order to meet the needs of modern signal recovery. With the advent of artificial intelligence technologies such as deep learning, academia and industry began to explore the potential of applying these techniques to the field of communication receivers, leading to the emergence of intelligent receivers. This paper then introduces the fundamentals of wireless communication systems and deep learning neural networks, laying the groundwork for a deeper understanding of the subsequent content. Chapter 3 provides a comprehensive overview of the application of intelligent receivers in signal reception, including channel estimation, signal detection, modulation identification, demodulation and decoding. Finally, the paper considers the practical applications of intelligent receivers and speculates on their future development.

Mechanism of acid-sensing ion channel modulation by Hi1a.

Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by extracellular acidification. Amongst many pathological roles, ASICs are an important mediator of ischemic cell death and hence an attractive drug target for stroke treatment as well as other conditions. A peptide called Hi1a, isolated from Australian funnel web spider venom, inhibits ASIC1a and attenuates cell death in a stroke model up to 8 h after stroke induction. Here, we set out to understand the molecular basis for Hi1a's action. Hi1a is a bivalent toxin with two inhibitory cystine knot domains joined by a short linker. We found that both Hi1a domains modulate human ASIC1a gating with the N-terminal domain impairing channel activation while the C-terminal domain produces a "pro-open" phenotype even at submicromolar concentrations. Interestingly, both domains bind at the same site since a single point mutation, F352A, abolishes functional effects and reduces toxin affinity in surface plasmon resonance measurements. Therefore, the action of Hi1a at ASIC1a appears to arise through a mutually exclusive binding model where either the N or C domain of a single Hi1a binds one ASIC1a subunit. An ASIC1a trimer may bind several inhibitory N domains and one or more pro-open C domains at any one time, accounting for the incomplete inhibition of wild type Hi1a. We also found that the functional differences between these two domains are partially transferred by mutagenesis, affording new insight into the channel function and possible novel avenues of drug design.

From Sudoscan to bedside: theory, modalities, and application of electrochemical skin conductance in medical diagnostics.

The human body has two main types of sweat glands: apocrine and eccrine. Eccrine glands are widely distributed across the skin, including areas with hair. While the eccrine glands on palms and soles help improve grip, those on the rest of the body primarily aid in thermoregulation. Sudomotor function, which controls sweating, is regulated by the sympathetic division of the autonomic nervous system through cholinergic and adrenergic pathways. The activation of eccrine glands involves intricate processes, including neurotransmitter binding, ion channel modulation, and voltage generation. Sudoscan technology utilizes electrochemical skin conductance (ESC) to non-invasively measure sudomotor function. This method, which has been standardized for accuracy, has established normative benchmarks and has proven reliable across diverse populations. Sudoscan's diagnostic performance is comparable to invasive methods such as intraepidermal nerve fiber density testing, making it a valuable tool for diagnosing small fiber neuropathy. Moreover, it has been shown to correlate with corneal nerve fiber length, providing insights into various neuropathic conditions. Compared to traditional sudomotor function tests, Sudoscan proves superior in terms of its accessibility, simplicity, and reliability, with the potential to replace or complement existing diagnostic methods. It is important to differentiate ESC, as measured by Sudoscan, from other skin conductance measures, such as galvanic skin response (GSR) or electrodermal activity (EDA). Although these methods share a common physiological principle, ESC is specifically designed for diagnosing sudomotor function, unlike GSR/EDA, which is typically used for continuous monitoring. Sudoscan's success has led to its integration into consumer health devices, such as the BodyScan from Withings, showcasing its versatility beyond clinical settings. Future research may explore ESC applications in diverse medical fields, leveraging real-world data from integrated consumer devices. Collaborative efforts between researchers and engineers promise to offer new insights into sudomotor function and its implications for broader health monitoring. This study provides a comprehensive overview of ESC, including topics such as eccrine gland physiology, sudomotor function, Sudoscan technology, normative benchmarks, diagnostic comparisons, and potential future applications.

Mitochondrial Dysfunction and Ion Imbalance in a Rat Model of Hemodialysis-Induced Myocardial Stunning.

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K+) and calcium (Ca2+) are implicated in the pathogenesis of HIMS. This study aims to investigate the role of mitochondrial dysfunction and the protective potential of mitochondrial ATP-sensitive potassium channels (mitoKATP) in mitigating HIMS. Methods: A 5/6 nephrectomy rat model was established to mimic chronic kidney disease and the subsequent HIMS. The effects of mitoKATP channel modulators were evaluated by administering diazoxide (DZX), a mitoKATP opener, and 5-hydroxydecanoate (5-HD), a mitoKATP blocker, before hemodialysis. Mitochondrial function was assessed by measuring membrane potential, ATP synthase activity, and intramitochondrial Ca2+ levels. Myocardial function was evaluated using speckle tracking echocardiography. Results: Rats undergoing hemodialysis exhibited significant reductions in left ventricular strain and synchrony. DZX administration significantly improved mitochondrial function and reduced myocardial strain compared to controls. Conversely, 5-HD worsened mitochondrial swelling and disrupted myocardial function. Higher K+ and Ca2+ concentrations in the dialysate were associated with improved mitochondrial energy metabolism and myocardial strain. Conclusions: Mitochondrial dysfunction and ion imbalances during hemodialysis are key contributors to HIMS. The activation of mitoKATP channels provides mitochondrial protection and may serve as a potential therapeutic strategy to mitigate HIMS.