Ion Channel Activity Research Articles

The Role of Bioelectric Signals in Cancer Genome Regulation and Potential Therapeutic Implication: An Overview

Bioelectrical signals which are directed by ion channels and membrane potential (V_mem), play a crucial role in many cellular processes including proliferation and differentiation. It has also been known to influence processes such as gene expression, epigenetics, and tumor progression which are key aspects of cancer development. This study explores the role of bioelectric signaling in oncogenesis, highlighting possible therapeutic implications. An inferential review of existing literature was done to understand the possible outcomes of integrating Tumor-Treating Fields (TTFields) with traditional therapies like chemotherapy and immunotherapy. Relevant sources were analyzed to gain mechanistic insights from clinical and non-clinical studies to deduce potential therapeutic implications. Dysregulated ion channel activity and abnormal cellular membrane potential are hallmark findings of cancer cells. Deviant bioelectric signals seen in tumors promote oncogene activation and tumor suppressor silencing. These bioelectric changes affect chromatin remodeling through pathways involving calcium signaling, histone modifications, and DNA methylation. Therapeutically, targeting ion channels, such as potassium and sodium-proton exchangers may offer a novel strategy to disrupt tumor growth. Bioelectric stimulation, using techniques like optogenetics, can also help reprogram cancer cells to induce differentiation or apoptosis. There are also potential diagnostic advancements that leverage bioelectric markers, such as depolarized membrane potential, for early cancer detection through electrophysiological imaging and wearable sensors. Bioelectric modulation can enhance drug uptake, improve immune responses by normalizing the tumor microenvironment, and enable targeted delivery using electroporation. Bioelectrical signals influence genome regulation and offer significant therapeutic and diagnostic potential. Further studies are recommended to provide essential insights into the potential of harnessing bioelectricity for advanced cancer management and improved patient outcomes.

Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives.

Lipids represent the most abundant molecular type in the brain, with a fat content of ∼60% of the dry brain weight in humans. Despite this fact, little attention has been paid to circumscribe the dynamic role of lipids in brain function and disease. Membrane lipids such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid, and endocannabinoids finely regulate both synaptic receptors and ion channels that ensure critical neural functions. After a brief introduction on brain lipids and their respective properties, we review here their role in regulating synaptic function and ion channel activity, action potential propagation, neuronal development, and functional plasticity and their contribution in the development of neurological and neuropsychiatric diseases. We also provide possible directions for future research on lipid function in brain plasticity and diseases.

The brain, rapid eye movement sleep, and major depressive disorder: A multimodal neuroimaging study

BackgroundEvidence has established the prominent involvement of rapid eye movement (REM) sleep disturbance in major depressive disorder (MDD). However, the neural correlates of REM sleep in MDD and their clinical significance are less clear. MethodsCross-sectional and longitudinal polysomnography and resting-state functional MRI data were collected from 131 MDD patients and 71 healthy controls to measure REM sleep and voxel-mirrored homotopic connectivity (VMHC). Correlation and mediation analyses were performed to examine the associations between REM sleep, VMHC, and clinical variables. Moreover, we conducted spatial correlations between the neural correlates of REM sleep and a multimodal collection of reference brain maps to facilitate genetic, structural and functional annotations. ResultsMDD patients exhibited REM sleep abnormalities manifesting as higher REM sleep latency and lower REM sleep duration, which were correlated with decreased VMHC of the precentral gyrus and inferior parietal lobe and mediated their associations with more severe anxiety symptoms. Longitudinal data showed that VMHC increase of the inferior parietal lobe was related to improvement of depression symptoms in MDD patients. Spatial correlation analyses revealed that the neural correlates of REM sleep in MDD were linked to gene categories primarily involving cellular metabolic process, signal pathway, and ion channel activity as well as linked to cortical microstructure, metabolism, electrophysiology, and cannabinoid receptor. ConclusionThese findings may add important context to the growing literature on the complex interplay between sleep and MDD, and more broadly may inform future treatment for depression via regulating sleep.

Inhibiting CFTR through inh-172 in primary neutrophils reveals CFTR-specific functional defects

The lungs of people with cystic fibrosis (PwCF) are characterized by recurrent bacterial infections and inflammation. Infections in cystic fibrosis (CF) are left unresolved despite excessive neutrophil infiltration. The role of CFTR in neutrophils is not fully understood. In this study, we aimed to assess which antimicrobial functions are directly impaired by loss of CFTR function in neutrophils. In order to do so, we used a specific inhibitor of CFTR ion channel activity, inh-172. CF neutrophils from PwCF harboring severe CFTR mutations were additionally isolated to further discern CFTR-specific functional defects. We evaluated phagocytosis, reactive oxygen species (ROS) production, neutrophil elastase (NE) and myeloperoxidase (MPO) exocytosis and bacterial killing. The inh-172 model identified decreased acidification of the phagosome, increased bacterial survival and decreased ROS production upon stimulation. In PwCF neutrophils, we observed reduced degranulation of both NE and MPO. When co-culturing neutrophils with CF sputum supernatant and airway epithelial cells, the extent of phagocytosis was reduced, underscoring the importance of recreating an inflammatory environment as seen in PwCF lungs to model immune responses in vitro. Despite low CFTR expression in blood neutrophils, functional defects were found in inh-172-treated and CF neutrophils. The inh-172 model disregards donor variability and allows pinpointing neutrophil functions directly impaired by dysfunctional CFTR.

Molecular Insights into Single-Chain Lipid Modulation of Acid-Sensing Ion Channel 3.

Polyunsaturated fatty acids (PUFAs) and their analogs play a significant role in modulating the activity of diverse ion channels, and recent studies show that these lipids potentiate acid-sensing ion channels (ASICs), leading to increased activity. The potentiation of the channel stems from multiple gating changes, but the exact mechanism of these effects remains uncertain. We posit a mechanistic explanation for one of these changes in channel function, the increase in the maximal current, by applying a combination of electrophysiology and all-atom molecular dynamics simulations on open-state hASIC3. Microsecond-scale simulations were performed on open-state hASIC3 in the absence and presence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analogue, N-arachidonyl glycine (AG). Intriguingly, our simulations in the absence of PUFA or PUFA analogs reveal that a tail from the membrane phospholipid POPC inserts itself into the pore of the channel through lateral fenestrations on the sides of the transmembrane segments, obstructing ion permeation through the channel. The binding of either DHA or AG prevented POPC from accessing the pore in our simulations, which relied on the block of ionic conduction by phospholipids. Finally, we use single-channel recording to show that DHA increases the amplitude of the single-channel currents in ASIC3, which is consistent with our hypothesis that PUFAs relieve the pore block of the channel induced by POPCs. Together, these findings offer a potential mechanistic explanation of how PUFAs modulate the ASIC maximal current, revealing a novel mechanism of action for PUFA-induced modulation of ion channels.

Human TMC1 and TMC2 are mechanically gated ion channels.

Mammalian transmembrane channel-like proteins 1 and 2 (TMC1 and TMC2) have emerged as very promising candidate mechanotransduction channels in hair cells. However, controversy persists because the heterogeneously expressed TMC1/2 in cultured cells lack evidence of mechanical gating, primarily due to their absence from the plasma membrane. By employing domain swapping with OSCA1.1 and subsequent point mutations, we successfully identified membrane-localized mouse TMC1/2 mutants, demonstrating that they are mechanically gated in heterologous cells. Further, whole-genome CRISPRi screening enabled wild-type human TMC1/2 localization in the plasma membrane, where they responded robustly to poking stimuli. In addition, wild-type human TMC1/2 showed stretch-activated currents and clear single-channel current activities. Deafness-related TMC1 mutations altered the reversal potential of TMC1, indicating that TMC1/2 are pore-forming mechanotransduction channels. In summary, our study provides evidence that human TMC1/2 are pore-forming, mechanically activated ion channels, supporting their roles as mechanotransduction channels in hair cells.

Inhaled Anesthetics: Beyond the Operating Room.

The development of inhaled anesthetics (IAs) has a rich history dating back many centuries. In modern times they have played a pivotal role in anesthesia and critical care by allowing deep sedation during periods of critical illness and surgery. In addition to their sedating effects, they have many systemic effects allowing for therapy beyond surgical anesthesia. In this narrative review we chronicle the evolution of IAs, from early volatile agents such as ether to the contemporary use of halogenated hydrocarbons. This is followed by a discussion of the mechanisms of action of these agents which primarily involve the modulation of lipid membrane properties and ion channel activity. IAs' systemic effects are also examined, including their effects on the cardiovascular, respiratory, hepatic, renal and nervous systems. We discuss of the role of IAs in treating systemic disease processes including ischemic stroke, delayed cerebral ischemia, status epilepticus, status asthmaticus, myocardial ischemia, and intensive care sedation. We conclude with a review of the practical and logistical challenges of utilizing IAs outside the operating room as well as directions for future research. This review highlights the expanding clinical utility of IAs and their evolving role in the management of a diverse range of disease processes, offering new avenues for therapeutic exploration beyond anesthesia.

Inflammation alters the expression and activity of the mechanosensitive ion channels in periodontal ligament cells.

Periodontal ligament cells (PDLCs) possess mechanotransduction capability, vital in orthodontic tooth movement (OTM) and maintaining periodontal homeostasis. The study aims to elucidate the expression profiles of mechanosensitive ion channel (MIC) families in PDLCs and how the inflammatory mediator alters their expression and function, advancing the understanding of the biological process of OTM. Human PDLCs were cultured and exposed to TNF-α. RNA sequencing was conducted to explore the mRNA transcriptome of both normal and TNF-α-treated PDLCs. Differentially expressed MICs were identified and analyzed. The functional expressions of TRPA1 and TRPM8 were further validated by RT-qPCR, Western blot, and calcium influx assays. All 10 identified MIC families or subfamilies were expressed in PDLCs, with the TRP family being the most abundant. KCNK2, PIEZO1, TMEM87A, and PKD2 were the most expressed ion channels in PDLCs. TNF-α altered the expression of the MIC families, resulting in increased expression of PIEZO, K2P, TRP, TMEM63, and TMEM87 families and decreased expression of ENaC/ASIC, TMC/TMHS/TMIE, TMEM150, TMEM120, and L/T/N-Type calcium channel families. Furthermore, 17 DEMICs were identified (false discovery rate < 0.05), with the top five (fold change ≥ 2), including upregulated TRPA1 and TRPM8. The functional expressions of TRPA1 and TRPM8 were verified, suggesting that TNF-α significantly increased their expression and sensitized their activities. The study provides comprehensive expression profiles of the MICs in PDLCs and reveals how inflammation alters the expression and activities of the MICs. Treatments targeting these MICs may offer promising strategies for improving OTM and preventing complications in inflammatory environments, ultimately leading to more effective and safer orthodontic practices.

ADPKD-Causing Missense Variants in Polycystin-1 Disrupt Cell Surface Localization or Polycystin Channel Function.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of this monogenic disorder, our limited mechanistic understanding of ADPKD has hindered therapeutic development. Here, we successfully developed bioassays that functionally classify missense variants in polycystin-1 (PC1). Strikingly, ADPKD pathogenic missense variants cluster into two major categories: 1) those that disrupt polycystin cell surface localization or 2) those that attenuate polycystin ion channel activity. We found that polycystin channels with defective surface localization could be rescued with a small molecule. We propose that small-molecule-based strategies to improve polycystin cell surface localization and channel function will be effective therapies for ADPKD patients.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Whole genome methylation sequencing identifies sex‐specific DNA methylation levels in late onset dementia due to Alzheimer’s disease

AbstractBackgroundLate onset dementia due to Alzheimer’s disease (AD) has a sex‐biased incidence with females comprising nearly two thirds of all cases. Females have a more rapid progression in cognitive decline and higher levels of known AD biomarker pathology compared to men. Genetic sequence variation does not account for the sex‐biased incidence of AD, directing attention to the emerging role of epigenetics in AD. Using whole genome methylation sequencing (WGMS), we previously reported 28,038 differentially methylated position (DMPs) within 2,707 genes between persons with and without AD. Here we report sex‐specific DNA methylation levels in AD.MethodWGMS data quantified DNA methylation levels at 25,406,945 CpG loci in 281 blood samples from 109 AD (47 female, 62 male) and 174 cognitively unimpaired (CU) individuals (90 female, 84 male) in the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention cohorts. Beta‐binomial regression models were developed to test for significant sex‐specific DNA methylation levels between CU and AD accounting for batch effects, estimated white blood cell proportions, BMI, and age. P‐values were corrected and local false discovery rates (lFDRs) were calculated.Result13,293 DMPs were identified in females and 20,719 DMPs were identified in males (Figure 1) when comparing CU and AD (lFDR &lt; 0.05; mean methylation difference &gt; 2.5%). Approximately 2% (280) of the DMPs overlap between sexes with 87 having opposite mean methylation differences. The majority of DMPs annotate to introns (55.9% females; 54.8% males) with most of the remainder intergenic (37.0% females; 37.9% males). Annotation of DMPs to genes identified 1,498 genes that are only differentially methylated in females, and 2,183 genes that are only differentially methylated in males, with 1,365 differentially methylated genes shared between females and males (Figure 2). Gene ontological analyses identified significant enrichment of pathways related to glutamate receptor and ion channel activity in shared gene sets (Figure 3).Conclusion33,732 unique, sex‐specific DMPs in AD were identified with more than 60% annotated to one of 5,067 genes. DMP‐associated genes have sex‐specific DNA methylation levels suggesting that these DMPs may play a role in the biased pathogenesis of AD.

Reversible Ca2+ signaling and enhanced paracellular transport in endothelial monolayer induced by acoustic bubbles and targeted microbeads

Ultrasound and microbubble mediated blood brain barrier opening is a non-invasive and effective technique for drug delivery to targeted brain region. However, the exact mechanisms are not fully resolved. The influences of Ca2+ signaling on sonoporation and endothelial tight junctional regulation affect the efficiency and biosafety of the technique. Therefore, an improved understanding of how ultrasound evokes Ca2+ signaling in the brain endothelial monolayer, and its correlation to endothelial permeability change is necessary. Here, we examined the effects of SonoVue microbubbles or integrin-targeted microbeads on ultrasound induced bioeffects in brain microvascular endothelial monolayer using an acoustically-coupled microscopy system, where focused ultrasound exposure and real-time recording of Ca2+ signaling and membrane perforation were performed. Microbubbles induced robust Ca2+ responses, often accompanied by cell poration, while ultrasound with microbeads elicited reversible Ca2+ response without membrane poration. At the conditions evoking reversible Ca2+ signaling, intracellular Ca2+ release and reactive oxygen species played key roles for microbubbles induced Ca2+ signaling while activation of mechanosensitive ion channels was essential for the case of microbeads. Trans-well diffusion analysis revealed significantly higher trans-endothelial transport of 70 kDa FITC-dextran for both integrin-targeted microbeads and microbubbles compared to the control group. Further immunofluorescence staining showed disruption of cell junctions with microbubble stimulation and reversible remodeling of many cell junctions by ultrasound with integrin-targeted microbeads. This investigation provides new insights for ultrasound induced Ca2+ signaling and its influence on endothelial permeability, which may help develop new strategies for safe and efficient drug/gene delivery in the vascular system.

Magnetic Iron Oxide Nanoparticles Enhance Exosome Production by Upregulating Exosome Transport and Secretion Pathways.

Exosomes are cell-released nanovesicles that regulate intercellular communication by transporting a variety of bioactive molecules. They play a crucial role in various physiological and pathological processes, such as the immune response, tissue regeneration, aging, and tumor progression. There has been growing interest in controlling exosome production, which could offer valuable tools for unraveling complex cell communication networks and enabling novel therapeutic applications. Magnetic iron oxide nanoparticles (MNPs), one of the few nanomaterials approved for clinical use, have been shown to remotely modulate cellular activities such as cytoskeleton reorganization, ion channel activation, and cell polarization. In this study, we systematically investigate the effects of MNPs, acting as nanoscale force transducers, on exosome production in two distinct cell types with different responses to mechanical stimuli. Our findings reveal that magnetic force applied to intracellular MNPs induces vesicle relocation and promotes the formation of actin stress fibers. Gene expression analysis further shows that intracellular magnetic force upregulates genes related to exosome transport and secretion as well as other pathways linked to exosome biogenesis. Notably, these forces substantially enhance exosome production, particularly MNP-containing exosomes, which are accompanied by increased intercellular exchange of MNPs. In summary, our study offers valuable insights into MNP-driven exosome production and presents potential strategies for enhancing cell communication and modulating nanoparticle distribution in nanomedicine.

Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer's disease.

Persons with Alzheimer's disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate. We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology. The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest. We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA Map2k3os. Map2k3os may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.

Sepsis, Hypothermia, and the Emergence of Osborn Waves: A Case Report

Hypothermia and sepsis are two serious clinical entities with overlapping presentations, both capable of inducing electrocardiogram (ECG) abnormalities. We present a rare case of a 43-year-old male patient with coincident sepsis, acute kidney injury, and profound hypothermia that was complicated by the development of Osborn ( J) waves and conduction abnormalities on the ECG. The patient’s core temperature was gradually restored to normal utilizing both passive and active rewarming techniques, resulting in the disappearance of the Osborn wave. Concurrently, his cognitive state and cardiovascular parameters became stable after intensive sepsis treatment. Osborn waves arise from changes in the action potential and ion channel activity between the epicardium and the endocardium. These phenomena can be detected in several medical circumstances, including hypothermia, sepsis, subarachnoid hemorrhage, Brugada syndrome, and acute coronary syndrome. This case highlights the complexity of the diagnosis and management of such clinical scenarios.

Co-targeting TMEM16A with a novel monoclonal antibody and EGFR with Cetuximab inhibits the growth and metastasis of esophageal squamous cell carcinoma.

The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.

Ion channels in acinar cells in acute pancreatitis: crosstalk of calcium, iron, and copper signals.

The initial stages of acute pancreatitis (AP) are characterized by a significant event - acinar ductal metaplasia (ADM). This process is a crucial feature of both acute and chronic pancreatitis, serving as the first step in the development of pancreatic cancer. Ion channels are integral transmembrane proteins that play a pivotal role in numerous biological processes by modulating ion flux. In many diseases, the expression and activity of ion channels are often dysregulated. Metal ions, including calcium ions (Ca2+), ferrous ions (Fe2+), and Copper ions (Cu2+), assume a distinctive role in cellular metabolism. These ions possess specific biological properties relevant to cellular function. However, the interactions among these ions exacerbate the imbalance within the intracellular environment, resulting in cellular damage and influencing the progression of AP. A more in-depth investigation into the mechanisms by which these ions interact with acinar cells is essential for elucidating AP's pathogenesis and identifying novel therapeutic strategies. Currently, treatment for AP primarily focuses on pain relief, complications prevention, and prognosis improvement. There are limited specific treatments targeting acinous cell dedifferentiation or ion imbalance. This study aims to investigate potential therapeutic strategies by examining ion crosstalk within acinar cells in the context of acute pancreatitis.

Mechanistic Insights Into Redox Damage of the Podocyte in Hypertension.

Podocytes are specialized cells within the glomerular filtration barrier, which are crucial for maintaining glomerular structural integrity and convective ultrafiltration. Podocytes exhibit a unique arborized morphology with foot processes interfacing by slit diaphragms, ladder-like, multimolecular sieves, which provide size and charge selectivity for ultrafiltration and transmembrane signaling. Podocyte dysfunction, resulting from oxidative stress, dysregulated prosurvival signaling, or structural damage, can drive the development of proteinuria and glomerulosclerosis in hypertensive nephropathy. Functionally, podocyte injury leads to actin cytoskeleton rearrangements, foot process effacement, dysregulated slit diaphragm protein expression, and impaired ultrafiltration. Notably, the renin-angiotensin system plays a pivotal role in podocyte function, with beneficial AT2R (angiotensin receptor 2)-mediated nitric oxide (NO) signaling to counteract AT1R (angiotensin receptor 1)-driven calcium (Ca2+) influx and oxidative stress. Disruption of this balance contributes significantly to podocyte dysfunction and drives albuminuria, a marker of kidney damage and overall disease progression. Oxidative stress can also lead to sustained ion channel-mediated Ca2+ influx and precipitate cytoskeletal disorganization. The complex interplay between GPCR (G-protein coupled receptor) signaling, ion channel activation, and redox injury pathways underscores the need for additional research aimed at identifying targeted therapies to protect podocytes and preserve glomerular function. Earlier detection of albuminuria and podocyte injury through routine noninvasive diagnostics will also be critical in populations at the highest risk for the development of hypertensive kidney disease. In this review, we highlight the established mechanisms of oxidative stress-mediated podocyte damage in proteinuric kidney diseases, with an emphasis on a hypertensive renal injury. We will also consider emerging therapies that have the potential to selectively protect podocytes from redox-related injury.

The neurobiological mechanisms of photoperiod impact on brain functions: a comprehensive review.

Variations in day length, or photoperiodism, whether natural or artificial light, significantly impact biological, physiological, and behavioral processes within the brain. Both natural and artificial light sources are environmental factors that significantly influence brain functions and mental well-being. Photoperiodism is a phenomenon, occurring either over a 24 h cycle or seasonally and denotes all biological responses of humans and animals to these fluctuations in day and night length. Conversely, artificial light occurrence refers to the presence of light during nighttime hours and/or its absence during the daytime (unnaturally long and short days, respectively). Light at night, which is a form of light pollution, is prevalent in many societies, especially common in certain emergency occupations. Moreover, individuals with certain mental disorders, such as depression, often exhibit a preference for darkness over daytime light. Nevertheless, disturbances in light patterns can have negative consequences, impacting brain performance through similar mechanisms albeit with varying degrees of severity. Furthermore, changes in day length lead to alterations in the activity of receptors, proteins, ion channels, and molecular signaling pathways, all of which can impact brain health. This review aims to summarize the mechanisms by which day length influences brain functions through neural circuits, hormonal systems, neurochemical processes, cellular activity, and even molecular signaling pathways.