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Toxicology Mechanisms and Methods Jun 2024Urolithiasis is one of the most prevalent benign urological disorders globally with a high incidence rate. Male Sprague-Dawley rats were chemically induced to have...
Urolithiasis is one of the most prevalent benign urological disorders globally with a high incidence rate. Male Sprague-Dawley rats were chemically induced to have urolithiasis and treated with triptonide and the standard antiurolithic drug cystone. Kidney weight was measured to detect calculi formation, and urinary parameters such as pH, 24-h urine volume, and protein content were measured to analyze the urolithiasis induction in rats. The inorganic ions, organic solutes, antioxidant levels, and inflammatory cytokines were measured in the experimental rats. Triptonide treatment significantly modulated the urinary pH, decreased the protein concentration, and increased the urinary outflow in urolithiasis induced rats. It also significantly decreased the urinary excretion of calcium and phosphorous and increased the excretion of magnesium, potassium, sodium, creatinine, and uric acid. SOD, CAT, and GPx levels were increased in triptonide-treated rats, and it significantly reduced the MDA levels. Triptonide treatment also decreased the levels of inflammatory cytokines and prevented the renal tissue from inflammation. To conclude, our results prove that triptonide significantly prevents calculi formation and protects renal tissue from urolithiasis-induced damage in rats. Further studies may prove triptonide a potent alternative to currently available antiurolithic drugs.
PubMed: 38922301
DOI: 10.1080/15376516.2024.2364882 -
Entropy (Basel, Switzerland) May 2024In the realm of cardiac research, the control of spiral waves and turbulent states has been a persistent focus for scholars. Among various avenues of investigation, the...
In the realm of cardiac research, the control of spiral waves and turbulent states has been a persistent focus for scholars. Among various avenues of investigation, the modulation of ion currents represents a crucial direction. It has been proved that the methods involving combined control of currents are superior to singular approaches. While previous studies have proposed some combination strategies, further reinforcement and supplementation are required, particularly in the context of controlling arrhythmias through the combined regulation of two potassium ion currents. This study employs the Luo-Rudy phase I cardiac model, modulating the maximum conductance of the time-dependent potassium current and the time-independent potassium current, to investigate the effects of this combined modulation on spiral waves and turbulent states. Numerical simulation results indicate that, compared to modulating a single current, combining reductions in the conductance of two potassium ion currents can rapidly control spiral waves and turbulent states in a short duration. This implies that employing blockers for both potassium ion currents concurrently represents a more efficient control strategy. The control outcomes of this study represent a novel and effective combination for antiarrhythmic interventions, offering potential avenues for new antiarrhythmic drug targets.
PubMed: 38920457
DOI: 10.3390/e26060446 -
Frontiers in Cellular Neuroscience 2024Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and...
Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures.
PubMed: 38919332
DOI: 10.3389/fncel.2024.1391858 -
Environmental Research Jun 2024Soil deterioration is a major cause of poor agricultural productivity, necessitating sufficient nutrient inputs like fertilizers and amendments for sustainable use. As...
Enhancement of root abscisic acid mediated osmotic regulation by macroalgal compounds promotes adaptability of Rice (Oryza sativa L.) in response to progressive metal ion mediated environmental stress.
Soil deterioration is a major cause of poor agricultural productivity, necessitating sufficient nutrient inputs like fertilizers and amendments for sustainable use. As one such strategy, the current study evaluates the potential of Sargassum wightii, a brown seaweed extract, as an osmopriming agent to improve seed germination, early establishment, and competent seedling performances in acidic soil. The elemental makeup of seaweed extract (BS) showed that it included major plant macro (Potassium, Nitrogen and Phosphorous), as well as micronutrients (Magnesium and Iron) and trace elements (Zinc, Copper, and Molybdenum). While seed germination was impacted by H ion toxicity, seeds primed with BS emerged earlier and showed a higher germination percentage (98.2%) and energy (92.4%). BS treatments enhanced seedling growth by 63% and had a positive effect on root growth (68.2%) as well as increases in root surface area (10%) and volume (67.01%). Stressed seedlings had 76.39% and 63.2% less carotenoid and chlorophyll, respectively. In seedlings treated with BS, an increase in protein and Total Soluble Sugars content of 14.56 and 7.19%, respectively, was seen. Fourier Transform-Infra Red analysis of postharvest soil indicated improved soil health with absorbance corresponding to enhanced soil water holding capacity and organic matter. Increased abscisic acid synthesis rate and associated antioxidant enzyme system (Malondialdehyde, Glutathione peroxidases and ascorbate peroxidase) activation, along with enhanced H adenosine triphosphate-ase and glutathione activities, help ameliorate and deport H ions from cells, scavenge Reactive Oxygen Species, thus protecting cells from injury. Seaweed extract successfully reduced H-induced ion toxicities in rice by promoting their germination, physiological, metabolically, and growth parameters that could ultimately increase their productivity and yield in a sustainable and environmentally friendly manner.
PubMed: 38917933
DOI: 10.1016/j.envres.2024.119485 -
PLoS Computational Biology Jun 2024Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed...
Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome.
PubMed: 38917196
DOI: 10.1371/journal.pcbi.1012244 -
Proceedings of the National Academy of... Jul 2024HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial...
HCN1-4 channels are the molecular determinants of the I/I current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
Topics: Ivabradine; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Molecular Dynamics Simulation; Humans; Cryoelectron Microscopy; Animals; Potassium Channels; Muscle Proteins
PubMed: 38917012
DOI: 10.1073/pnas.2402259121 -
BioRxiv : the Preprint Server For... Jun 2024The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to...
The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to differences in the types and numbers of low-voltage-gated potassium channels found in the neurons' membranes. Expression for some low-voltage gated ion channels like KCNQ4 is upregulated during early post-natal development; suggesting that ion channel composition and neuronal diversity may be shaped by hair cell activity. This idea is consistent with recent work showing that glutamatergic input from hair cells is necessary for the normal diversification auditory neurons. To test if biophysical diversity is similarly dependent on glutamatergic input in vestibular neurons, we examined the maturation of the vestibular epithelium and ganglion neurons in mice whose hair cell synapses lack glutamate. Despite lacking glutamatergic input, the knockout mice showed no notable balance deficits and crossed challenging balance beams with little difficulty. Immunolabeling of the vestibular epithelia showed normal development as indicated by an identifiable striolar zone with calyceal terminals labeled by molecular marker calretinin, and normal expression of KCNQ4 by the end of the second post-natal week. We found similar numbers of Type I and Type II hair cells in the knockout and wildtype animals, regardless of epithelial zone. Thus, the presumably quiescent Type II hair cells are not cleared from the epithelium. Patch-clamp recordings showed that biophysical diversity of vestibular ganglion neurons in the mice is comparable to that found in wildtype controls, with a similar range firing patterns at both immature and juvenile ages. However, our results suggest a subtle biophysical alteration to the largest ganglion cells (putative somata of central zone afferents); those in the knockout had smaller net conductance and were more excitable than those in the wild type. Thus, unlike in the auditory nerve, glutamatergic signaling is unnecessary for producing biophysical diversity in vestibular ganglion neurons. And yet, because the input signals from vestibular hair cells are complex and not solely reliant on quantal release of glutamate, whether diversity of vestibular ganglion neurons is simply hardwired or regulated by a more complex set of input signals remains to be determined.
PubMed: 38915604
DOI: 10.1101/2024.06.12.597464 -
BioRxiv : the Preprint Server For... Jun 2024Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the...
UNLABELLED
Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the potassium channel disrupts Bone Morphogenetic Protein (BMP) signaling within the developing palate. BMP signaling is essential for the correct development of several skeletal structures, including the palate, though little is known about the mechanisms that govern BMP secretion. We introduce a tool to image the release of bone morphogenetic protein 4 (BMP4) from mammalian cells. Using this tool, we show that depolarization induces BMP4 release from mouse embryonic palate mesenchyme cells in a calcium-dependent manner. We show native transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day (E) 9.5 to 13.5 mice. Disruption of significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Together, these data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and changes in intracellular calcium for mammalian craniofacial morphogenesis.
SUMMARY
We show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium. Depolarization of these cells induces BMP4 release suggesting that ion channels are a node in BMP4 signaling.
PubMed: 38915514
DOI: 10.1101/2024.06.11.598333 -
ACS Applied Materials & Interfaces Jun 2024The depletion of lithium resources has prompted exploration into alternative rechargeable energy storage systems, and potassium-ion batteries (PIBs) have emerged as...
The depletion of lithium resources has prompted exploration into alternative rechargeable energy storage systems, and potassium-ion batteries (PIBs) have emerged as promising candidates. As an active cathode material for PIBs, potassium vanadate (KVO) usually suffers from structural damage during electrochemical K-ion insertion/extraction and hence leading to unsatisfactory cycling performance. Here, we introduce Ca ions as pillars into the potassium vanadate to enhance its structural stability and smooth its phase transition behavior. The additional Ca not only stabilizes the layered structure but also promotes the rearrangement of interlayer ions and leads to a smooth solid-solution phase transition. The optimal composition KCaVO (KCVO) exhibits outstanding cyclic stability, delivering a capacity of ∼90 mA h g at 20 mA g with negligible capacity decay even after 700 cycles at 500 mA g. Theoretical calculations indicate lower energy barriers for K diffusion, promoting rapid reaction kinetics. The excellent performances and detailed investigations offer insights into the structural regulation of layered vanadium cathodes.
PubMed: 38913604
DOI: 10.1021/acsami.4c04712 -
Nanoscale Jun 2024We conduct all-atom molecular dynamics simulations to systematically investigate the underlying mechanisms governing ion transport through a sub-nanometer pore decorated...
We conduct all-atom molecular dynamics simulations to systematically investigate the underlying mechanisms governing ion transport through a sub-nanometer pore decorated with negative charges in a "Janus" MoSSe membrane. The charge imbalance between S and Se atoms on each side of the membrane induces different types of ion adsorption processes depending on the pore inner charge configuration, and the polarity of external biases, which leads to asymmetry in ionic - characteristics. Statistical analysis of the total translocation times including adsorption-desorption processes, and ion dwell times indicates that potassium ions predominantly remain adsorbed during their interaction with the membrane before undertaking a quick translocation through the pore. High applied biases suppress cation adsorption, which results in fast translocation with the current flow boosted by negative inner charges around the pore. We also show that in a membrane consisting of several "Janus" layers, the applied bias necessary to overcome the sub-nm pore barrier increases with the number of layers, providing control over the ionic current.
PubMed: 38912547
DOI: 10.1039/d4nr00589a