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Biomolecules Jun 2024Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that (Nb) infection or its derived products could...
Anti-Inflammatory Responses Produced with -Derived Uridine via the Mitochondrial ATP-Sensitive Potassium Channel and Its Anti-Atherosclerosis Effect in an Apolipoprotein E Gene Knockout Mouse Model.
Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from , showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.
Topics: Animals; Mice; Atherosclerosis; Uridine; Anti-Inflammatory Agents; Nippostrongylus; Mice, Knockout; Apolipoproteins E; Disease Models, Animal; KATP Channels; Male; Mitochondria
PubMed: 38927075
DOI: 10.3390/biom14060672 -
Biomolecules Jun 2024The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further... (Review)
Review
The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress. VDAC, a pore in the outer membrane of mitochondria, shuttles metabolites between mitochondria and the cytosol and normally protects cells from oxidative damage, but when a cell's integrity is greatly compromised it initiates cell death. There are three isoforms of VDAC, and existing evidence indicates that all three are expressed in the retina. However, their precise localization and function in each cell type is unknown. It appears that most retinal cells express substantial amounts of VDAC2 and VDAC3, presumably to protect them from oxidative stress. Photoreceptors express VDAC2, HK2, and PKM2-key proteins in the Warburg pathway that also protect these cells. Consistent with its role in initiating cell death, VDAC is overexpressed in the retinal degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), and glaucoma. Treatment with antioxidants or inhibiting VDAC oligomerization reduced its expression and improved cell survival. Thus, VDAC may be a promising therapeutic candidate for the treatment of these diseases.
Topics: Humans; Voltage-Dependent Anion Channels; Retina; Animals; Oxidative Stress; Retinal Diseases; Mitochondria; Retinitis Pigmentosa
PubMed: 38927058
DOI: 10.3390/biom14060654 -
Biomolecules May 2024Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in sensitivity to a plethora of irritating agents and endogenous mediators of...
Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in sensitivity to a plethora of irritating agents and endogenous mediators of oxidative stress. TRPA1 influences neuroinflammation and macrophage and lymphocyte functions, but its role is controversial in immune cells. We reported earlier a detectable, but orders-of-magnitude-lower level of mRNA in monocytes and lymphocytes than in sensory neurons by qRT-PCR analyses of cells from lymphoid organs of mice. Our present goals were to (a) further elucidate the expression of mRNA in immune cells by RNAscope in situ hybridization (ISH) and (b) test the role of TRPA1 in lymphocyte activation. RNAscope ISH confirmed that transcripts were detectable in CD14 and CD4 cells from the peritoneal cavity of mice. A selective TRPA1 agonist JT010 elevated Ca levels in these cells only at high concentrations. However, a concentration-dependent inhibitory effect of JT010 was observed on T-cell receptor (TcR)-induced Ca signals in CD4 T lymphocytes, while JT010 neither modified B cell activation nor ionomycin-stimulated Ca level. Based on our present and past findings, TRPA1 activation negatively modulates T lymphocyte activation, but it does not appear to be a key regulator of TcR-stimulated calcium signaling.
Topics: TRPA1 Cation Channel; Animals; Mice; Lymphocyte Activation; T-Lymphocytes; Ligands; CD4-Positive T-Lymphocytes; Acetanilides; Mice, Inbred C57BL; Calcium; Receptors, Antigen, T-Cell; RNA, Messenger; Male; Calcium Signaling
PubMed: 38927036
DOI: 10.3390/biom14060632 -
Scientific Reports Jun 2024Based on the auditory periphery and the small head size, Etruscan shrews (Suncus etruscus) approximate ancestral mammalian conditions. The auditory brainstem in this...
Based on the auditory periphery and the small head size, Etruscan shrews (Suncus etruscus) approximate ancestral mammalian conditions. The auditory brainstem in this insectivore has not been investigated. Using labelling techniques, we assessed the structures of their superior olivary complex (SOC) and the nuclei of the lateral lemniscus (NLL). There, we identified the position of the major nuclei, their input pattern, transmitter content, expression of calcium binding proteins (CaBPs) and two voltage-gated ion channels. The most prominent SOC structures were the medial nucleus of the trapezoid body (MNTB), the lateral nucleus of the trapezoid body (LNTB), the lateral superior olive (LSO) and the superior paraolivary nucleus (SPN). In the NLL, the ventral (VNLL), a specific ventrolateral VNLL (VNLLvl) cell population, the intermediate (INLL) and dorsal (DNLL) nucleus, as well as the inferior colliculus's central aspect were discerned. INLL and VNLL were clearly separated by the differential distribution of various marker proteins. Most labelled proteins showed expression patterns comparable to rodents. However, SPN neurons were glycinergic and not GABAergic and the overall CaBPs expression was low. Next to the characterisation of the Etruscan shrew's auditory brainstem, our work identifies conserved nuclei and indicates variable structures in a species that approximates ancestral conditions.
Topics: Animals; Shrews; Superior Olivary Complex; Auditory Pathways; Neurons; Inferior Colliculi; Calcium-Binding Proteins; Brain Stem; Male; Olivary Nucleus
PubMed: 38926520
DOI: 10.1038/s41598-024-65451-0 -
Toxins Jun 2024Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them,... (Comparative Study)
Comparative Study
Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this study, we present a comparative investigation using electrophysiological approaches and computational analysis between two alpha toxins from evolutionarily close scorpion species of the genus , namely, Tst3 and Ts3 from and , respectively. These toxins exhibit three natural substitutions near the C-terminal region, which is directly involved in the interaction between alpha toxins and Nav channels. Additionally, we characterized the activity of the Tst3 toxin on Nav1.1-Nav1.7 channels. The three natural changes between the toxins did not alter sensitivity to Nav1.4, maintaining similar intensities regarding their ability to alter opening probabilities, delay fast inactivation, and induce persistent currents. Computational analysis demonstrated a preference for the down conformation of VSD4 and a shift in the conformational equilibrium towards this state. This illustrates that the sequence of these toxins retained the necessary information, even with alterations in the interaction site region. Through electrophysiological and computational analyses, screening of the Tst3 toxin on sodium isoform revealed its classification as a classic α-NaTx with a broad spectrum of activity. It effectively delays fast inactivation across all tested isoforms. Structural analysis of molecular energetics at the interface of the VSD4-Tst3 complex further confirmed this effect.
Topics: Scorpion Venoms; Animals; Scorpions; Brazil; Humans; Xenopus laevis; Ion Channel Gating; Amino Acid Sequence; Animals, Poisonous
PubMed: 38922152
DOI: 10.3390/toxins16060257 -
Toxins May 2024Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate... (Review)
Review
Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate (e.g., cell proliferation, dif-ferentiation, and apoptosis). The intricate balance in the PAs' levels in the tissues will determine whether beneficial or detrimental effects will affect homeostasis. It's crucial to note that endoge-nous polyamines, like spermine and spermidine, play a pivotal role in our understanding of neu-rological disorders as they interact with membrane receptors and ion channels, modulating neuro-transmission. In spiders and wasps, monoamines (histamine, dopamine, serotonin, tryptamine) and polyamines (spermine, spermidine, acyl polyamines) comprise, with peptides and other sub-stances, the low molecular weight fraction of the venom. Acylpolyamines are venom components exclusively from spiders and a species of solitary wasp, which cause inhibition chiefly of iono-tropic glutamate receptors (AMPA, NMDA, and KA iGluRs) and nicotinic acetylcholine receptors (nAChRs). The first venom acylpolyamines ever discovered (argiopines, Joro and Nephila toxins, and philanthotoxins) have provided templates for the design and synthesis of numerous analogs. Thus far, analogs with high potency exert their effect at nanomolar concentrations, with high se-lectivity toward their ionotropic and ligand receptors. These potent and selective acylpolyamine analogs can serve biomedical purposes and pest control management. The structural modification of acylpolyamine with photolabile and fluorescent groups converted these venom toxins into use-ful molecular probes to discriminate iGluRs and nAchRs in cell populations. In various cases, the linear polyamines, like spermine and spermidine, constituting venom acyl polyamine backbones, have served as cargoes to deliver active molecules via a polyamine uptake system on diseased cells for targeted therapy. In this review, we examined examples of biogenic amines that play an essential role in neural homeostasis and cell signaling, contributing to human health and disease outcomes, which can be present in the venom of arachnids and hymenopterans. With an empha-sis on the spider and wasp venom acylpolyamines, we focused on the origin, structure, derivatiza-tion, and biomedical and biotechnological application of these pharmacologically attractive, chemically modular venom components.
Topics: Animals; Polyamines; Spider Venoms; Insecticides; Wasps; Humans; Spiders
PubMed: 38922129
DOI: 10.3390/toxins16060234 -
Cells Jun 2024Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we...
Dysfunction of Small-Conductance Ca-Activated Potassium (SK) Channels Drives Amygdala Hyperexcitability and Neuropathic Pain Behaviors: Involvement of Epigenetic Mechanisms.
Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels. Brain slice electrophysiology found hyperexcitability of CeA neurons in the neuropathic pain condition due to the loss of SK channel-mediated medium afterhyperpolarization (mAHP), which was accompanied by decreased SK2 channel protein and mRNA expression, consistent with a pretranscriptional mechanisms. The underlying mechanisms involved the epigenetic silencing of the SK2 gene due to the increased DNA methylation of the CpG island of the SK2 promoter region and the change in methylated CpG sites in the CeA in neuropathic pain. This study identified the epigenetic dysregulation of SK channels in the amygdala (CeA) as a novel mechanism of neuropathic pain-related plasticity and behavior that could be targeted to control abnormally enhanced amygdala activity and chronic neuropathic pain.
Topics: Animals; Small-Conductance Calcium-Activated Potassium Channels; Neuralgia; Epigenesis, Genetic; Male; Amygdala; Rats; Rats, Sprague-Dawley; DNA Methylation; Behavior, Animal; Neurons
PubMed: 38920682
DOI: 10.3390/cells13121055 -
Cells Jun 2024This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (K) channels in the pathogenesis of atrial fibrillation (AF), a common... (Review)
Review
This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (K) channels in the pathogenesis of atrial fibrillation (AF), a common cardiac arrhythmia. It delves into the molecular and cellular mechanisms that underpin AF, emphasizing the vital function of K channels in modulating the atrial action potential and facilitating arrhythmogenic conditions. This study underscores the dual nature of K activation and its genetic regulation, revealing that specific variations in potassium channel genes, such as Kir3.4 and K3.1, significantly influence the electrophysiological remodeling associated with AF. Furthermore, this manuscript identifies the crucial role of the K-mediated current, , in sustaining arrhythmia through facilitating shorter re-entry circuits and stabilizing the re-entrant circuits, particularly in response to vagal nerve stimulation. Experimental findings from animal models, which could not induce AF in the absence of muscarinic activation, highlight the dependency of AF induction on K channel activity. This is complemented by discussions on therapeutic interventions, where K channel blockers have shown promise in AF management. Additionally, this study discusses the broader implications of K channel behavior, including its ubiquitous presence across different cardiac regions and species, contributing to a comprehensive understanding of AF dynamics. The implications of these findings are profound, suggesting that targeting K channels might offer new therapeutic avenues for AF treatment, particularly in cases resistant to conventional approaches. By integrating genetic, cellular, and pharmacological perspectives, this manuscript offers a holistic view of the potential mechanisms and therapeutic targets in AF, making a significant contribution to the field of cardiac arrhythmia research.
Topics: Atrial Fibrillation; Humans; Animals; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Action Potentials; Acetylcholine
PubMed: 38920645
DOI: 10.3390/cells13121014 -
Journal of Biosciences 2024Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an... (Review)
Review
Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl and other anions. A dysfunctional CFTR due to abnormalities in the gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme.
Topics: Cystic Fibrosis; Humans; India; Cystic Fibrosis Transmembrane Conductance Regulator; Developing Countries; Genetic Therapy; Neonatal Screening; Infant, Newborn; Mutation
PubMed: 38920104
DOI: No ID Found -
F1000Research 2024Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive... (Review)
Review
Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive compounds like proteins, peptides, and small molecules, which may possess medicinal properties against epilepsy. In recent years, research has shown that venoms from various organisms such as spiders, ants, bees, wasps, and conus snails have anticonvulsant and antiepileptic effects by targeting specific receptors and ion channels. This review underscores the significance of purified proteins and toxins from these sources as potential therapeutic agents for epilepsy. In conclusion, this review emphasizes the valuable role of animal venoms as a natural resource for further exploration in epilepsy treatment research.
Topics: Animals; Anticonvulsants; Humans; Venoms; Epilepsy
PubMed: 38919947
DOI: 10.12688/f1000research.147027.1