Calcium Influx Research Articles

Breaking through with ultrasound: TP53-driven efficacy of calcium sonoporation in pediatric rhabdomyosarcoma cells.

Ultrasound-mediated sonoporation is a promising technique that temporarily permeabilizes cell membranes to enhance delivery of therapeutic agents directly to tumor sites while minimizing systemic side effects. Calcium, a critical regulator of cell death and proliferation, can be introduced into cells by ultrasound, offering a novel therapeutic approach. This study investigates calcium sonoporation (CaSP), which combines ultrasound with calcium ions and microbubbles, to target pediatric rhabdomyosarcoma A204 and RD cells. Our findings showed that CaSP disrupted cellular homeostasis by facilitating the controlled influx of calcium, leading to oxidative stress, mitochondrial dysfunction, cell cycle arrest and activation of apoptotic pathways. The study revealed that the TP53 mutational status significantly influences the cellular response to CaSP. TP53-wild-type A204 cells were particularly susceptible to CaSP, exhibiting marked increases in apoptosis and oxidative damage. In contrast, TP53-mutated RD cells exhibited a reduced oxidative stress and apoptotic response, highlighting the critical role of TP53 in mediating the effects of CaSP. This differential response underscored the potential of TP53 gene as a biomarker for predicting the efficacy of CaSP, offering a pathway toward more personalized cancer therapies. Furthermore, the study demonstrated that CaSP can selectively target cancer cells while sparing healthy tissue. The research laid the groundwork for future studies to optimise sonoporation parameters and explore its integration with existing cancer treatments. The insights gained from this study pave the way for developing more personalized cancer treatment strategies, particularly for tumors influenced by specific genetic contexts, such as TP53 mutations.

Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans.

The Shaker/Kv1 subfamily of voltage-gated potassium (K+) channels is essential for modulating membrane excitability. Their loss results in prolonged depolarization and excessive calcium influx. These channels have also been implicated in a variety of other cellular processes, but the underlying mechanisms remain poorly understood. Through comprehensive screening of K+ channel mutants in C. elegans, we discovered that shk-1 mutants are highly susceptible to bacterial pathogen infection and oxidative stress. This vulnerability is associated with reduced glycogen levels and substantial mitochondrial dysfunction, including decreased ATP production and dysregulated mitochondrial membrane potential under stress conditions. SHK-1 is predominantly expressed and functions in body wall muscle to maintain glycogen storage and mitochondrial homeostasis. RNA-sequencing data reveal that shk-1 mutants have decreased expression of a set of cation-transporting ATPases (CATP), which are crucial for maintaining electrochemical gradients. Intriguingly, overexpressing catp-3, but not other catp genes, restores the depolarization of mitochondrial membrane potential under stress and enhances stress tolerance in shk-1 mutants. This finding suggests that increased catp-3 levels may help restore electrochemical gradients disrupted by shk-1 deficiency, thereby rescuing the phenotypes observed in shk-1 mutants. Overall, our findings highlight a critical role for SHK-1 in maintaining stress tolerance by regulating glycogen storage, mitochondrial homeostasis, and gene expression. They also provide insights into how Shaker/Kv1 channels participate in a broad range of cellular processes.

Involvement of Piezo 1 in inhibition of shear-induced platelet activation and arterial thrombosis by ginsenoside Rb1.

Shear-induced platelet activation and aggregation (SIPA) play crucial roles in arterial thrombosis. Piezo1 is a mechanosensitive calcium channel that promotes platelet hyperactivation under pathological high-shear conditions. This study explores the function of platelet Piezo1 in SIPA and arterial thrombosis, and the inhibitory effects and mechanisms of ginsenoside Rb1 on these processes. Transgenic mice with platelet-specific Piezo1 deficiency (Piezo1ΔPlt) were used to elucidate the role of platelet Piezo1 in SIPA and arterial thrombosis. A microfluidic channel system was employed to assess platelet aggregation, calcium influx, calpain activity, talin cleavage, integrin αIIbβ3 activation and P-selectin expression under shear flow. Cellular thermal shift assay was used to determine binding between Rb1 and Piezo1. Folts-like model in mice was used to evaluate antithrombotic effects of Rb1. Piezo1 deficiency in platelets reduced platelet activation and aggregation induced by a high shear rate of 4000 s-1 and attenuated arterial thrombosis induced by Folts-like mouse model. Rb1 inhibited SIPA with an IC50 of 10.8 μM. Rb1 inhibited shear-induced Ca2+-dependent platelet activation and aggregation, as well as thrombus formation in Folts-like model in Piezo1fl/fl mice. Rb1 significantly improved thermal stability of Piezo1 in platelets by binding to Piezo1. Treatment of Piezo1ΔPlt mice with Rb1 did not exhibit further inhibitory effects on SIPA and thrombosis. Platelet Piezo1 is essential for SIPA and arterial thrombosis induced by high shear. Rb1 exerted anti-platelet and anti-thrombotic effects at high shear rates via Piezo1 channels, providing a potential candidate as antiplatelet therapeutic agent.

N-Methyl-D-aspartate receptor antagonists for the prevention of chronic postsurgical pain: a narrative review

The N-methyl-D-aspartate receptor (NMDAR) has been linked to the development of chronic postsurgical pain (CPSP), defined as pain after surgery that does not resolve by 3 months. Once the combination...

Exercise-induced cytosolic calcium oscillations: mechanisms and modulation of T-cell function.

This study investigated time-dependent changes in intracellular Ca2⁺ levels in T cells, regulatory mechanisms, and functional effects after acute exercise. Male C57BL/6 mice were assigned to control and exercise groups, with the latter sacrificed at different intervals post-exercise. Murine splenic lymphocytes were isolated, and cytosolic Ca2⁺ levels were measured using Fluo-3/AM. T-cell proliferation was assessed by flow cytometry and CFSE labeling, apoptosis by Annexin V/PI staining, and cytokine levels by CBA. RNA sequencing results were validated by qRT-PCR. The findings revealed that exercise significantly altered intracellular calcium oscillations in CD3+ cells, leading to reduced mitogen-stimulated proliferation, increased IL-6, IL-5, and IL-13 production, and decreased IL-2 secretion. Additionally, there was an increase in the apoptotic fraction of CD3+ cells, with upregulated expression of Cav1.1, Cav3.2, Cav3.3, SERCA2B, PKCθ, Bcl-xL, and FADD, and downregulated Ryr3 (p<0.05). Transcriptomic analysis identified 607 differentially expressed genes involved in calcium ion binding and related pathways, including calcium signaling and cytokine-cytokine receptor interactions. Thus, acute exercise induces specific calcium oscillation patterns in T cells, mediated by PKCθ, affecting proliferation, apoptosis, and cytokine production. These changes are attributed to increased calcium influx through Cav1.1, Cav3.2, and Cav3.3 channels, decreased calcium reuptake via SERCA2B, and reduced calcium release through Ryr3. This research provides novel insights into how exercise modulates immune cell function by altering calcium levels, potential implications for enhancing immune responses or reducing inflammation.

Eu-Doped TiO2 Coatings via One-Step In Situ Preparation Enhance Macrophage Polarization and Osseointegration of Implants.

The controllable regulation of immune and osteogenic processes plays a critical role in the modification of biocompatible materials for tissue regeneration. In this study, titanium dioxide-europium coatings (MAO/Eu) were prepared on the surface of a titanium alloy (Ti-6Al-4V) via a one-step process combining microarc oxidation (MAO) and in situ doping. The incorporation of Eu significantly improved the hydrophilic and mechanical properties of the TiO2 coatings without altering their morphology. The presence of Eu effectively stimulated calcium influx in macrophages and activated β-catenin through the wnt/β-catenin signaling pathway. Consequently, macrophage M2 polarization was accelerated through the overexpression of prostaglandin E2 (PGE2). Additionally, Ca2+ promoted the osteogenic differentiation of MC3T3-E1 cells through the synergistic upregulation of transcription factors (e.g., AP-1, BMP-2). In vivo studies demonstrated that MAO/Eu coatings significantly enhanced osseointegration compared with the titanium alloy group. Therefore, MAO/Eu shows promising potential as an ideal coating for implants that offers effective immunomodulatory strategies and improves bone integration.

Osteoblast-Derived Mitochondria Formulated with Cationic Liposome Guide Mesenchymal Stem Cells into Osteogenic Differentiation.

While mitochondria are known to be essential for intracellular energy production and overall function, emerging evidence highlights their role in influencing cell behavior through mitochondrial transfer. This phenomenon provides a potential basis for the development of treatment strategies for tissue damage and degeneration. This study aims to evaluate whether mitochondria isolated from osteoblasts can promote osteogenic differentiation in mesenchymal stem cells (MSCs). Mitochondria from MSCs, which primarily utilize glycolysis, are compared with those from MG63 cells, which depend on oxidative phosphorylation. Mitochondria from both cell types are then encapsulated in cationic liposomes and transferred to MSCs, and their impact on differentiation is assessed. Mitochondria delivery from MG63 cells to MSCs grown in both two- and three-dimensional cultures results in increased expression of osteogenic markers, including Runt-related transcription factor 2, Osterix, and Osteopontin, and upregulation of genes involved in Bone morphogenetic protein 2 signaling and calcium import. This is accompanied by increased calcium influx and regulated by the Wnt/β-catenin signaling pathway. Transplantation of spheroids containing MSCs with MG63-derived mitochondria in bone defect animal models improves bone regeneration. The results suggest that delivery of MG63-derived mitochondria effectively guides MSCs toward osteogenesis, paving the way for the development of mitochondria-transplantationtherapies.

Lactobacillus johnsonii Generates Cyclo(pro-trp) and Promotes Intestinal Ca2+ Absorption to Alleviate CKD-SHPT.

Patients with chronic kidney disease (CKD) are at a high risk of developing secondary hyperparathyroidism (SHPT), which may cause organ dysfunction and increase patient mortality. The main clinical interventions for CKD-SHPT involve calcium supplements to boost absorption, but ineffective for some patients, and the reasons remain unclear. Here, CKD mice are divided into high and low groups based on intact parathyroid hormone (iPTH) levels. The high group exhibits significant changes in gut microbes, including a decrease in Lactobacillus, an increase in parathyroid hyperplasia, and a decrease in intestinal calcium. Fecal microbiota transplantation and L. johnsonii colonization indicate a link between gut microbes and CKD-SHPT. Clinically, higher L. johnsonii levels are correlated with milder hyperparathyroidism CKD-SHPT. The receiver operating characteristic (ROC) curve for L. johnsonii abundance and surgical risk is 0.81, with the calibration curve confirming predictive accuracy, and decision curve analysis revealing good clinical applicability. In vivo and in vitro experiments show that cyclo(pro-trp) enhance calcium inflow and lower iPTH levels in intestinal epithelial cells via a calcium-sensing receptor and transient receptor potential vanilloid 4 pathways. This study identified the crucial role of L. johnsonii in CKD-SHPT, unveiling a new mechanism for calcium imbalance and offering novel strategies for SHPT treatment and drug development.

Nanoscale Ligand Spacing Regulates Mechanical Force-Induced Cancer Cell Killing.

Cancer cells sense and respond to the extracellular environment, with differences in nanoscale ligand spacing affecting their behavior. Emerging reports show that stretch/ultrasound-mediated mechanical forces promote apoptosis (mechanoptosis) by increasing myosin contractility. Since myosin contractility is critical for nanoscale-ligand spacing-regulated cell behavior, we study the effect of ligand spacing on mechanoptosis. Gold nanoparticle arrays were created with 35, 50, and 70 nm spacings and functionalized with cyclic-RGD peptide. Interestingly, the highest level of apoptosis was observed on 50 and 70 nm ligand spacing, where increased myosin contractility and peripheral Piezo1 channel localization causing calcium influx were observed. Perturbing cell-matrix interactions by nanomolar doses of Cilengitide (cyclic RGD pentapeptide) increases mechanoptosis on 35 nm ligand spacing to similar levels observed on 50 and 70 nm. Thus, nanoscale-level changes in binding domains regulate mechanoptosis through cell-matrix mediated mechanotransduction, and the synergistic action of ultrasound and Cilengitide can ultimately be applied to enhance tumor treatment.

The calcitron: A simple neuron model that implements many learning rules via the calcium control hypothesis.

Theoretical neuroscientists and machine learning researchers have proposed a variety of learning rules to enable artificial neural networks to effectively perform both supervised and unsupervised learning tasks. It is not always clear, however, how these theoretically-derived rules relate to biological mechanisms of plasticity in the brain, or how these different rules might be mechanistically implemented in different contexts and brain regions. This study shows that the calcium control hypothesis, which relates synaptic plasticity in the brain to the calcium concentration ([Ca2+]) in dendritic spines, can produce a diverse array of learning rules. We propose a simple, perceptron-like neuron model that has four sources of [Ca2+]: local (following the activation of an excitatory synapse and confined to that synapse), heterosynaptic (resulting from the activity of other synapses), postsynaptic spike-dependent, and supervisor-dependent. We demonstrate that by modulating the plasticity thresholds and calcium influx from each calcium source, we can reproduce a wide range of learning and plasticity protocols, such as Hebbian and anti-Hebbian learning, frequency-dependent plasticity, and unsupervised recognition of frequently repeating input patterns. Moreover, by devising simple neural circuits to provide supervisory signals, we show how the calcitron can implement homeostatic plasticity, perceptron learning, and BTSP-inspired one-shot learning. Our study bridges the gap between theoretical learning algorithms and their biological counterparts, not only replicating established learning paradigms but also introducing novel rules.

Low hydrostatic pressure promotes functional homeostasis of nucleus pulposus cells through the TRPV4/CRT/FA complex axis

The low hydrostatic pressure in the intervertebral disc plays a crucial role in maintaining the homeostasis of the disc environment, particularly in supporting the physiological functions of nucleus pulposus cells (NPCs). However, the underlying mechanisms remain poorly understood. TRPV4, a baroreceptor in the intervertebral disc, is primarily responsible for converting extracellular pressure signals into intracellular chemical signals. Upon activation, TRPV4 facilitates the influx of calcium ions, thereby regulating the physiological behavior of NP cells. Calreticulin (CRT), an endoplasmic reticulum retention protein, performs various physiological functions, including the regulation of intracellular calcium levels. CRT also exhibits distinct roles depending on its subcellular localization. In this study, we observed that under low hydrostatic pressure, TRPV4 activation and subsequent calcium influx led to an increase in CRT synthesis and a significant rise in its cytosolic expression. This was followed by the depolymerization of focal adhesion (FA) complexes, primarily consisting of FAK and integrin β1, which resulted in an increase in collagen type II (Col II) and a decrease in collagen type I (Col I). These changes in extracellular matrix (ECM) composition helped maintain the physiological function of NP cells. Furthermore, overexpression of CRT enhanced the ability of NP cells to resist partial functional damage caused by high hydrostatic pressure. Taken together, our findings suggested that low hydrostatic pressure enhanced NP cell function by regulating the TRPV4/CRT/FA complex signaling axis.

Comprehensive mutational characterization of the calcium-sensing STIM1 EF-hand reveals residues essential for structure and function.

Calcium signaling is a fundamental molecular means of cellular regulation. Store operated calcium entry (SOCE) is a major intracellular signaling module, wherein calcium release from the endoplasmic reticulum triggers transmembrane STIM1 proteins to conformationally shift and oligomerize to prompt calcium influx from the extracellular environment. STIM1 senses ER calcium concentrations with its canonical EF-hand domain, and missense variants can dysregulate SOCE and cause Tubular Aggregate Myopathy, Stormorken Syndrome or immunodeficiency. Few STIM1 EF-hand variants are characterized, obscuring how STIM1 sequence controls its function, and hampering clinical interpretation of STIM1 variants observed in patients. We leveraged fitness costs caused by overexpression of STIM1 variants in cultured human cells to functionally characterize 706 of the 720 possible single amino acid variants of the STIM1 canonical EF-hand. The calcium-coordinating EF-hand residues exhibited varying mutational patterns. The trailing helix possessed a core of immutable residues, even depleting during library propagation in bacteria, implicating residues normally restraining STIM1 aggregation. The leading helix only exhibited toxicity in cells with endogenous STIM1, implicating a multimerization-dependent STIM1 regulatory module. No cytotoxic STIM1 variants were observed in healthy human populations. Some disease-associated variants had low scores, but most pathogenic variants were not overtly cytotoxic in our assay. We demonstrate that orthogonal measurements for STIM1 oligomerization, cytoplasmic calcium influx, and cellular stress complement the cytotoxicity phenotypes to enhance variant understanding. Collectively, these data reveal the complex molecular roles embedded in the STIM1 canonical EF-hand sequence for its function in promoting calcium signaling through SOCE.

The myometrial transcriptome changes in mares with endometrosis

Mares with endometrosis exhibit histological changes not only in the endometrium but also in the myometrium that suggest possible functional impairment. The molecular background of these changes is not well understood. We hypothesize that the transcriptomic profile of the mare myometrium varies depending on the degree of endometrosis in mares. Myometria were collected from mares in the mid-luteal phase of the estrous cycle with endometrium categories I, IIA, IIB, and III (∑n = 23), according to Kenney and Doig´s histopathological classification. Myometrial RNA was isolated and subjected to RNA-seq analysis to identify differentially expressed transcriptionally active regions (deTARs) and their contribution to signaling pathways (KEGG database) and biological processes (GO terms). In results, 665, 491 and 499 deTARs were found in the myometrium of mares with endometrium IIA vs I, IIB vs I and III vs I, respectively. 200 common deTARs in the myometrium across all stages of endometrosis (IIA, IIB, and III) vs I were identified. Evaluated deTARs enriched several KEGG pathways including calcium signaling, cAMP signaling, oxytocin signaling, ECM-receptor interaction, and focal adhesion, and were classified into various GO terms including adaptive immune response, tissue homeostasis, muscle contractions, muscle development, and other. In conclusion, transcriptomic alterations in the myometrium of mares with endometrosis may indicate an impaired function of the contractile machinery, mechanisms regulating calcium influx and handling, as well as changes in ECM composition, leading to a decreased contractile activity and structural changes in the myometrium of affected mares.

Visual activity enhances neuronal excitability in thalamic relay neurons.

Amblyopia, a highly prevalent loss of visual acuity, is classically thought to result from cortical plasticity. The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a passive relay for visual information, but recent findings suggest a largely underestimated functional plasticity in the dLGN. However, the cellular mechanisms supporting this plasticity have not yet been explored. We show here that monocular deprivation (MD), an experimental model of amblyopia, reduces the intrinsic excitability of dLGN cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 hertz or when spikes are induced with current injection. LTP-IE is observed after eye opening, requires calcium influx, is expressed through the down-regulation of Kv1 channels, and is altered following MD. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN neurons induced by natural stimuli.

Anillin tunes contractility and regulates barrier function during Rho flare-mediated tight junction remodeling.

To preserve barrier function, cell-cell junctions must dynamically remodel during cell shape changes. We have previously described a rapid tight junction repair pathway characterized by local, transient activation of RhoA, termed "Rho flares", which repair leaks in tight junctions via promoting local actomyosin-mediated junction remodeling. In this pathway, junction elongation is a mechanical trigger that initiates RhoA activation through an influx of intracellular calcium and recruitment of p115RhoGEF. However, mechanisms that tune the level of RhoA activation and Myosin II contractility during the process remain uncharacterized. Here, we show that the scaffolding protein Anillin localizes to Rho flares and regulates RhoA activity and actomyosin contraction at flares. Knocking down Anillin results in Rho flares with increased intensity but shorter duration. These changes in active RhoA dynamics weaken downstream F-actin and Myosin II accumulation at the site of Rho flares, resulting in decreased junction contraction. Consequently, tight junction breaks are not reinforced following Rho flares. We show that Anillin-driven RhoA regulation is necessary for successfully repairing tight junction leaks and protecting junctions from repeated barrier damage. Together, these results uncover a novel regulatory role for Anillin during tight junction repair and barrier function maintenance. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

Lipidic folding pathway of α-Synuclein via a toxic oligomer

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization of a toxic pre-fibrillar aggregation intermediate (I1) on pathway to the formation of lipidic fibrils, which incorporate lipid molecules on protofilament surfaces during fibril growth on membranes. Super-resolution microscopy reveals a tetrameric state, providing insights into the early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover a structural reorganization essential for the transition of I1 to mature lipidic L2 fibrils. The reorganization involves the transformation of anti-parallel β-strands during the pre-fibrillar I1 state into a β-arc characteristic of amyloid fibrils. This structural reconfiguration occurs in a conserved structural kernel shared by a vast number of αS-fibril polymorphs including extracted fibrils from Parkinson’s and Lewy Body Dementia patients. Consistent with reports of anti-parallel β-strands being a defining feature of toxic αS pre-fibrillar intermediates, I1 impacts viability of neuroblasts and disrupts cell membranes, resulting in an increased calcium influx. Our results integrate the occurrence of anti-parallel β-strands as salient features of toxic oligomers with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.

Piezoelectric Nanoarrays with Mechanical-Electrical Coupling Microenvironment for Innervated Bone Regeneration.

The involvement of neurons in the peripheral nervous system is crucial for bone regeneration. Mimicking extracellular matrix cues provides a more direct and effective strategy to regulate neuronal activity and enhance bone regeneration. However, the simultaneous coupling of the intrinsic mechanical-electrical microenvironment of implants to regulate innervated bone regeneration has been largely neglected. Inspired by the mechanical and bioelectric properties of the bone microenvironment, this study constructed a mechanical-electrical coupling microenvironment (M-E) model based on barium titanate piezoelectric nanoarrays, which could effectively promote innervated bone regeneration. The study found that the mechanical microenvironment provided by the nanostructure, coupled with the electrical microenvironment provided by the piezoelectric properties, created a controllable M-E. In vitro cell experiments demonstrated that this coupled microenvironment activated Piezo2 and VGCC ion channels, promoted calcium influx in DRG neurons, and activated downstream PI3K-AKT and RAS pathways. This cascade of events led to the synthesis and release of CGRP in sensory nerves, ultimately enhancing the osteogenic differentiation of BMSCs. This work not only broadens the current understanding of biomaterials that mimic the bone extracellular matrix but also provides new insights into innervated bone regeneration.

Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease

Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4 autoantibodies as a biomarker of immune-mediated RMD (iRMD), though the underlying disease-mechanisms remain poorly understood. Transcriptomic studies were performed on muscle biopsies of 8 patients (5 males; 3 females; ages 26-to-80) with iRMD. Subsequent pathway analysis compared iRMD to human non-disease control and disease control (dermatomyositis) muscle samples. Transcriptomic studies demonstrated changes in key pathways of muscle contraction and development. All iRMD samples had significantly upregulated cavin-4 expression compared to controls, likely compensatory for autoantibody-mediated protein degradation. Proteins involved in muscle relaxation (including SERCA1, PMCA and PLN) were significantly increased in iRMD compared to controls. Comparison of iRMD to dermatomyositis transcriptomics demonstrated significant overlap in immune pathways, and the IL-6 signaling pathway was markedly increased in all iRMD patient muscle biopsies and increased in the majority of iRMD patients’ serum. This study represents the first muscle transcriptomic analysis of iRMD patients and dissects underlying disease mechanisms. Increase of sarcolemmal and cellular calcium channels as well as PLN, an inhibitor of the SERCA pump for calcium into the sarcoplasm, likely alters the calcium dynamics in iRMD. These changes in crucial components of muscle relaxation may underlie rippling by altering calcium flux. Our findings provide crucial insights into the differential expression of genes regulating muscle relaxation and highlight potential disease pathomechanisms.

Mechanosensitive Ca2+ channel TRPV1 activated by low-intensity pulsed ultrasound ameliorates acute kidney injury through Notch1-Akt-eNOS signaling.

Acute Kidney Injury (AKI) is a significant medical condition characterized by the abrupt decline in kidney function.Low-intensity pulsed ultrasound (LIPUS), a non-invasive therapeutic technique employing low-intensity acoustic wave pulses, has shown promise in promoting tissue repair and regeneration. A novel LIPUS system was developed and evaluated in rat AKI models, focusing on its effects on glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine (SCr), and the Notch1-Akt-eNOS signaling pathway. The results demonstrated that LIPUS treatment improved GFR, BUN, SCr levels, and renal pathology in AKI rats. Invitro experiments using HUVEC cells revealed that LIPUS stimulation promoted angiogenesis, cell migration mechanically-dependent calcium ion influx, which was partially attenuated by TRPV1 knockdown. RNA sequencing analysis indicated LIPUS-induced activation of the Notch pathway, phosphorylation of Akt and eNOS. Furthermore, inhibition or genetic silencing of Notch1 abolished the beneficial effects of LIPUS on angiogenesis, renal function, and Akt-eNOS phosphorylation in both cells and AKI rats. These findings suggest that LIPUS-induced calcium influx promotes Akt-eNOS phosphorylation, nitric oxide (NO) production, angiogenesis, and improved renal function in AKI via Notch1-Akt-eNOS signaling, positioning LIPUS as a promising therapeutic strategy for AKI by targeting vascular regeneration.

Matrix stiffness regulates NPC invasiveness by modulating a mechanoresponsive TRPV4-Nox4-IL-8 signaling axis.

Matrix stiffness is a critical determinant of tumorigenesis and cancer progression. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive calcium channel, regulates angiogenesis and stromal stiffness in various tumors. However, it is unclear whether matrix stiffness regulates the invasiveness of nasopharyngeal carcinoma (NPC) cells through TRPV4. In this study, we found that increased matrix stiffness of NPC tissues correlated with advanced tumor stages. Furthermore, simulation of high matrix stiffness in vitro upregulated TRPV4, and increased the migration, invasion, and epithelial mesenchymal transition (EMT) of NPC cells. Knockdown or pharmacological inhibition of TRPV4 significantly suppressed the calcium influx in NPC cells, and inhibited their invasiveness and EMT under high-stiffness conditions. Mechanistically, TRPV4 modulated the invasiveness of NPC cells in response to matrix stiffness via the NOX4/IL-8 axis. Notably, TRPV4 and IL-8 levels were significantly increased in the high-stiffness NPC tissues, and showed a positive correlation. Taken together, matrix stiffness promotes the malignant progression of NPC cells through the activation of the TRPV4/NOX4/IL-8 axis, which could be explored further as a potential target for NPC therapy.