Mechanosensitive Ion Channel Reprogramming

BACKGROUND: Ovarian cancer (OC) is a significant health concern due to the complex nature of its causes, difficulties in early detection, and low 5-year survival rate. The function of mechanosensitive ion channel (MIC)-related prognostic gene signatures in OC is still not clearly defined. Our aim was to clarify the function of the MIC in OC. METHODS: We created OC subtypes and a prognostic model based on MICs to forecast patient outcomes using RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA) database. RESULTS: In this study, the top 20 genes were identified based on their relevance scores and included PIEZO1, SCN5A, KCNQ1, CFTR, PIEZO2, KCNMA1, ASIC2, CACNA1C, ASIC3, SCN1A, TRPV4, TRPV1, KCNN4, SCNN1B, SCNN1A, CACNA1B, SCNN1G, TRPM7, KCNK2, and TRPA1. Patients were distinctly categorized into a high-risk group (cluster 1) and a low-risk group (cluster 2) based on genes related to MICs. Functional analysis revealed that the upregulated differentially expressed genes (DEGs) in cluster 1 were significantly enriched in pathways such as focal adhesion, axon guidance, proteoglycans in cancer, extracellular matrix (ECM)-receptor interaction, Wnt signaling pathway, Hippo signaling pathway, and thyroid hormone signaling pathway. Conversely, the downregulated DEGs in cluster 1 were predominantly enriched in pathways including oxidative phosphorylation, chemical carcinogenesis-reactive oxygen species, and nonalcoholic fatty liver disease. Gene Ontology (GO) analysis

PURPOSE: The purpose of this study was twofold: to determine the molecular link between corticosteroid exposure and mechanosensation and to establish the role of mechanosensitive TWIK-related potassium channel-1 (TREK-1) in the regulation of aqueous humor outflow and corticosteroid-induced ocular hypertension (OHT). METHODS: Real-time PCR was used to determine the corticosteroid dexamethasone (DEX) dependence of expression of tandem-pore potassium (K2P), transient receptor potential vanilloid (TRPV), Piezo channel, extracellular matrix (ECM), and fibrotic marker genes in mouse trabecular meshwork (mTM) cells. Immunohistochemistry was employed to assess TREK-1 localization, iPerfusion to determine the TREK-1 dependence of conventional outflow, and tonometry to track intraocular pressure (IOP) in mouse eyes. Telemetry additionally tested TREK-1 dependence of OHT in rat. Steroid-induced transcriptional suppression of mTM Kcnk2 was validated by whole-cell recording in primary human trabecular meshwork (TM) cells. RESULTS: The tandem pore K+ channel transcriptome in mTM cells was dominated by Trek-1 (Kcnk2) mRNA; with residual levels of Traak and Thik-2 transcripts; and low levels of Trek-2, Twik3, and Task1 expression. DEX upregulated Fsp1 and suppressed Kcnk2 expression without affecting Trpv4, Piezo1, or Trpc1 mRNA content. The TREK-1 agonist ML-402 doubled outflow facility in mouse eyes and reduced IOP in the mouse model of DEX-induced OHT and in rat eyes with spontaneously el

Clinicians are often forced into the dilemma of whether to battle ocular inflammation or preserve vision imperiled by elevated intraocular pressure (IOP). Anti-inflammatory treatments utilizing glucocorticosteroid regimens may induce glaucoma by chronically elevating IOP via increased trabecular meshwork (TM) resistance to the flow of aqueous humor, but it is not known whether pressure transduction itself is impacted by steroids and how changes in TM mechanosignaling affect conventional outflow

Piezo1, a trimeric mechanosensitive cation channel discovered in 2010 and recognized with the 2021 Nobel Prize for its seminal role in mechanotransduction, has emerged as a key transducer of mechanical forces into calcium ions (Ca2+) signaling. Its distinctive propeller-like structure confers high mechanosensitivity, enabling rapid and graded Ca2+ influx under diverse mechanical stimuli such as shear stress, stretch, or compression. This Ca2+ entry establishes localized nanodomains and amplifies signals via Ca2+-induced Ca2+ release, thereby activating a spectrum of downstream effectors including CaMKII, NFAT, and YAP/TAZ. Through these pathways, Piezo1 orchestrates critical physiological processes including vascular tone, skeletal remodeling, immune responses, neural plasticity, and organ development. Conversely, its dysregulation drives numerous pathologies, ranging from hypertension and atherosclerosis to neurodegeneration, fibrosis, osteoarthritis, and cancer. Advances in pharmacological modulators (e.g., Yoda1, GsMTx4), gene-editing, and nanomedicine underscore promising therapeutic opportunities, though challenges persist in tissue specificity, off-target effects, and nonlinear Ca2+ dynamics. This review synthesizes current knowledge on Piezo1-mediated Ca2+ signaling, delineates its dual roles in physiology and disease, and evaluates emerging therapeutic strategies. Future integration of structural biology, systems mechanobiology, and artificial intelligence is poised t

Diabetic neuropathy (DN) is a major and debilitating complication of diabetes mellitus, marked by progressive nerve dysfunction, chronic pain, and degeneration of both peripheral and autonomic neurons. Its complex pathophysiology involves persistent hyperglycemia, metabolic imbalance, vascular dysfunction, oxidative stress, and inflammation. Recent advances in mechanobiology have implicated that PIEZO1, a mechanosensitive ion channel, has emerged as a central player in mechanotransduction and is increasingly implicated in the pathophysiology of diabetic neuropathy. This review provides insights into the role of PIEZO1 in diabetic complications, particularly under conditions of chronic hyperglycemia, where its aberrant activation contributes to neuronal injury, oxidative stress, and inflammatory signalling. PIEZO1 modulates calcium influx in neurons, glia, endothelial cells, and immune cells, triggering downstream cascades that are intimately linked with neurodegeneration, chronic pain, and microvascular dysfunction. In diabetic neuropathy, PIEZO1 overexpression exacerbates nerve damage by disrupting Schwann cell function, impairing blood-nerve barrier integrity, and promoting neuroinflammation. Its expression in dorsal root ganglia further implicates it in the sensitization of nociceptive pathways and neuropathic pain. Beyond neural tissues, PIEZO1 modulate survival of pancreatic β-cell, endothelial responses to shear stress, and immune cell polarization, positioning it at th

Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda-1, induces demyelination and neuronal damage. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co-administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well-characterized model of focal demyelination. GsMTx4 also attenuated both LPC-induced astrocyte toxicity and microglial reactivity within the l

Amyloid beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether-and if so how-Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant vascular cell type in the cerebral circulation, and we recently showed that the mechanosensitive ion channel Piezo1 is functionally expressed in the plasma membrane of ECs. Since Aβ disrupts membrane structures, we hypothesized that Aβ1-40, the predominantly deposited isoform in the cerebral circulation, alters endothelial Piezo1 function. Using patch-clamp electrophysiology and freshly isolated capillary ECs, we assessed the impact of the Aβ1-40 peptide on single-channel Piezo1 activity. We show that Aβ1-40 increased Piezo1 open probability and channel open time. Aβ1-40 effects were absent when Piezo1 was genetically deleted or when a superoxide dismutase/catalase mimetic was used. Further, Aβ1-40 enhanced Piezo1 mechanosensitivity and lowered the pressure of half-maximal Piezo1 activation. Our data collectively suggest that Aβ1-40 facilitates higher Piezo1-mediated cation influx in brain ECs. These novel findings have the potential to unravel the possible involvement of Piezo1 modulation in the pathophysiology of neurodegenerative diseases characterized by Aβ accumulation.

Since the discovery of the mechanosensitive Piezo1 channel in 2010, there has been a significant amount of research conducted to explore its regulatory role in the physiology and pathology of various organ systems. Recently, a growing body of compelling evidence has emerged linking the activity of the mechanosensitive Piezo1 channel to health and disease of the central nervous system. However, the exact mechanisms underlying these associations remain inadequately comprehended. This review systematically summarizes the current research on the mechanosensitive Piezo1 channel and its implications for central nervous system mechanobiology, retrospects the results demonstrating the regulatory role of the mechanosensitive Piezo1 channel on various cell types within the central nervous system, including neural stem cells, neurons, oligodendrocytes, microglia, astrocytes, and brain endothelial cells. Furthermore, the review discusses the current understanding of the involvement of the Piezo1 channel in central nervous system disorders, such as Alzheimer's disease, multiple sclerosis, glaucoma, stroke, and glioma.

Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia-neuronal activity-to-vascular response-the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae.

Interoception broadly refers to awareness of one's internal milieu. Although the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferent signalling and corresponding brain circuits that shape perception of the viscera are not entirely clear. Here, we use mice to parse neural circuits subserving interoception of the heart and gut. We determine that vagal sensory neurons expressing the oxytocin receptor (Oxtr), referred to as NGOxtr, send projecti

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell-specific deficiency of Piezo1 (Ghrl-Piezo1-/-) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1-/- mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1-/- mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.

Immunotherapies modulate the body's defense system to treat cancer. While these therapies have shown efficacy against multiple types of cancer, patient response rates are limited, and the off-target effects can be severe. Typical approaches in developing immunotherapies tend to focus on antigen targeting and molecular signaling, while overlooking biophysical and mechanobiological effects. Immune cells and tumor cells are both responsive to biophysical cues, which are prominent in the tumor micro

Mechanically activated (MA) ion channels have rapidly gained prominence as vital conduits bridging aberrant mechanical cues in tissues with the dysregulated immune responses at the core of autoimmune diseases. Once regarded as peripheral players in inflammation, these channels, exemplified by PIEZO1, TRPV4, and specific K2P family members, now play a central role in modulating T-cell effector functions, B- cell activation and the activity of macrophages and dendritic cells. Their gating is intimately tied to physical distortions such as increased tissue stiffness, osmotic imbalances, or fluid shear, triggering a cascade of ionic fluxes that elevate proinflammatory signaling and drive tissue-destructive loops. Recognition of these channels as central mediators of mechanical stress-induced inflammation responses in autoimmune pathogenesis is rapidly expanding. In parallel, the emerging therapeutic strategies aim to restrain overactive mechanosensors or selectively harness them in affected tissues. Small molecules, peptide blockers, and gene-targeting approaches show preclinical promise, although off-target effects and the broader homeostatic roles of these channels warrant caution. This review explores how integrating mechanobiological concepts with established immunological paradigms enables a more detailed understanding of autoimmune pathogenesis. By elucidating how mechanical forces potentiate or dampen pathological immunity, we propose innovative strategies that exploit mec

5-HT(3)-receptor antagonists are highly selective competitive inhibitors of the 5-HT(3)-receptor with negligible affinity for other receptors. They are potent, rapidly absorbed and easily penetrate the blood-brain barrier; metabolized by the cytochrome P450-system with half-life varying from 3-10 hours. The compounds investigated so far do not modify normal behaviour in animals or man and are well tolerated over wide dose ranges, the most common side effects being headache or constipation. Clinical efficacy was first established in chemotherapy-induced emesis (and then in radiotherapy-induced and post-operative emesis), where 5-HT(3)-receptor antagonists set a new standard of antiemetic efficacy and tolerability. The 5-HT(3) receptor antagonists, via a central and / or peripheral action, have been shown to reduce secretion and motility in the gut and possess clinical utility in irritable bowel syndrome, and possibly other visceral pain disorders. Their value in fibromyalgia is being evaluated. In preclinical behavioural assays they induce effects consistent with anxiolysis, improved cognition, anti-dopaminergic activity and use in drug abuse and withdrawal. There is some evidence that ondansetron may reduce alcohol consumption in moderate alcohol abusers but overall, 5-HT(3) receptor antagonists seem to be of limited use in psychiatric disorders: where effects have been seen, they seem to be unusually sensitive to dose and stage of disease. Nevertheless, their antiemetic pote

Astrocytes are intimately linked with brain blood vessels, an essential relationship for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as an important player in postnatal gliovascular maturation.

BACKGROUND: Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disease of the central nervous system that is characterized mainly by recurrent optic neuritis and longitudinally extensive transverse myelitis. The aim of this article is to present current knowledge on the clinical features, diagnosis, pathogenesis and treatment of the condition. METHOD: The article is based on a discretionary selection of English-language original articles, meta-analyses and review articles found in PubMed, and on the authors' own experience with the patient group. RESULTS: Neuromyelitis optica was previously assumed to be a variant of multiple sclerosis (MS), but the discovery of aquaporin-4 antibodies in patients with neuromyelitis optica has led to this view being revised. The cause of the condition is still unknown, but it has been shown that the antibodies bind selectively to a water channel expressed mainly on astrocytes at the blood-brain-barrier, which has an important role in the regulation of brain volume and ion homeostasis. Clinically, the condition presents as optic neuritis and/or transverse myelitis. A diagnosis is made on the basis of case history, clinical examination, MRI of the brain and spinal cord, analysis of cerebrospinal fluid, visual evoked potentials and a blood test with analysis of aquaporin-4 antibodies. Once a diagnosis has been made, rapid treatment is important. In the acute phase, intravenous methylprednisolone is recommended. There are several options

Piezo1, a mechanosensitive ion channel protein, is a highly promising target for drug development. We systematically review the latest advances in its structural features, signal transduction mechanisms, and functional roles in various pathological processes including neurological diseases, cardiovascular diseases, and cancer. Furthermore, we provide an in-depth analysis of three key challenges in developing Piezo1-targeted drugs, including the complexity of its dynamic structure and regulatory network, the difficulty of achieving specific targeting, and the off-target risks and potential systemic toxicity arising from its widespread physiological functions. Finally, we highlight that integrating cutting-edge technologies, such as super-resolution imaging, artificial intelligence (AI)-assisted drug design, and organoid/organ-on-a-chip models, holds great promise for overcoming these challenges and accelerating the development and clinical translation of Piezo1-targeted drugs.

BACKGROUND: Renal fibrosis-characterized by microcirculatory disturbances and endothelial-mesenchymal transition (EndMT)-is a major pathological feature of chronic kidney disease (CKD) and remains a significant therapeutic challenge. The mechanosensitive ion channel Piezo1 plays a pivotal role in endothelial mechanotransduction and has been implicated in fibrogenesis, yet specific pharmacological interventions targeting Piezo1 are lacking. METHODS: We evaluated the renoprotective effects of paeoniflorin (PF), a bioactive monoterpene glycoside, in 5/6 nephrectomy-induced chronic renal failure (CRF) rats and diabetic kidney disease (DKD) db/db mice. PF-Piezo1 interactions were characterized using molecular docking, surface plasmon resonance (SPR), and functional assays. In vitro studies employing models of matrix stiffness, endothelial-fibroblast crosstalk, and HIF-1α inhibition were performed to elucidate the underlying mechanisms. RESULTS: PF treatment preserved renal function, reduced glomerulosclerosis, and ameliorated microvascular rarefaction in both CRF and DKD. Molecular docking and SPR analyses revealed that PF binds Piezo1 with high affinity, thereby inhibiting Yoda1-induced Ca2+ influx and attenuating stiffness-induced EndMT. PF restored the expression of endothelial markers including VE-cadherin and eNOS, and suppressed HIF-1α-mediated upregulation of Vimentin and TGF-β1. Moreover, co-culture experiments demonstrated that PF disrupted endothelial-derived TGF-β1 para