Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation DOI Creative Commons
Ting Wang, Avinash Soundararajan, Jeffrey Rabinowitz

и другие.

The FASEB Journal, Год журнала: 2023, Номер 37(11)

Опубликована: Окт. 12, 2023

Abstract Trabecular meshwork (TM) cells are contractile and mechanosensitive, they aid in maintaining intraocular pressure (IOP) homeostasis. Lipids attributed to modulating TM contractility, with poor mechanistic understanding. In this study using human cells, we identify the mechanosensing role of transcription factors sterol regulatory element binding proteins (SREBPs) involved lipogenesis. By constitutively activating SREBPs pharmacologically inactivating SREBPs, have mechanistically deciphered attributes regulating properties TM. The pharmacological inhibition by fatostatin molecular inactivation ex vivo vivo, respectively, results significant IOP lowering. As a proof concept, significantly decreased responsive genes enzymes lipogenic pathways as well levels phospholipid, cholesterol, triglyceride. Further, show that mitigated actin polymerization machinery stabilization, ECM synthesis secretion. We thus postulate lowering lipogenesis outflow pathway can hold key modifying biomechanics.

Язык: Английский

Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy DOI Creative Commons

Haifen Luo,

Jingqi Lv,

Peiye Wen

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 8, 2025

Despite the tremendous therapeutic promise of activating stimulators interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder cytotoxicity T cells against tumor cells. Blocking cancer cell evasion provides a feasible strategy for augmenting STING activation-mediated anti-tumor efficacy. Here, we fabricate redox-responsive Methyl-β-cyclodextrin (MeβCD)-based supramolecular polyrotaxanes (MSPs), where amphiphilic diselenide-bridged axle polymer loads MeβCD by host-guest interaction and end-caping with two near-infrared (NIR) fluorescence probes IR783. The MSPs self-assemble agonists diABZIs into nanoparticles (RDPNs@diABZIs), which simultaneous release in redox microenvironment. After released activate on antigen-presenting (APCs), responses are initiated. Meanwhile, depletes membrane cholesterol overcome cancer-cell mechanical softness, enhances CTL-mediated killing In female tumor-bearing mouse model, demonstrate that RDPNs@diABZIs lead effective regression generate long-term immunological memory. Furthermore, can achieve significant eradication, these mice remaining survival at least 2 months. Activation stimulator is promising initiating but authors report nanoformulations augment overcoming softness.

Язык: Английский

Процитировано

1
Retinal TRP channels: Cell-type-specific regulators of retinal homeostasis and multimodal integration DOI Creative Commons
David Križaj,

Soenke Cordeiro,

Olaf Strauß

и другие.

Progress in Retinal and Eye Research, Год журнала: 2022, Номер 92, С. 101114 - 101114

Опубликована: Сен. 24, 2022

Язык: Английский

Процитировано

38
Implications of High-Density Cholesterol Metabolism for Oocyte Biology and Female Fertility DOI Creative Commons
Andreína Arias,

Alonso Quíroz,

Nicolás Santander

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Сен. 14, 2022

Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes synthesis uptake from circulating lipoproteins. In contrast, induces the efflux high-density lipoproteins (HDL) their transport liver for excretion, a process known as reverse transport. studies suggest that abnormal HDL metabolism hinders female fertility. only detected in substantial amounts follicular fluid (FF), size composition correlate with embryo quality. Oocytes obtain cumulus cells via gap junctions they cannot synthesize de novo lack receptors. Recent evidence has supported possibility FF play major role taking up unesterified (UC) oocyte. Indeed, genetically modified mouse models disruptions transport, some which show excessive UC levels, exhibit infertility. accumulation can affect egg´s viability, reported other types, activate plasma membrane structure activity proteins. mice deficient receptor Scavenger Class B Type I (SR-B1), oocytes impairs meiosis arrest developmental capacity egg. cells, addition activates calcium channels dysregulates death/survival signaling pathways, suggesting these may link altered Although cholesterol, lipids general, usually not evaluated infertile patients, one study high women showing longer time pregnancy outcome Based on described above, we propose existence well-regulated largely unexplored system homeostasis controlling traffic between oocytes, significant implications

Язык: Английский

Процитировано

30
Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity DOI
Yifei Zhu, Yuan Chu, Sheng Wang

и другие.

Hypertension, Год журнала: 2023, Номер 80(4), С. 757 - 770

Опубликована: Фев. 16, 2023

Vascular endothelium and smooth muscle work together to keep the balance of vasomotor tone jointly maintain vascular homeostasis. Ca2+-permeable ion channel TRPV4 (transient receptor potential vanilloid family member 4) in endothelial cells regulates endothelium-dependent vasodilation contraction various states. However, how cell (TRPV4SMC) contributes function blood pressure regulation physiological pathologically obese condition has not been fully studied.We generated TRPV4-deficient mice developed diet-induced model analyzed role TRPV4SMC intracellular Ca2+ ([Ca2+]i) vasoconstriction. Vasomotor changes mouse mesenteric artery were measured by wire, myography. [Ca2+]i fluo-4 staining. Blood was recorded telemetric device.Vascular played different roles regulating than due their features regulation. Loss attenuated U46619- phenylephrine-induced contraction, suggesting its involvement contractility. Mesenteric arteries from showed SMC hyperplasia, an increased level TRPV4SMC. did influence development obesity but protected obesity-induced vasoconstriction hypertension. In deficient TRPV4, SMCs F-actin polymerization RhoA dephosphorylation under contractile stimuli. Moreover, SMC-dependent inhibited human resistance with inhibitor application.Our data identify as a regulator both states mice. ontogeny hypertension induced over-expression artery.

Язык: Английский

Процитировано

20
Pathophysiological Roles of the TRPV4 Channel in the Heart DOI Creative Commons
Sébastien Chaigne, Solène Barbeau, Thomas Ducret

и другие.

Cells, Год журнала: 2023, Номер 12(12), С. 1654 - 1654

Опубликована: Июнь 17, 2023

The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation that mostly permeable to calcium (Ca2+), which participates in intracellular Ca2+ handling cardiac cells. It widely expressed through the body and activated by large spectrum of physicochemical stimuli, conferring it role variety sensorial physiological functions. Within cardiovascular system, TRPV4 expression reported cardiomyocytes, endothelial cells (ECs) smooth muscle (SMCs), where modulates mitochondrial activity, homeostasis, cardiomyocytes electrical activity contractility, embryonic development fibroblast proliferation, as well vascular permeability, dilatation constriction. On other hand, channels participate several pathological processes such fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarction arrhythmia. In this manuscript, we provide an overview implications physiology discuss therapeutic target against diseases.

Язык: Английский

Процитировано

19
TRPV4 and chloride channels mediate volume sensing in trabecular meshwork cells DOI
Jackson M. Baumann, Oleg Yarishkin, Mónika Lakk

и другие.

AJP Cell Physiology, Год журнала: 2024, Номер 327(2), С. C403 - C414

Опубликована: Июнь 17, 2024

Aqueous humor drainage from the anterior eye determines intraocular pressure (IOP) under homeostatic and pathological conditions. Swelling of trabecular meshwork (TM) alters its flow resistance but mechanisms that sense transduce osmotic gradients remain poorly understood. We investigated TM osmotransduction role in calcium chloride homeostasis using molecular analyses, optical imaging, electrophysiology. Anisosmotic conditions elicited proportional changes cell volume, with swelling, not shrinking, evoking elevations intracellular concentration [Ca

Язык: Английский

Процитировано

8
Cholesterol regulation of mechanosensitive ion channels DOI Creative Commons

Katie M. Beverley,

Irena Levitan

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Янв. 25, 2024

The purpose of this review is to evaluate the role cholesterol in regulating mechanosensitive ion channels. Ion channels discussed are sensitive two types mechanical signals, fluid shear stress and/or membrane stretch. Cholesterol regulates primarily ways: 1) indirectly through localizing into cholesterol-rich domains where they interact with accessory proteins 2) direct binding channel at specified putative sites. may also regulate function via changes biophysical properties bilayer. Changes affect both mechanosensitivity and basal function. We focus on four Piezo, Kir2, TRPV4, VRAC Piezo were shown be regulated by auxiliary that enhance high domains. mechanism was Kir2.1 TRPV4 inhibits Finally, regulation attributed physical lipid Additional studies should performed determine physiological implications these sterol effects complex cellular environments.

Язык: Английский

Процитировано

7
Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension DOI Creative Commons
Mónika Lakk,

Grace F. Hoffmann,

Aruna Gorusupudi

и другие.

Journal of Lipid Research, Год журнала: 2021, Номер 62, С. 100145 - 100145

Опубликована: Янв. 1, 2021

Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, stretch-activated transient receptor potential vanilloid isoform 4 (TRPV4) channel human trabecular meshwork (TM) cells. Physiological levels cyclic stretch resulted time-dependent decreases cholesterol/phosphatidylcholine ratio upregulation stress fibers. Depleting m-β-cyclodextrin (MβCD) augmented TRPV4 activation by agonist GSK1016790A, swelling effects reversed supplementation. MβCD increased expression TRPV4, caveolin-1, flotillin. did colocalize or interact caveolae lipid rafts, apart from a truncated ∼75 kDa variant partially precipitated caveolin-1 antibody. induced currents TRPV4-expressing Xenopus laevis oocytes. Thus, regulates transduction information, channels mainly located outside cholesterol-enriched domains. Moreover, biomechanical milieu itself shapes content TM membranes. Diet, metabolism, might modulate conventional outflow pathway intraocular pressure glaucoma diabetes part modulating mechanosensing.

Язык: Английский

Процитировано

39
Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands DOI
Nannan Su,

Wenxuan Zhen,

Heng Zhang

и другие.

Nature Chemical Biology, Год журнала: 2022, Номер 19(1), С. 72 - 80

Опубликована: Сен. 26, 2022

Язык: Английский

Процитировано

28
Caveolar and non-Caveolar Caveolin-1 in ocular homeostasis and disease DOI Creative Commons
Eric Enyong, Jami M. Gurley, Michael L. De Ieso

и другие.

Progress in Retinal and Eye Research, Год журнала: 2022, Номер 91, С. 101094 - 101094

Опубликована: Июнь 18, 2022

Язык: Английский

Процитировано

25