Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, Journal Year: 2024, Volume and Issue: 327, P. 125325 - 125325
Published: Oct. 23, 2024
Language: Английский
Nature Nanotechnology, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 2, 2025
Abstract Quantifying the mechanical response of biological milieu (such as cell’s interior) and complex fluids biomolecular condensates) would enable a better understanding cellular differentiation aging accelerate drug discovery. Here we present time-shared optical tweezer microrheology to determine frequency- age-dependent viscoelastic properties materials. Our approach involves splitting single laser beam into two near-instantaneous traps carry out simultaneous force displacement measurements quantify ranging from millipascals kilopascals across five decades frequency. To create practical robust nanorheometer, leverage both numerical analytical models analyse typical deviations ideal behaviour offer solutions account for these discrepancies. We demonstrate versatility technique by measuring liquid–solid phase transitions MEC-2 stomatin CPEB4 condensates, intracellular compartments zebrafish progenitor cells. In Caenorhabditis elegans , uncover how mutations in nuclear envelope proteins LMN-1 lamin A, EMR-1 emerin LEM-2 LEMD2, which cause premature disorders humans, soften cytosol intestinal cells during organismal age. that offers rapid phenotyping material inside protein blends, can be used biomedical drug-screening applications.
Language: Английский
Citations
2
Diabetes & Metabolism, Journal Year: 2023, Volume and Issue: 50(1), P. 101506 - 101506
Published: Dec. 21, 2023
With the rising tide of fatty liver disease related to metabolic dysfunction worldwide, association this common with chronic kidney (CKD) has become increasingly evident. In 2020, more inclusive term dysfunction-associated (MAFLD) was proposed replace old nonalcoholic (NAFLD). 2023, a modified Delphi process led by three large pan-national associations. There consensus change nomenclature and definition include presence at least one five cardiometabolic risk factors as diagnostic criteria. The name chosen NAFLD steatotic (MASLD). from MAFLD then MASLD resulted in reappraisal epidemiological trends associations developing CKD. observed between MAFLD/MASLD CKD our understanding that can be an epiphenomenon linked underlying support notion individuals are substantially higher incident than those without MASLD. This narrative review provides overview literature on (a) evolution criteria for diagnosing highly prevalent disease, (b) evidence linking CKD, (c) mechanisms which (and strongly MASLD) may increase (d) potential drug treatments benefit both
Language: Английский
Citations
38
JHEP Reports, Journal Year: 2023, Volume and Issue: 5(11), P. 100869 - 100869
Published: Aug. 2, 2023
The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues organs in a dynamic balance characterized by constant remodelling adaptative processes. Environmental properties can be interpreted as complex set information instructions that cells read continuously, to which they respond. In cirrhosis, chronic inflammation injury drive liver dysfunction, leading excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion parenchymal extinction. These pathological events result marked microarchitecture, is cause abnormal environmental forces, triggering sustaining long-standing progressive process fibrosis. Multiple forces such strain, shear stress, hydrostatic pressure converge at different stages disease until reaching point no return where fibrosis considered non-reversible. Thereafter, reciprocal communication their niches becomes driving force for progression. Accumulating evidence supports idea that, rather than being passive consequence portal hypertension (PH), force-mediated pathways could themselves represent strategic targets novel therapeutic approaches. this manuscript, we aim provide comprehensive review PH, furnishing an introduction on most important mechanisms, integrating these concepts into discussion pathogenesis exploring potential strategies.
Language: Английский
Citations
24
American Journal Of Pathology, Journal Year: 2023, Volume and Issue: 193(12), P. 1887 - 1899
Published: Sept. 7, 2023
Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty disease. Lipotoxic proteotoxic can activate the unfolded response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, activating transcription factor 6α. Collectively, these pathways expression of genes that encode functions to resolve folding defect by increasing capacity degradation misfolded proteins. The is also intimately connected with metabolism, including de novo ceramide synthesis, phospholipid cholesterol droplet formation. Following their activation, UPR transducers regulate lipogenic liver. With persistent stress, cellular adaptation fails, resulting hepatocyte apoptosis, a pathological marker In addition ER–nucleus signaling activated UPR, interact other organelles via membrane contact sites. Modulating intracellular communication between endosomes, droplets, mitochondria restore could have therapeutic efficacy ameliorating Recent studies demonstrated cells convey release extracellular vesicles. This review discusses lipotoxic central role communicating MASLD pathogenesis. Metabolic disease, or MASLD, earlier most common chronic worldwide an overall prevalence 32.4%.1Riazi K. Azhari H. Charette J.H. Underwood F.E. King J.A. Afshar E.E. Swain M.G. Congly S.E. Kaplan G.G. Shaheen A.A. incidence NAFLD worldwide: systematic meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text PDF PubMed Scopus (440) Google Scholar background consistently rising obesity, affects up 48% US population foremost cause liver-related mortality morbidity.1Riazi encompasses clinico-pathological spectrum includes liver, benign, nonprogressive macrovesicular accumulation lipids steatohepatitis (MASH), more severe progressive condition evidence cell injury, inflammation, degeneration, fibrosis. MASH has potential progress cirrhosis, antecedent end-stage hepatocellular carcinoma.2Parthasarathy G. Revelo X. Malhi Pathogenesis steatohepatitis: overview.Hepatol Commun. 2020; 4: 478-492Crossref (222) primary insult hepatic lipotoxicity occurs when hepatocyte's handle export free acids (FA) exceeded either due excessive FA influx lipogenesis. Several molecular mechanisms orchestrate lipotoxicity, oxidative autophagy, lipoapoptosis.3Rada P. Gonzalez-Rodriguez A. Garcia-Monzon C. Valverde A.M. Understanding pathogenesis: CD36 key driver?.Cell Death Dis. 11: 802Crossref (201) organelle whose folding, modification, trafficking been well studied. It plays vital synthesizing glycoproteins, cholesterol, phospholipids, while maintaining calcium homeostasis.4Malhotra J.D. Kaufman R.J. Endoplasmic stress: vicious cycle double-edged sword?.Antioxid Redox Signal. 2007; 9: 2277-2293Crossref (1285) Scholar,5Xu Bailly-Maitre B. Reed J.C. life death decisions.J Clin Invest. 2005; 115: 2656-2664Crossref (1969) When perturbed, occurs, which implicated various conditions diabetes mellitus, atherosclerosis, disorders, cancers.6Hotamisligil G.S. atherosclerosis.Nat Med. 2010; 16: 396-399Crossref (240) Scholar, 7Hotamisligil inflammatory basis disease.Cell. 140: 900-917Abstract (2196) 8Hummasti S. Hotamisligil inflammation obesity diabetes.Circ Res. 107: 579-591Crossref (343) Cellular impacts membranous organelles, mitochondria, lysosomes, functional contacts ER, turn exert direct indirect effects on outcome signaling.9Xiong Kuang Ansari Liu T. Gong J. Wang Zhao X.-Y. Ji Y. Li Guo L. Zhou Chen Z. Leon-Mimila Chung M.T. Kurabayashi Opp Campos-Pérez F. Villamil-Ramirez Canizales-Quinteros Lyons R. Lumeng C.N. Qi Huertas-Vazquez Lusis A.J. Xu X.Z.S. Yu J.Z. Lin Landscape intercellular crosstalk healthy NASH revealed single-cell secretome gene analysis.Mol Cell. 2019; 75: 644-660.e5Abstract (396) this article, authors offer succinct insights into processes underlie particular emphasis its evolution MASLD/MASH. addition, global landscape mediators show promise targets reviewed. interconnected network largely made three main structures: nuclear envelope, peripheral consisting smooth tubules rough sheets, cortical abuts plasma membrane. envelope composed two bilayers, inner outer membrane, numerous pores facilitate transport RNAs continuous sheets cisternae through shared lumen. Sheets are flat structures stacked appearance parallel arrangement layers consistent luminal spacing. curved regions edges connect them one another.10Terasaki M. Shemesh Kasthuri N. Klemm R.W. Schalek Hayworth K.J. Hand A.R. Yankova Huber Lichtman J.W. Rapoport T.A. Kozlov M.M. Stacked helicoidal motifs.Cell. 2013; 154: 285-296Abstract (168) Rough possess ribosomes cytosolic surface, thus allowing partake synthesis folding. Smooth dynamic constantly remodeling characterized scant ribosome attachment binding. Cortical abutting combination tubules, signaling.11Schwarz D.S. Blower M.D. reticulum: structure, function signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref (841) distinctions subcellular architecture differences ratio across types diverse functions.12Staehelin L.A. plant ER: large number discrete domains.Plant 1997; 1151-1165Crossref For instance, high secretory demand such B (antibody secretion) pancreatic acinar (insulin amounts whereas involved hepatocytes Leydig ER. difference identified because different shaping proteins, prominent being reticulon family vivo change structure respect tubule formation alter changes normal metabolism leading increase droplets (LDs) triglyceride content, up-regulation enzymes Primary from obese mice models shown enriching sheet ER-shaping proteins 63-kDa cytoskeleton-linking (Climp-63) decrease lipogenesis glucose production.13Parlakgul Arruda A.P. Pang Cagampan E. Min Guney Lee G.Y. Inouye Hess H.F. C.S. Regulation controls homeostasis.Nature. 603: 736-742Crossref (35) Thus, spatial organization provides flexibility diversity cell. Structural complexity components aid meeting complex demands maximizing efficiency multicellular organisms. Numerous extensively relation homeostasis, revealing structural critical influencing respective functions.13Parlakgul A biosynthetic ensure cotranslational nascent polypeptides, whether they secreted intended for within Golgi, lysosomes. Translation begins cytosol, where ribosome–mRNA formed. topogenic signal sequence polypeptide recognition particle, SRP.14Walter Blobel Translocation reticulum. II. Signal (SRP) mediates selective binding microsomal membranes in-vitro-assembled polysomes protein.J Cell Biol. 1981; 91: 551-556Crossref (282) Scholar,15Walter Ibrahimi I. binds 545-550Crossref (433) encounters polypeptide–SRP complex, four-component ribosome, mRNA, polypeptide, SRP recruited it docks receptor.16Meyer D.I. Krause Dobberstein Secretory translocation membranes-the 'docking protein.Nature. 1982; 297: 647-650Crossref (365) continues Depending directed be integral secreted, will pause embedding transported completely lumen, respectively. event aggregates, remain lumen enter ER-associated degradation. quality control prevent secretion anomalous proteins.17Ruggiano Foresti O. Carvalho Quality control: degradation: beyond.J 2014; 204: 869-879Crossref Apart second process biogenesis, reviewed elsewhere detail.18Jacquemyn Cascalho Goodchild R.E. ins outs reticulum-controlled biosynthesis.EMBO Rep. 2017; 18: 1905-1921Crossref (142) hepatocytes, abundant site almost all classes. Most transmembrane located both membranes, some focused subdomains ER–organelle sites.18Jacquemyn Phospholipids synthesized cytosol-facing bilayer Ceramides formed exported Golgi further enzymatically modified generate glycosphingolipids sphingomyelin lumen-facing bilayer.19Promlek Ishiwata-Kimata Shido Sakuramoto Kohno Kimata Membrane aberrancy sensor Ire1 ways.Mol Biol 2011; 22: 3520-3532Crossref (195) sphingolipid LD lipoprotein occur membrane.20Olzmann Dynamics droplets.Nat Rev 20: 137-155Crossref (1185) double Due continuity, share many Like metabolism. Mutations may pathogenic, multisystem lipodystrophies susceptibility MASH. These genetic links demonstrate at envelope. connections chromatin, affect programs.21Östlund Hernandez-Ono Shin J.Y. pathogenesis NAFLD.Biology (Basel). 338PubMed Lastly, crucial rule employing pumping Ca2+ cytosol against electrochemical gradient, storing way sequestering using releasing back channels along gradient. Calcium maintained ATPase (SERCA) transporters, pump 1,4,5-triphosphate (IP3) receptor activation–mediated stored cytosol.11Schwarz aforementioned underscore organismal homeostasis. homeostatic conditions, several checks balances place ER.22Ajoolabady Kaplowitz Lebeaupin Kroemer Ren diseases.Hepatology. 2023; 77: 619-639Crossref (51) accumulate and/or undergo stress. this, maintain compensatory translation inhibition, chaperones unfolded/misfolded Failure recover triggers death. mammals, mediated proximal sensors: enzyme 1α (IRE1α), kinase-like kinase (PERK), 6α (ATF6α). sensors inactive basally, configuration, domains bound chaperone 78-kDa glucose-regulated (GRP78)/binding immunoglobulin (BiP) (Figure 1). Misfolded trigger activation GRP78/BiP interactions sensors. There described sensing IRE1α. association model, postulated conformational changes, result stabilization IRE1α homodimers peptide pocket created domain dimers, endoribonuclease activities.19Promlek Scholar,23Credle J.J. Finer-Moore J.S. Papa F.R. Stroud R.M. Walter On mechanism reticulum.Proc Natl Acad Sci U S 102: 18773-18784Crossref (422) competition prevents dimerization domain.24Amin-Wetzel Saunders R.A. Kamphuis M.J. Rato Preissler Harding H.P. Ron D. J-protein co-chaperone recruits BiP monomerize IRE1 repress response.Cell. 171: 1625-1637.e13Abstract (157) dissociation facilitated nucleotide exchange factors.25Behnke Feige Hendershot L.M. factors Grp170 Sil1: action biological functions.J 2015; 427: 1589-1608Crossref (135) allosteric substrate (SBD) causes change.26Santiago Goncalves D.L. Morano K.A. Mechanisms stress.Exp 395112240Crossref (16) undergoes autophosphorylation, RNase activity, then splices X-box 1 (XBP1) mRNA sXBP1 encodes soluble active (sXBP1). transcriptionally encoding Although spliced unspliced forms XBP1 potent factor. PERK, like IREα, protein, N-terminal BiP. PERK autotransphosphorylation leads phosphorylation eukaryotic initiation 2-α (eIF2α).27Harding Zhang Protein coupled endoplasmic-reticulum-resident kinase.Nature. 1999; 397: 271-274Crossref (2650) eIF2α results attenuation 4 (ATF4). ATF4 thereafter up-regulate C/EBP homologous (CHOP), proapoptotic negative feedback loop, CHOP induces GADD34, phosphatase (PP1) dephosphorylates eIF2α, proceed.28Malhi disease.J 54: 795-809Abstract (918) third sensor, ATF6α, translocates apparatus, cleaved sequentially site-1 protease site-2 fragment (ATF6f) factor.29Ye Rawson R.B. Komuro Dave U.P. Prywes Brown M.S. Goldstein J.L. cleavage membrane-bound ATF6 same proteases SREBPs.Mol 2000; 6: 1355-1364Abstract (1454) Overall, work concert proteostasis. If restoration proteostasis sustained apoptosis. stress–induced apoptosis CHOP, mitogen c-Jun (JNK), 5, Bcl-2 calcium, redox caspase activation.30Brancolini Iuliano Proteotoxic cancer cells.Cancers 12: 2385Crossref (32) Lipotoxicity defined dysregulation environment composition transient generation toxic lipids, injury death, β-cells.31Malhi Gores G.J. Molecular disease.Semin Liver 2008; 28: 360-369Crossref (447) induced species saturated (SFA) palmitate, sphingolipids (C16:0 ceramide), lysophosphatidylcholine (LPC), cholesterol. By contrast, monosaturated FAs, oleate palmitoleate, protect SFA-induced toxicity. excess palmitate incorporated triglycerides serve LPC Ceramide C16 causing disturbance PERK/ATF4 ATF6α arms induction expression.32Aflaki Doddapattar Radovic Povoden Kolb Vujic Wegscheider Koefeler Hornemann Graier W.F. Malli Madeo Kratky triacylglycerol-induced macrophages.Cell 2012; 3e280Crossref (50) 33Epstein Kirkpatrick C.L. Castillon G.A. Muñiz Riezman David F.P.A. Wollheim C.B. Activation pathway yeast INS-1E insulinoma cells.J Lipid 53: 412-420Abstract 34Pettus B.J. Chalfant C.E. Hannun Y.A. apoptosis: overview current perspectives.Biochim Biophys Acta. 2002; 1585: 114-125Crossref (697) promote proinflammatory vesicles IRE1a/XBP1-dependent manner transcriptional pathway.35Kakazu Mauer A.S. Yin Hepatocytes ceramide-enriched pro-inflammatory IRE1alpha-dependent manner.J 57: 233-245Abstract (208) Scholar,36Dasgupta Nakao Thompson J.M. Sehrawat T.S. Liao C.Y. Krishnan Lucien Q. Xue Fukushima Katsumi Bansal Pandey M.K. Maiers DeGrado Ibrahim S.H. Revzin Pavelko K.D. Barry M.A. IRE1A stimulates hepatocyte-derived steatohepatitis.Gastroenterology. 159: 1487-1503.e17Abstract (96) Through motifs domain, specific 2).37Tam A.B. Roberts L.S. Chandra V. Rivera I.G. Nomura D.K. Forbes D.J. Niwa Activator responds distinct mechanisms.Dev 2018; 46: 327-343.e7Abstract (101) ceramides phenotypes associated MAFLD LDs resolved inhibition remains elucidated. ER–lipid composition, stiffness function.38Cao Dai D.-L. Yao H.-H. Ning Cheng W.-H. Shen W. Yang Z.-X. Saturated acid human PERK/ATF4/CHOP pathway.Mol Biochem. 364: 115-129Crossref (189) Sterol content determinant fluidity normally low membrane.39Pineau Colas Dupont Beney Fleurat-Lessard Berjeaud Berges Ferreira Lipid-induced synergistic sterols acids.Traffic. 2009; 10: 673-690Crossref (159) Abnormally increased sterol SFA concentrations stretch stiffness, triggering oligomerization 2) UPR.40Radanovic Ernst guardian pathway.Cells. 2021; 2965Crossref (23) Exploring how detect might elicit physical reveal potentially druggable targets. important mediator MASH.41Han Park S.Y. Shinzawa Kim K.W. J.-H. Kwon C.H. K.-W. C.K. W.J. Hwang Yan J.-J. Song D.-K. Tsujimoto M.-S. Lysophosphatidylcholine effector lipoapoptosis hepatocytes.J 49: 84-97Abstract (198) Scholar,42Song non alcoholic disease.Pharmacol Ther. 203107401Crossref (79) monolayers, very density (VLDL).43Neuschwander-Tetri B.A. Hepatic nontriglyceride metabolites.Hepatology. 52: 774-788Crossref (818) intracellularly phospholipase A2 (PLA2) phosphatidylcholine (PC) extracellularly lecithin-cholesterol acyltransferase. PLA2 palmitate-induced apoptosis.44Kakisaka Cazanave S.C. Fingas C.D. Guicciardi M.E. Bronk S.F. Werneburg N.W. Mott lysophosphatidylcholine-induced lipoapoptosis.Am J Physiol Gastrointest Physiol. 302: G77-84Crossref (166) depletes PC loss integrity, vesicle (EV) release, apoptosis.42Song Additionally, phosphorylation, expression, JNK BH3-only PUMA (p53 upregulated modulator apoptosis). Increased Bax caspa
Language: Английский
Citations
23
Developmental Cell, Journal Year: 2024, Volume and Issue: 59(7), P. 841 - 852.e7
Published: Feb. 21, 2024
The cortex controls cell shape. In mouse oocytes, the thickens in an Arp2/3-complex-dependent manner, ensuring chromosome positioning and segregation. Surprisingly, we identify that oocytes lacking Arp2/3 complex undergo cortical actin remodeling upon division, followed by contractions are unprecedented mammalian oocytes. Using genetics, imaging, machine learning, show these stir cytoplasm, resulting impaired organelle organization activity. Oocyte capacity to avoid polyspermy is impacted, leading a reduced female fertility. We could diminish rescue cytoplasmic anomalies. Similar were observed human collected as byproducts during IVF (in vitro fertilization) procedures. These correlate with increased motion, but not defects spindle assembly or aneuploidy mice humans. Our study highlights multiscale effect connecting F-actin, contractions, affecting oocyte quality, implications for
Language: Английский
Citations
11
The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(8)
Published: May 22, 2023
The nucleus in many cell types is a stiff organelle, but fat-filled lipid droplets (FDs) cytoplasm are seen to indent and displace the nucleus. FDs phase-separated liquids with poorly understood interfacial tension γ that determines how interact other organelles. Here, micron-sized remain spherical as they peri-nuclear actomyosin nucleus, while causing local dilution of Lamin-B1 independent Lamin-A,C sometimes triggering nuclear rupture. Focal accumulation cytosolic DNA sensor cGAS at rupture site accompanied by sustained mislocalization repair factors cytoplasm, increased damage, delayed cycle. Macrophages show engulfed rigid beads cause similar indentation dilution. Spherical shapes small indicate high γ, which we measure for mechanically isolated from fresh adipose tissue ∼40 mN/m. This value far higher than protein condensates, typical oils water sufficiently perturb structures including nuclei.
Language: Английский
Citations
17
Biomaterials, Journal Year: 2024, Volume and Issue: 305, P. 122462 - 122462
Published: Jan. 1, 2024
Language: Английский
Citations
6
Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(5), P. 2264 - 2272
Published: Jan. 24, 2024
Lipid metabolism diseases have become a tremendous risk worldwide, along with the development of productivity and particular attention to public health. It has been an urgent necessity exploit reliable imaging strategies for lipids thus monitor fatty liver diseases. Herein, by converting NIR-I signal NIR-II IR1061 monitoring lipid, in vivo disease was promoted on contrast visual effect. The main advantages promotion this work included long emission wavelength, rapid response, high signal-background-ratio (SBR) value. After promoting signal, achieved higher SBR value exhibited dose-dependent fluorescence intensity at 1100 nm increase EtOH proportion as well steady selective optical responses toward liposomes. further applied lipid In spite differences body weight gain TC level between healthy mice two models, high-resolution region status. This might be informatic clinical diagnosis therapeutical treatments
Language: Английский
Citations
6
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: April 23, 2025
Abstract Chromatin organization regulates gene expression, with nanoscale heterochromatin domains playing a fundamental role. Their size varies microenvironmental stiffness and epigenetic interventions, but how these factors regulate their formation influence transcription remains unclear. To address this, we developed sequencing-informed copolymer model that simulates chromatin evolution through diffusion active reactions. Our predicts the of quantifies domain scales reaction rates, showing compaction changes primarily occur at boundaries. We validated predictions via Hi-C super-resolution imaging hyperacetylated melanoma cells identified differential expression metastasis-related genes RNA-seq. our findings in hMSCs, where rates respond to stiffness. Conclusively, simulations reveal boundaries memory. These demonstrate external cues drive transcriptional memory development disease.
Language: Английский
Citations
0
Seminars in Liver Disease, Journal Year: 2023, Volume and Issue: 43(04), P. 367 - 382
Published: Oct. 5, 2023
The steatotic diseases of metabolic dysfunction-associated liver disease (MASLD), alcohol-associated (ALD), and chronic hepatitis C (HCV) account for the majority prevalence, morbidity, mortality worldwide. While these have distinct pathogenic clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence pathogenesis in all three. With increasing understanding hepatocyte LD biology, we now understand roles proteins involved but also how genetics modulate to either exacerbate or protect against phenotypes associated with diseases. Here, review history its biogenesis catabolism. We this is critical not only phenotype their advanced phenotypes. Finally, summarize latest attempts challenges leveraging therapeutic gain In conclusion, study may lead novel therapeutics prevention progression highly prevalent MASLD, ALD, HCV.
Language: Английский
Citations
9