The role of declining adaptive homeostasis in ageing

The Journal of Physiology, Journal Year: 2017, Volume and Issue: 595(24), P. 7275 - 7309

Published: Oct. 13, 2017

Adaptive homeostasis is "the transient expansion or contraction of the homeostatic range for any given physiological parameter in response to exposure sub-toxic, non-damaging, signalling molecules events, removal cessation such events" (Davies, 2016). enables biological systems make continuous short-term adjustments optimal functioning despite ever-changing internal and external environments. Initiation adaptation an appropriate signal allows organisms successfully cope with much greater, normally toxic, stresses. These responses are initiated following effective signals, including hypoxia, cold shock, heat oxidative stress, exercise-induced adaptation, caloric restriction, osmotic mechanical immune response, even emotional stress. There now substantial literature detailing a decline adaptive that, unfortunately, appears manifest ageing, especially last third lifespan. In this review, we present hypothesis that one hallmark ageing process significant capacity. We discuss mechanistic importance diminished capacity (reversible) (both biochemical transduction/gene expression-based) changing conditions, survival lifespan healthspan. Studies cultured mammalian cells, worms, flies, rodents, simians, apes, humans, all indicate declining as potential contributor age-dependent senescence, increased risk disease, mortality. Emerging work points Nrf2-Keap1 transduction pathway inhibitors, Bach1 c-Myc, both whose tissue concentrations increase age, possible major causes loss homeostasis.

Language: Английский

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Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

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The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100759 - 100759

Published: Jan. 1, 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 global pandemic, utilizes host receptor angiotensin-converting enzyme (ACE2) for viral entry. However, other factors might also play important roles in SARS-CoV-2 infection, providing new directions antiviral treatments. GRP78 is a stress-inducible chaperone entry and infectivity many viruses. Recent molecular docking analyses revealed putative interaction between receptor-binding domain (RBD) Spike protein (SARS-2-S). Here we report that can form complex with SARS-2-S ACE2 on surface at perinuclear region typical endoplasmic reticulum VeroE6-ACE2 cells substrate-binding critical this interaction. In vitro binding studies further confirmed directly bind to RBD ACE2. To investigate role complex, knocked down cells. Loss markedly reduced cell expression led activation markers unfolded response. Treatment lung epithelial humanized monoclonal antibody (hMAb159) selected its safe clinical profile preclinical models depleted expression, as well SARS-2-S-driven infection vitro. Our data suggest an auxiliary factor potential target combat novel pathogen viruses utilize combination therapy.

Language: Английский

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Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Cancers, Journal Year: 2021, Volume and Issue: 13(5), P. 1102 - 1102

Published: March 4, 2021

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, acquire hypoxia-resistant phenotype with characteristic alterations signaling, gene expression and metabolism. Both lack by itself hypoxia-responsive phenotypic modulations render more radioresistant, so that hypoxic serious challenge for radiotherapy. An understanding causes radioresistance would help develop novel ways overcoming this challenge. Molecular targets various approaches radiosensitizing considered present review. It is here analyzed how hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, proteins, glucose-regulated epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition exosome generation contribute be inhibited attenuating radioresistance. The pretreatments multitarget inhibition cancer cell adaptation seem promising approach sensitizing carcinomas, gliomas, lymphomas, sarcomas radiotherapy and, also, liver radioembolization.

Language: Английский

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NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(10), P. 1782 - 1798.e8

Published: Aug. 15, 2023

Language: Английский

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Structural and functional complexity of HSP90 in cellular homeostasis and disease

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(11), P. 797 - 815

Published: July 31, 2023

Language: Английский

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4-tert-butylphenol triggers common carp hepatocytes ferroptosis via oxidative stress, iron overload, SLC7A11/GSH/GPX4 axis, and ATF4/HSPA5/GPX4 axis

Ecotoxicology and Environmental Safety, Journal Year: 2022, Volume and Issue: 242, P. 113944 - 113944

Published: Aug. 1, 2022

4-tert-butylphenol (4-tBP) is a toxic environmental pollutant with moderate bioaccumulation, persistence, and long-term toxicity. Its toxicity to aquatic organisms has become an issue of concern. However, the molecular mechanism 4-tBP remained unclear. Liver target organ for pollutants. Here, we established 4-tBP-exposed model in vivo primary hepatocyte vitro common carp (Cyprinus carpio L.). We found increased hepatic-somatic index (HSI) abnormal serum biochemical indexes (ALT, AST, LDH) after exposure, indicating liver damage. further revealed that damaged structural integrity livers typical features ferroptosis. Based on toxicogenomics analysis, ferroptosis likely be involved 4-tBP-induced Moreover, our experiment provided evidences 4-tBP-exposure led excess oxidative stress, iron overload, decreased MMP, expression ferroptosis-related factors. Interestingly, ferrostatin-1 (Fer-1, inhibitor) pretreatment alleviated above changes. In summary, demonstrated triggered hepatocytes via SLC7A11/GSH/GPX4 axis, ATF4/HSPA5/GPX4 axis. For first time, discovered Fer-1 can ameliorate 4-tBP, which needs more investigations. Our results scientific basis fish poisoning.

Language: Английский

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ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(31)

Published: July 24, 2023

Cancer cells are commonly subjected to endoplasmic reticulum (ER) stress. To gain survival advantage, cancer exploit the adaptive aspects of unfolded protein response such as upregulation ER luminal chaperone GRP78. The finding that when overexpressed, GRP78 can escape other cellular compartments new functions regulating homeostasis and tumorigenesis represents a paradigm shift. Here, toward deciphering mechanisms whereby knockdown suppresses EGFR transcription, we find nuclear is prominent in stressed uncover localization signal critical for its translocation activity. Furthermore, regulate expression genes pathways, notably those important cell migration invasion, by interacting with inhibiting activity transcriptional repressor ID2. Our study reveals mechanism respond stress via regulation mediated adopt an invasive phenotype.

Language: Английский

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Antioxidant and Prooxidant Nanozymes: From Cellular Redox Regulation to Next‐Generation Therapeutics

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(33)

Published: April 21, 2023

Nanozymes, nanomaterials with enzyme-mimicking activity, have attracted tremendous interest in recent years owing to their ability replace natural enzymes various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating cellular redox status by mimicking antioxidant mammalian cells are great therapeutic significance oxidative-stress-mediated disorders. As distinction physiological oxidative stress (oxidative eustress) pathological distress) occurs at a fine borderline, it is challenge design that can differentially sense two extremes cells, tissues organs mediate appropriate chemical reactions. this Review, we summarize advances development redox-active applications. We primarily highlight prooxidant disease model systems, cancer, neurodegeneration, cardiovascular diseases. The future perspectives emerging area research challenges associated applications described.

Language: Английский

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ER Stress and Angiogenesis

Cell Metabolism, Journal Year: 2015, Volume and Issue: 22(4), P. 560 - 575

Published: Aug. 13, 2015

Language: Английский

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