Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

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

Published: Jan. 8, 2024

Abstract Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of intricate mechanisms underlying I/R hinders development effective therapeutic interventions. Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system pathways involved in injury. This review article elucidates signaling, as well complex interplay between and including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca 2+ -Activin A, Hippo-Yes-associated toll-like receptor 4/toll-interleukine-1 domain-containing adapter-inducing interferon-β, hepatocyte factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, apoptosis, inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, blood-brain barrier damage Our comprehensive analysis reveals that activation canonical promotes organ recovery, while non-canonical exacerbates Moreover, explore novel approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, clinical trials. objective this is provide deeper insights roles its I/R-mediated processes dysfunction, facilitate innovative agents for

Language: Английский

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Frontiers in Aging, Journal Year: 2022, Volume and Issue: 3

Published: July 12, 2022

The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These have shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of opposite effects, extending lifespan. In humans, levels decline with age, chronic kidney diabetes, Alzheimer's disease other conditions. Low correlate an increase the death rate from all causes. acts either obligate coreceptor fibroblast growth factor 23 (FGF23), or soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced kidneys, but also brain, pancreas tissues. On tubular-cell membranes, it associates FGF receptors to bind FGF23. Produced bones, FGF23 regulates excretion phosphate (phosphaturic effect) vitamin D metabolism. Lack results hyperphosphatemia hypervitaminosis D. With human function often deteriorates, lowering levels. This appears promote age-related pathology. Remarkably, inhibits four pathways that been linked aging various ways: Transforming β (TGF-β), insulin-like 1 (IGF-1), Wnt NF-κB. can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis neoplasia. Furthermore, increases cell-protective antioxidant enzymes through Nrf2 FoxO. accord, preclinical therapy ameliorated renal, cardiovascular, diabetes-related neurodegenerative diseases, well cancer. s-Klotho injection was effective, requires further investigation. Several drugs enhance circulating levels, some cross blood-brain barrier potentially act brain. clinical trials, increased noted renin-angiotensin system inhibitors (losartan, valsartan), statin (fluvastatin), mTOR (rapamycin, everolimus), pentoxifylline. work, antidiabetic (metformin, GLP-1-based, GABA, PPAR-γ agonists) enhanced Klotho. traditional medicines and/or nutraceuticals rodents, including astaxanthin, curcumin, ginseng, ligustilide resveratrol. Notably, exercise sport activity review addresses molecular, physiological therapeutic aspects

Language: Английский

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Cancer stem cells: advances in knowledge and implications for cancer therapy

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

Published: July 5, 2024

Abstract Cancer stem cells (CSCs), a small subset of in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, maintain tumor heterogeneity. continues be significant global disease burden. In the past, surgery, radiotherapy, chemotherapy were main cancer treatments. The technology treatments develop advance, emergence targeted therapy, immunotherapy provides more options for patients certain extent. However, limitations efficacy treatment resistance still inevitable. Our review begins with brief introduction historical discoveries, original hypotheses, pathways regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, their crosstalk. We focus on role CSCs various therapeutic outcomes resistance, including how affect content alteration related molecules, CSCs-mediated clinical value targeting refractory, progressed or advanced tumors. summary, efficacy, method is difficult determine. Clarifying regulatory mechanisms biomarkers currently mainstream idea.

Language: Английский

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FOXO transcription factors as mediators of stress adaptation

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(1), P. 46 - 64

Published: Sept. 14, 2023

Language: Английский

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Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Language: Английский

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Fusobacterium nucleatum modulates the Wnt/β-catenin pathway in colorectal cancer development

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 299, P. 140196 - 140196

Published: Jan. 21, 2025

Language: Английский

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Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 28, 2023

Primordial follicles are the starting point of follicular development and basic functional unit female reproduction. formed around birth, most primordial then enter a dormant state. Since limited in number can’t be renewed, cannot reversed once they growing Thus, orderly occurrence selective activation directly affects rate follicle consumption thus determines length reproductive lifespan. Studies have found that appropriately inhibiting can effectively slow down consumption, maintain fertility delay ovarian aging. Based on known mechanisms activation, vitro (IVA) technique has been clinically developed. IVA help patients with premature failure, middle-aged infertile women, or women due to gynecological surgery treatment solve infertility problems. The study mechanism contribute more efficient safe techniques. In this paper, recent its clinical application reviewed.

Language: Английский

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WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

Acta Physiologica, Journal Year: 2023, Volume and Issue: 237(3)

Published: Jan. 4, 2023

Abstract The WNT/β‐catenin pathway is a master regulator of cardiac development and growth, its activity low in healthy adult hearts. However, even this essential for maintaining normal heart function. Acute activation the signaling cascade considered to be cardioprotective after infarction through upregulation prosurvival genes reprogramming metabolism. Chronically high causes profibrotic hypertrophic effects heart. New data suggest more complex functions β‐catenin metabolic maturation perinatal heart, establishing an pattern glucose fatty acid utilization. Additionally, basal maintains oxidative metabolism reactivated by physiological or pathological stimuli meet higher energy needs This review summarizes current state knowledge organization canonical WNT function cardiogenesis, maturation, function, remodeling. We also discuss role glucose, lipid metabolism, mitochondrial physiology.

Language: Английский

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p63: a crucial player in epithelial stemness regulation

Oncogene, Journal Year: 2023, Volume and Issue: 42(46), P. 3371 - 3384

Published: Oct. 17, 2023

Abstract Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker ESCs, an indispensable factor for their biological activities during development. The diversity p63 isoforms expressed in distinct tissues allows this transcription to have wide array effects. coordinates genes involved cell survival, self-renewal, migration, differentiation, epithelial-to-mesenchymal transition. Through regulation these processes, contributes to, not only normal development, but also epithelium-derived cancer pathogenesis. In review, we provide overview role stemness regulation, including proliferation, senescence. We describe differential expression TAp63 ΔNp63 functional tumors. Furthermore, summarize signaling cascades modulating as well downstream pathways regulation.

Language: Английский

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YAP and β-catenin cooperate to drive H. pylori -induced gastric tumorigenesis

Gut Microbes, Journal Year: 2023, Volume and Issue: 15(1)

Published: March 23, 2023

H. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated crosstalk between YAP in pylori-associated tumorigenesis. Immunohistochemical analysis expression was performed human cancer tissues. small molecules Super-TDU KYA1797K, pharmacological inhibitors β-catenin, respectively, were used to investigate role these signaling pylori-induced carcinogenesis murine models infection. common downstream targets evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU spheroid assays used. promoted nuclear accumulation transcriptional activity epithelial cells transgenic insulin–gastrin (INS-GAS) mice, whereas silencing both synergistically inhibited proliferation expansion. addition, found directly interact knockdown suppressed translocation β-catenin. Moreover, genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) RuvB like AAA ATPase (RUVBL1) shared signaling. Furthermore, treatment inhibitor or KYA1797A significantly alleviated inflammation DNA damage pylori-infected mice. Finally, elevation positively correlated These findings indicate that promote via their physical interaction reveal CDX2, LGR5 RUVBL1 are pathways, potentially contribute pathogenesis.

Language: Английский

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