Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 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

Язык: Английский

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Frontiers in Aging, Год журнала: 2022, Номер 3

Опубликована: Июль 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

Язык: Английский

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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Июль 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.

Язык: Английский

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FOXO transcription factors as mediators of stress adaptation

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(1), С. 46 - 64

Опубликована: Сен. 14, 2023

Язык: Английский

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

Nature Reviews Molecular Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

Язык: Английский

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Cell communication and relevant signaling pathways in osteogenesis–angiogenesis coupling

Bone Research, Год журнала: 2025, Номер 13(1)

Опубликована: Апрель 7, 2025

Язык: Английский

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

Frontiers in Physiology, Год журнала: 2023, Номер 14

Опубликована: Фев. 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.

Язык: Английский

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p63: a crucial player in epithelial stemness regulation

Oncogene, Год журнала: 2023, Номер 42(46), С. 3371 - 3384

Опубликована: Окт. 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.

Язык: Английский

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

Acta Physiologica, Год журнала: 2023, Номер 237(3)

Опубликована: Янв. 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.

Язык: Английский

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Structure of the Wnt–Frizzled–LRP6 initiation complex reveals the basis for coreceptor discrimination

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(11)

Опубликована: Март 9, 2023

Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate β-catenin signaling. The cryo-EM structure a initiation complex an affinity-matured XWnt8–Frizzled8–LRP6 elucidates basis coreceptor discrimination by canonical means their N termini linker domains that engage LRP6 E1E2 domain funnels. Chimeric bearing modular “grafts” were able transfer specificity between different enable non-canonical Wnt5a signal through pathway. Synthetic peptides comprising serve as Wnt-specific antagonists. provides topological blueprint orientation proximity within cell surface signalosome.

Язык: Английский

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