Fisetin is a senotherapeutic that extends health and lifespan

EBioMedicine, Год журнала: 2018, Номер 36, С. 18 - 28

Опубликована: Сен. 29, 2018

Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent have been demonstrated play causal role driving aging and age-related diseases using genetic pharmacologic approaches. We previously that the combination dasatinib flavonoid quercetin potent senolytic improving numerous conditions including frailty, osteoporosis cardiovascular disease. The goal this study was identify flavonoids with more activity.

Язык: Английский

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Ageing, Cellular Senescence and Neurodegenerative Disease

International Journal of Molecular Sciences, Год журнала: 2018, Номер 19(10), С. 2937 - 2937

Опубликована: Сен. 27, 2018

Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence homeostatic biological process that has key role in driving ageing. There evidence senescent cells accumulate the nervous system with ageing and disease may predispose person to appearance of condition or aggravate its course. Research into long been hindered by variable cell-type specific features lack universal marker unequivocally detect cells. Recent advances markers genetically modified animal models have boosted our knowledge on cellular age-related disease. The aim now fully elucidate neurodegeneration order efficiently safely exploit as therapeutic target. Here, we review neurons glial discuss putative Alzheimer's disease, Parkinson's multiple sclerosis provide, first time, glia sclerosis, using novel GL13 lipofuscin stain senescence.

Язык: Английский

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Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice

Biomedicine & Pharmacotherapy, Год журнала: 2019, Номер 122, С. 109772 - 109772

Опубликована: Дек. 30, 2019

Sepsis is defined as end-organ dysfunction resulting from the host's inflammatory response to infection. One of most common sepsis-injured organs kidneys, in acute kidney injury (AKI) that contributes high morbidity and mortality, especially patients intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported protect against rat lipopolysaccharide (LPS)-induced lung injury. However, effect fisetin on septic AKI remains unknown.The current study proposed systematically investigate renoprotective effects underlying mechanisms mice.The model was established male C57BL/6 J mice by single intraperitoneal injection LPS (10 mg/kg). Fisetin administrated gavage at 100 mg/kg for 3 consecutive days before were sacrificed 16 h after injection. The serum samples evaluated biochemical analysis, histopathological examinations well inflammation apoptosis related gene/protein expression.Pretreatment with significantly alleviated elevated levels creatinine blood urea nitrogen LPS-treated mice. Consistently, induced renal damage implied score increased markers NGAL KIM-1, which attenuated fisetin. Meanwhile, triggered proinflammatory cytokine production proteins kidneys. inhibited expression IL-6, IL-1β, TNF-α, HMGB1, iNOS COX-2 improve response. Furthermore, effectively reduced number TUNEL positive apoptotic cells suppressed protein Bcl-2, BAX cleaved caspase-3 kidneys LPS-induced AKI. Mechanistically, stimulated TLR4 phosphorylation NF-κB p65, MAPK (p38, ERK1/2 JNK), Src AKT injured while notably corresponding expression.Fisetin via inhibiting Src-mediated p65 signaling pathways.

Язык: Английский

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Cellular Senescence in Brain Aging

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Фев. 25, 2021

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in structural plasticity dendritic spines. Decreased number maturity spines aged animals humans, together synaptic transmission, may reflect aberrant neuronal directly associated impaired functions. In extreme, neurodegenerative disease, completely devastates basic functions brain, develop. While cellular senescence peripheral tissues recently linked aging aging-related disorders, its involvement is just beginning be explored. However, accumulated evidence suggests that cell play role it documented other organs. Senescent cells stop dividing shift their activity strengthen secretory function, leads acquisition so called senescence-associated phenotype (SASP). have also characteristics, such altered morphology proteostasis, decreased propensity undergo apoptosis, autophagy impairment, accumulation lipid droplets, increased senescence-associated-β-galactosidase (SA-β-gal), epigenetic alterations, including DNA methylation, chromatin remodeling, histone post-translational modifications that, consequence, result gene expression. Proliferation-competent glial both vitro vivo , they likely participate neuroinflammation, characteristic for brain. apart from proliferation-competent cells, consists post-mitotic neurons. Interestingly, emerged recently, non-proliferating present or cultivated some hallmarks, SASP, typical senescent ceased divide. It senolytics, by definition, eliminate improve ability mice models. this review, we ask questions about impairments how senolytics them. We will discuss whether plasticity, defined morphological functional at level neurons spines, hallmark susceptible effects senolytics.

Язык: Английский

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Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Cancers, Год журнала: 2020, Номер 12(8), С. 2134 - 2134

Опубликована: Июль 31, 2020

Cellular senescence is a key component of human aging that can be induced by range stimuli, including DNA damage, cellular stress, telomere shortening, and the activation oncogenes. Senescence generally regarded as tumour suppressive process, both preventing cancer cell proliferation suppressing malignant progression from pre-malignant to disease. It may also effector mechanism many types anticancer therapies, such chemotherapy, radiotherapy, endocrine directly via bioactive molecules released senescent cells stimulate an immune response. However, contribute reduced patient resilience therapies provide pathway for disease recurrence after therapy. A new group drugs, senotherapies, (drugs which interact with interfere their pro-aging impacts either selectively destroying (senolytic drugs) or inhibiting function (senostatic drugs)) are under active investigation determine whether they enhance efficacy improve treatments. Senolytic drugs include quercetin, navitoclax, fisetin preclinical early phase clinical data emerging potential role in treatments, although none yet routine use clinically. This article provides review these issues.

Язык: Английский

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Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice

Molecular Neurobiology, Год журнала: 2016, Номер 54(3), С. 2269 - 2285

Опубликована: Март 5, 2016

Язык: Английский

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The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Окт. 10, 2022

Oxidative stress (OS) disrupts the chemical integrity of macromolecules and increases risk neurodegenerative diseases. Fisetin is a flavonoid that exhibits potent antioxidant properties protects cells against OS. We have viewed NCBI database, PubMed, Science Direct (Elsevier), Springer-Nature, ResearchGate, Google Scholar databases to search collect relevant articles during preparation this review. The keywords are OS, diseases, fisetin, etc. High level ROS in brain tissue decreases ATP levels, mitochondrial membrane potential induces lipid peroxidation, chronic inflammation, DNA damage, apoptosis. subsequent results various neuronal polyphenolic compound, commonly present dietary ingredients. diminish oxidative stress, production, neurotoxicity, neuro-inflammation, neurological disorders. Moreover, it maintains redox profiles, functions inhibits NO production. At molecular level, fisetin regulates activity PI3K/Akt, Nrf2, NF-κB, protein kinase C, MAPK pathways prevent inflammatory response, cytotoxicity. protect neural from inflammation apoptotic degeneration. Thus, can be used prevention

Язык: Английский

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Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics

Pharmaceuticals, Год журнала: 2023, Номер 16(2), С. 196 - 196

Опубликована: Янв. 28, 2023

Cancer is one of the major causes mortality, globally. Cancerous cells invade normal and metastasize to distant sites with help lymphatic system. There are several mechanisms involved in development progression cancer. Several treatment strategies including use phytoconstituents have evolved been practiced for better therapeutic outcomes against Fisetin such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, anticancer properties. It inhibits rapid growth, invasiveness, metastasis tumors by hindering multiplication cancer cells, prompts apoptosis avoiding cell division related actuation caspase-9 caspase-8. However, its poor bioavailability associated extreme hydrophobicity hampers clinical utility. The issues fisetin delivery can be addressed adapting developmental aspects nanomedicines, as formulating it into lipid or polymer-based systems, nanocochleates liposomes. This review aims provide in-depth information regarding a potential candidate therapy, properties various formulation strategies.

Язык: Английский

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The PI3K-Akt-mTOR and Associated Signaling Pathways as Molecular Drivers of Immune-Mediated Inflammatory Skin Diseases: Update on Therapeutic Strategy Using Natural and Synthetic Compounds

Cells, Год журнала: 2023, Номер 12(12), С. 1671 - 1671

Опубликована: Июнь 20, 2023

The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, vitiligo, is associated with poor treatment outcomes. Improved comprehension the consequences PI3K/Akt/mTOR patients resulted development novel therapeutic approaches. Nonetheless, more studies are necessary to validate regulatory role this create effective preventive methods for a wide range skin diseases. Several have revealed that certain natural products synthetic compounds can obstruct expression/activity PI3K/Akt/mTOR, underscoring their potential managing common persistent disorders. This review summarizes recent advances understanding activated components discusses bioactive products, scaffolds, biologic agents prevention treatment. However, further research develop therapies

Язык: Английский

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Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies

Pharmacological Reviews, Год журнала: 2023, Номер 75(4), С. 675 - 713

Опубликована: Фев. 2, 2023

An increase in life expectancy developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence prominent role cellular senescence many these pathologies. Key traits senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift senescence-associated secretory phenotype resulting increased secretion various intermediate bioactive factors important for pathophysiology. However, is highly phenotypically heterogeneous process, hindering discovery totally specific accurate biomarkers. Also, strategies prevent pathologic effect accumulation during aging by impairing onset or promoting clearance shown great potential vivo studies, some are already early stages clinical translation. The adaptability senotherapeutic approaches human application been questioned due lack proper targeting involvement physiologic functions. this review, we explore its influence on expression biomarkers currently used detection. We also discuss current regarding efficacy, reliability, development stage, applicability main existing strategies.

Significance Statement

This paper an extensive review what known about complex process explores most defining features. body discussion focuses how multifeature fluctuation physiological both caused limitation search truly reliable progression senotherapies.

Язык: Английский

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