Stress-induced biological aging: A review and guide for research priorities

Brain Behavior and Immunity, Год журнала: 2022, Номер 104, С. 97 - 109

Опубликована: Июнь 1, 2022

Exposure to chronic adverse conditions, and the resultant activation of neurobiological response cascade, has been associated with an increased risk early onset age-related disease and, recently, older biological age. This body research led hypothesis that exposure stressful life experiences, when occurring repeatedly or over a prolonged period, may accelerate rate at which ages. The mechanisms through psychosocial stress influences distinct aging pathways alter rates likely involve multiple layers in physiological-molecular network. In this review, we integrate using animal, human, vitro models begin delineate impact aging, as well neuroendocrine mediators (i.e., norepinephrine, epinephrine, glucocorticoids) drive these effects. Findings highlight key connections between namely cellular metabolic activity, DNA damage, telomere length, senescence, inflammatory patterns. We conclude guiding framework conceptual model outlines most promising by conditions could point missing gaps knowledge where future best answer pressing questions.

Язык: Английский

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Dual-Parameter Recognition-Directed Design of the Activatable Fluorescence Probe for Precise Imaging of Cellular Senescence

Analytical Chemistry, Год журнала: 2023, Номер 95(8), С. 3996 - 4004

Опубликована: Фев. 16, 2023

Specific imaging of cellular senescence emerges as a promising strategy for early diagnosis and treatment various age-related diseases. The currently available probes are routinely designed by targeting single senescence-related marker. However, the inherently high heterogeneity makes them inaccessible to achieve specific accurate detection broad-spectrum senescence. Here, we report design dual-parameter recognition fluorescent probe precise This remains silent in non-senescent cells, yet produces bright fluorescence after sequential responses two senescence-associated markers, namely, SA-β-gal MAO-A. In-depth studies reveal that this allows high-contrast senescence, independent cell source or stress type. More impressively, such further it distinguish SA-β-gal/MAO-A from cancer-related β-gal/MAO-A, compared commercial previous single-marker probes. study offers valuable molecular tool which is expected significantly expand basic on facilitate advances disease theranostics.

Язык: Английский

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Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer’s disease

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Ноя. 13, 2023

Alzheimer's disease (AD) is a progressive brain characterised by memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered contribute pathologies Therefore, we reviewed dual (AChE) MAO-B developed in last five years. In this review, these dual-target were classified into six groups according basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine hydrazine, other scaffolds. Their design strategies, structure-activity relationships (SARs), molecular docking studies with AChE analysed discussed, giving valuable insights subsequent development inhibitors. Challenges balanced potent noted, corresponding solutions provided.

Язык: Английский

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Multi-Target-Directed Cinnamic Acid Hybrids Targeting Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(1), С. 582 - 582

Опубликована: Янв. 1, 2024

Progressive cognitive decline in Alzheimer’s disease (AD) is a growing challenge. Present therapies are based on acetylcholinesterase inhibition providing only temporary relief. Promising alternatives include butyrylcholinesterase (BuChE) inhibitors, multi-target ligands (MTDLs) that address the multi-factorial nature of AD, and compounds target oxidative stress inflammation. Cinnamate derivatives, known for their neuroprotective properties, show potential when combined with established AD agents, demonstrating improved efficacy. They being positioned as therapeutic leads due to ability inhibit Aβ accumulation provide neuroprotection. This article highlights remarkable cinnamic acid basic structure easily adaptable combinable different active groups struggle against disease. Compounds methoxy substitution at para-position display increased efficacy, whereas electron-withdrawing generally more effective. The effect molecular volume worthy further investigation.

Язык: Английский

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A second life for MAO inhibitors? From CNS diseases to anticancer therapy

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116180 - 116180

Опубликована: Янв. 24, 2024

Monoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters xenobiotics. Despite decades studies, MAO inhibitors (MAOIs) find today limited therapeutic space as second-line drugs the treatment depression Parkinson's disease. In recent years, a renewed interest in MAOIs has been raised up by several studies investigating role MAOs, particularly tumor insurgence progression, efficacy coadjutants therapy chemoresistant tumors. this survey, we highlight implication MAOs biochemical pathways tumorigenesis review state-of-the-art preclinical clinical anticancer agents used monotherapy or combination with antitumor chemotherapeutics.

Язык: Английский

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Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(9), С. 1828 - 1881

Опубликована: Апрель 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Язык: Английский

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Interplay between hypoxia inducible Factor-1 and mitochondria in cardiac diseases

Free Radical Biology and Medicine, Год журнала: 2024, Номер 221, С. 13 - 22

Опубликована: Апрель 30, 2024

Ischemic heart diseases and cardiomyopathies are characterized by hypoxia, energy starvation mitochondrial dysfunction. HIF-1 acts as a cellular oxygen sensor, tuning the balance of metabolic oxidative stress pathways to provide ATP sustain cell survival. Acting on mitochondria, regulates different processes such substrate utilization, phosphorylation dynamics. In turn, homeostasis modifications impact activity. This underlies that mitochondria tightly interconnected maintain homeostasis. Despite many evidences linking mechanistic insights far from being understood, particularly in context cardiac diseases. Here, we explore current understanding how HIF-1, reactive species metabolism interconnected, with specific focus function We also discuss divergent roles HIF acute chronic order highlight interaction deserves be deeply investigated. While strategies aiming at stabilizing have provided beneficial effects ischemic injury, some deleterious were observed during prolonged activation. Thus, deciphering link between will help optimize modulation new therapeutic perspectives for treatment cardiovascular pathologies.

Язык: Английский

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Monoamine Oxidase (MAO) as a Potential Target for Anticancer Drug Design and Development

Molecules, Год журнала: 2021, Номер 26(19), С. 6019 - 6019

Опубликована: Окт. 4, 2021

Monoamine oxidases (MAOs) are oxidative enzymes that catalyze the conversion of biogenic amines into their corresponding aldehydes and ketones through deamination. Owing to crucial role MAOs in maintaining functional levels neurotransmitters, implications its distorted activity have been associated with numerous neurological diseases. Recently, an unanticipated tumor progression metastasis has reported. The chemical inhibition might be a valuable therapeutic approach for cancer treatment. In this review, we reported computational approaches exploited design development selective MAO inhibitors accompanied by biological activities. Additionally, generated pharmacophore model MAO-A active identify structural motifs invoke activity.

Язык: Английский

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Targeting mitochondrial degradation by chimeric autophagy-tethering compounds

Chemical Science, Год журнала: 2023, Номер 14(40), С. 11192 - 11202

Опубликована: Янв. 1, 2023

The ability to regulate mitophagy in a living system with small molecules remains great challenge. We hypothesize that adding fragments specific the key autophagosome protein LC3 mitochondria will mimic receptor-mediated mitophagy, thus engaging autophagy-lysosome pathway induce mitochondrial degradation. Herein, we develop general biochemical approach modulate dubbed mito-ATTECs, which employ chimera composed of LC3-binding moieties linked mitochondria-targeting ligands. Mito-ATTECs trigger via targeting autophagosomes through direct interaction between mito-ATTECs and on membranes. Subsequently, containing rapidly fuse lysosomes facilitate degradation mitochondria. Therefore, circumvent detrimental effects related disruption membrane integrity by inducers routinely used manipulate provide versatile investigate physiological roles mitophagy. Furthermore, found sustained lead depletion autophagic cell death several malignant lines (lethal mitophagy). Among them, apoptosis-resistant melanoma are particularly sensitive lethal therapeutic efficacy has been further evaluated using subcutaneous pulmonary metastatic models. Together, achieved may demonstrate concept inducing cancer lethality excessive clearance, establishing promising paradigm for tumors.

Язык: Английский

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Synthesis and in-vitro cytotoxicity activity of 1,3,4-oxa-diazolbenzamide derivatives and inhibition of human MAO-A enzyme: A in-silico approaches

Analytical Chemistry Letters, Год журнала: 2025, Номер unknown, С. 1 - 20

Опубликована: Янв. 12, 2025

The report from the WHO, there are 2 million deaths in worldwide due to cancer year 2023. Due increase death rate, researchers need find a new drug for targeting cancer. For development of medication cancer, researcher now worked on target like MAO-A, because these group enzymes highly expressed cells. present study deals with designing various substituted N-(1,3,4-oxadiazol- 2-yl) benzamide and it was synthesized. docking studies revealed that, compound AA5 (-11.5 kcal/mol) showing similar binding affinity standard molecule clorgyline towards targeted protein molecules shows conventional hydrogen bonds Tyr 407 Met 445 amino acid residues. entire 10 synthesized compounds evaluated their cytotoxicity activity by in-vitro MTT assay using MCF-7, A549 normal breast cell line MCF-10. most promising sensitivity all but AA8 (31.546±0.71 nM), (34.969±0.53 AA35 (37.733±0.78 nM) AA6 (39.984±0.56 nM). In MCF-7 showed four derivatives such as (32.292±0.67 (33.933±0.96 AA7 (34.146±0.19 39.328±0.11 addition this, subjected MAO-A enzyme inhibition assay. results methyl (28.00±0.3 highest substantial inhibition, followed pyridine moiety (29.28±0.4 furan (31.04±0.4), significant compared other tested compounds. both cytotoxic AA5, more sensitive enzymes. Moreover, lines that less toxic lines. designed also demonstrated higher score human enzyme. addition, in-silico ADMET screening low toxicity have adequate pharmacokinetic properties.

Язык: Английский

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