Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

Archives of Toxicology, Journal Year: 2023, Volume and Issue: 97(10), P. 2499 - 2574

Published: Aug. 19, 2023

Abstract A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or “good stress” characterized by low to mild levels oxidants involved in the regulation various biochemical transformations such carboxylation, hydroxylation, peroxidation, modulation signal transduction pathways Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2–related 2 (Nrf2) other processes. Increased ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result a harmful condition stress (“bad stress”). Although it widely accepted, that many chronic diseases are multifactorial origin, they share common denominator. Here we review importance mechanisms through which contributes pathological states an organism. Attention focused on chemistry ROS RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl nitric oxide, peroxynitrite), their role damage DNA, proteins, membrane lipids. Quantitative qualitative assessment biomarkers also discussed. Oxidative pathology cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer’s Parkinson’s Down syndrome), psychiatric (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, cancer), aging. The concerted action antioxidants ameliorate effect achieved antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), small molecular weight (vitamins C E, flavonoids, carotenoids, melatonin, ergothioneine, others). Perhaps one most effective vitamin first line defense against peroxidation promising approach appears be use flavonoids), showing weak prooxidant properties may boost cellular systems thus act preventive anticancer agents. Redox metal-based enzyme mimetic compounds potential pharmaceutical interventions sirtuins therapeutic targets for age-related anti-aging strategies

Language: Английский

---

Hallmarks of neurodegenerative diseases

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

---

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

---

Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(6), P. 688 - 701

Published: June 1, 2022

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons five AD mouse models vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of pH, multiplex confocal imaging correlative light electron microscopy. Autolysosome acidification declines well before extracellular amyloid deposition, associated with lowered vATPase activity build-up Aβ/APP-βCTF selectively enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This pattern, termed PANTHOS (poisonous anthos (flower)), also present brains. Additional AVs coalesce peri-nuclear networks tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal permeabilization, cathepsin release lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual exhibiting are the principal source senile plaques precursor protein models.

Language: Английский

---

Alzheimer’s Disease: Treatment Strategies and Their Limitations

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 13954 - 13954

Published: Nov. 12, 2022

Alzheimer’s disease (AD) is the most frequent case of neurodegenerative and becoming a major public health problem all over world. Many therapeutic strategies have been explored for several decades; however, there still no curative treatment, priority remains prevention. In this review, we present an update on clinical physiological phase AD spectrum, modifiable non-modifiable risk factors treatment with focus prevention strategies, then research models used in AD, followed by discussion limitations. The methods can significantly slow evolution are currently best strategy possible before advanced stages disease. Indeed, current drug treatments only symptomatic effects, disease-modifying not yet available. Drug delivery to central nervous system complex process represents challenge developing preventive strategies. Studies underway test new techniques facilitate bioavailability molecules brain. After deep study literature, find use soft nanoparticles, particular nanoliposomes exosomes, as innovative approach reducing solving problems brain bioavailability. show promising role exosomes smart systems able penetrate blood–brain barrier target tissues. Finally, different administration neurological disorders discussed. One intranasal which should be preclinical studies diseases.

Language: Английский

---

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 2, 2022

Abstract Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative and cancers, particularly CVD which accumulation lipids (mainly cholesteryl esters) within macrophage/foam cells underneath endothelial layer drives formation atherosclerotic lesions eventually. More more studies have shown that lowering level, especially low-density lipoprotein protects system prevents events effectively. Maintaining is determined by biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All processes should be precisely controlled regulatory pathways. Based on regulation homeostasis, many interventions been developed to lower inhibiting biosynthesis uptake or enhancing utilization Herein, we summarize historical review research events, current understandings molecular pathways playing key regulating cholesterol-lowering clinics preclinical well new targets their clinical advances. importantly, discuss benefits those for treatment including obesity, diabetes, nonalcoholic fatty liver disease, cancer, osteoporosis virus infection.

Language: Английский

---

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(6), P. 1420 - 1453

Published: Jan. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Language: Английский

---

Biomarker modeling of Alzheimer’s disease using PET-based Braak staging

Nature Aging, Journal Year: 2022, Volume and Issue: 2(6), P. 526 - 535

Published: April 25, 2022

Abstract Gold-standard diagnosis of Alzheimer’s disease (AD) relies on histopathological staging systems. Using the topographical information from [ 18 F]MK6240 tau positron-emission tomography (PET), we applied Braak system to 324 living individuals. We used PET-based stage model trajectories amyloid-β, phosphorylated (pTau) in cerebrospinal fluid (pTau 181 , pTau 217 231 and 235 ) plasma ), neurodegeneration cognitive symptoms. identified nonlinear AD biomarker corresponding spatial extent tau-PET, with modest changes detectable by II significant occurring at stages III–IV, followed plateaus. Early were associated isolated memory impairment, whereas V–VI incompatible normal cognition. In 159 individuals follow-up progression beyond III took place uniquely presence amyloid-β positivity. Our findings support as a framework natural history monitor severity humans.

Language: Английский

---

The neuroimmune axis of Alzheimer’s disease

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Jan. 26, 2023

Abstract Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial pathological roles for innate immune genes cells, peripheral cells such as T which can infiltrate brain either ameliorate or exacerbate AD neuropathogenesis. These findings support neuroimmune axis of AD, in interplay adaptive systems inside outside critically impacts etiology pathogenesis AD. In this review, we discuss complexities neuropathology at levels genetics cellular physiology, highlighting signaling pathways associated risk interactions among brain. We emphasize role mechanisms by monocytes, influence neuropathology, microglial clearance amyloid-β peptide, key component plaque cores, pro-inflammatory cytotoxic activity microglia, astrogliosis, their vasculature. Finally, review challenges outlook establishing immune-based therapies treating preventing

Language: Английский

---

Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: July 14, 2023

Abstract Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed aggregated β-amyloid (Aβ) hyperphosphorylated tau protein, respectively. In past few decades, disease-modifying therapy targeting Aβ has been focus AD drug development. Even though it is encouraging that two these drugs have recently received accelerated US Food Drug Administration approval for treatment, their efficacy or long-term safety controversial. Tau increasing attention as a potential therapeutic target, since evidence indicates pathology more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies pathological processes also linked deficits. Accumulating inflammation complex tight interplay pathology. Here, we review recent on interaction between pathology, focusing post-translational modification dissemination, neuroinflammatory responses, including glial cell activation inflammatory signaling pathways. Then, summarize latest clinical trials neuroinflammation. Sustained increased responses in cells neurons pivotal cellular drivers regulators exacerbation which further its worsening by aggravating responses. Unraveling precise mechanisms underlying relationship neuroinflammation will provide new insights into discovery translation targets other tau-related diseases (tauopathies). Targeting multiple pathologies precision strategies be crucial direction developing tauopathies.

Language: Английский

---