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Cited by 916Antioxidant Activity and Oxidative StressRedox biology and oxidative stressExercise and Physiological Responses

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Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives

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Hajam, Younis Ahmad, Rani, Raksha, Ganie, Shahid Yousuf, Sheikh, Tariq Ahmad, Javaid, Darakhshan, Qadri, Syed Sanober, Pramodh, Sreepoorna, Alsulimani, Ahmad, Alkhanani, Mustfa F., Harakeh, Steve, Hussain, Arif, Haque, Shafiul, Reshi, Mohd Salim·2022·Cells
DOI 10.3390/cells11030552PMC PMC8833991
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Abstract

Reactive oxygen and nitrogen species (RONS) are generated through various endogenous and exogenous processes; however, they are neutralized by enzymatic and non-enzymatic antioxidants. An imbalance between the generation and neutralization of oxidants results in the progression to oxidative stress (OS), which in turn gives rise to various diseases, disorders and aging. The characteristics of aging include the progressive loss of function in tissues and organs. The theory of aging explains that age-related functional losses are due to accumulation of reactive oxygen species (ROS), their subsequent damages and tissue deformities. Moreover, the diseases and disorders caused by OS include cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases and cancer. OS, induced by ROS, is neutralized by different enzymatic and non-enzymatic antioxidants and prevents cells, tissues and organs from damage. However, prolonged OS decreases the content of antioxidant status of cells by reducing the activities of reductants and antioxidative enzymes and gives rise to different pathological conditions. Therefore, the aim of the present review is to discuss the mechanism of ROS-induced OS signaling and their age-associated complications mediated through their toxic manifestations in order to devise effective preventive and curative natural therapeutic remedies.

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Figures

Figure 1 The mechanism for the production of ROS: Autoxidation with excess glucose alters the overall metabolic process and produces free radicals, inhibiting the antioxidant enzymes (GPX, CAT). ROS cause DNA damage. GPx: Glutathione peroxidase, CAT: Catalase, Trx: Thioredoxin, GSIS: glucose-stimulated insulin secretion.
Figure 1 The mechanism for the production of ROS: Autoxidation with excess glucose alters the overall metabolic process and produces free radicals, inhibiting the antioxidant enzymes (GPX, CAT). ROS cause DNA damage. GPx: Glutathione peroxidase, CAT: Catalase, Trx: Thioredoxin, GSIS: glucose-stimulated insulin secretion.CC BY · PubMed Central
Figure 2 ROS-mediated toxic manifestations such as ROS-mediated DNA damage; peroxidative damage of membrane lipids, degradation of proteins caused ROS, Base modifications of Bases, where MDA: Malondialdehyde, TBARS: Thiobarbituric acid-reactive species, *, unpaired electron.
Figure 2 ROS-mediated toxic manifestations such as ROS-mediated DNA damage; peroxidative damage of membrane lipids, degradation of proteins caused ROS, Base modifications of Bases, where MDA: Malondialdehyde, TBARS: Thiobarbituric acid-reactive species, *, unpaired electron.CC BY · PubMed Central
Figure 3 Effect of reactive oxygen species (ROS). ROS generation induces Alzheimer’s disease by accumulation of β-Amyloid proteins, activation of BK and Kv and finally decreases excitability property of neurons and neuro-degeneration of the heart, liver and kidneys, where KATP; ATP-sensitive potassium, NADPH oxidase: Nicotinamide dinucleotide Phosphate reduced, p38MAPK; p38 mitogen-activated protein kinases, MMP; Matrix metalloproteinases/tissue inhibitor of metalloproteinases, HIFA-α; Hypoxia-inducible factor 1-alpha, FOXO1; Forkhead box transcription factors, mPTP: mitochondrial permeability transition pore, PDK: Protein 3-phosphoinositide-dependent protein kinase, NLRP: Nucleotide-binding oligomerization domain, MCP: Monocyte Chemoattractant Protein, TNF-α: Tumor necrosis factor alpha, IL-1β: Interleukin-1 beta. Note: Upward arrows indicate increase and downward arrows indicate decrease.
Figure 3 Effect of reactive oxygen species (ROS). ROS generation induces Alzheimer’s disease by accumulation of β-Amyloid proteins, activation of BK and Kv and finally decreases excitability property of neurons and neuro-degeneration of the heart, liver and kidneys, where KATP; ATP-sensitive potassium, NADPH oxidase: Nicotinamide dinucleotide Phosphate reduced, p38MAPK; p38 mitogen-activated protein kinases, MMP; Matrix metalloproteinases/tissue inhibitor of metalloproteinases, HIFA-α; Hypoxia-inducible factor 1-alpha, FOXO1; Forkhead box transcription factors, mPTP: mitochondrial permeability transition pore, PDK: Protein 3-phosphoinositide-dependent protein kinase, NLRP: Nucleotide-binding oligomerization domain, MCP: Monocyte Chemoattractant Protein, TNF-α: Tumor necrosis factor alpha, IL-1β: Interleukin-1 beta. Note: Upward arrows indicate increase and downward arrows indicate decrease.CC BY · PubMed Central
Figure 4 Hyperglycemic condition is one of the major sources of ROS and leads to modulation of various metabolic downregulatory pathways. Increased glucose results in auto-oxidation and production of H2O2, ·OH and activation of downregulatory pathways such as PDX-1 and insulin-(mRNA) and increases the secretion, where DAG: Diacyl glycerol, PKC-β: Protein kinase-beta, NF-κB: Nuclear factor kappa light chain enhancer of activated B cells, AGEs: Advanced glycated end products, UDP-Glac-NAc: Uridine diphosphate N-acetylglucosamine, TGF-β; Transforming growth factor beta, PDX1; pancreatic and duodenal homeobox-1, PARP: Poly (ADP-ribose) polymerase. Closure of K+-ATP-dependent channels results in membrane depolarization and activation of voltage-dependent calcium channels, leading to an increase in intracellular calcium concentration; this triggers pulsatile insulin secretion. Note: Upward arrows indicate increase and downward arrows indicate decrease.
Figure 4 Hyperglycemic condition is one of the major sources of ROS and leads to modulation of various metabolic downregulatory pathways. Increased glucose results in auto-oxidation and production of H2O2, ·OH and activation of downregulatory pathways such as PDX-1 and insulin-(mRNA) and increases the secretion, where DAG: Diacyl glycerol, PKC-β: Protein kinase-beta, NF-κB: Nuclear factor kappa light chain enhancer of activated B cells, AGEs: Advanced glycated end products, UDP-Glac-NAc: Uridine diphosphate N-acetylglucosamine, TGF-β; Transforming growth factor beta, PDX1; pancreatic and duodenal homeobox-1, PARP: Poly (ADP-ribose) polymerase. Closure of K+-ATP-dependent channels results in membrane depolarization and activation of voltage-dependent calcium channels, leading to an increase in intracellular calcium concentration; this triggers pulsatile insulin secretion. Note: Upward arrows indicate increase and downward arrows indicate decrease.CC BY · PubMed Central
Figure 5 The diagram shows the role of feedback mechanism of leptin, POMC neurons, and NPY-AgRP neurons in the regulation of satiety and starving, where POMC: proopiomelanocortin, NPY/AgRP: neuropeptide Y/Agouti-related protein, Lep-R: Leptin receptor, α-MSH: Alpha melanin-stimulating hormone, MC4-R: Melanocortin receptor-4. Note: Upward arrows indicate increase and downward arrows indicate decrease.
Figure 5 The diagram shows the role of feedback mechanism of leptin, POMC neurons, and NPY-AgRP neurons in the regulation of satiety and starving, where POMC: proopiomelanocortin, NPY/AgRP: neuropeptide Y/Agouti-related protein, Lep-R: Leptin receptor, α-MSH: Alpha melanin-stimulating hormone, MC4-R: Melanocortin receptor-4. Note: Upward arrows indicate increase and downward arrows indicate decrease.CC BY · PubMed Central
Figure 6 The diagram shows ROS-induced cardiac hypertrophy through the up-regulation of various pathways. ROS induces the activation of endotjelin-1 protein which in turn causes break down of PIP3 into IP3 and DAG, both of these activates the calcium channels and releases calcium from endoplasmic reticulum. Liberation of Ca from ER inhibits the activation of Calcineurin, also mediated by KMUP-1, and finally causes cardiac hypertrophy through the activation of AP-1DNA binding activity of NFATc4. Moreover, ROS activates HIFI-1, FOXO-α and Myc pathways and leads to the activation of hypertrophic remodeling. ROS also induce cardiac hypertrophy through the opening of mPTP channel, release of cytochrome C and induction of apoptosis of myocardial muscles. Additionally, ROS induces inhibition of P13K, Akt and GSK-3β. All these pathways induce cardiac hypertrophy, where ET-1: Endothelin-1, mPTP: Mitochondrial Permeability Transition Pore, ASK-1: Apoptosis signal-regulating kinase-1, MMP. TIMP: Matrix metalloproteinase/Tissue inhibitors of metalloproteinases, AP-1: Activator protein 1, NF-κβ: Nuclear factor-κ Beta, KATP; ATP-sensitive potassium, NADPH oxidase: Nicotinamide dinucleotide phosphate reduced, p38MAPK; p38 mitogen-activated protein kinases, HIFA-α; Hypoxia-inducible factor 1-alpha, FOXO1; Fork-head box transcription factors, PDK: Protein 3-phosphoinositide-dependent protein kinase, NLRP: Nucleotide-binding oligomerization domain, MCP: Monocyte Chemo-attractant Protein, TNF-α:Tumor necrosis factor alpha, IL-1β: Interleukin-1 beta.
Figure 6 The diagram shows ROS-induced cardiac hypertrophy through the up-regulation of various pathways. ROS induces the activation of endotjelin-1 protein which in turn causes break down of PIP3 into IP3 and DAG, both of these activates the calcium channels and releases calcium from endoplasmic reticulum. Liberation of Ca from ER inhibits the activation of Calcineurin, also mediated by KMUP-1, and finally causes cardiac hypertrophy through the activation of AP-1DNA binding activity of NFATc4. Moreover, ROS activates HIFI-1, FOXO-α and Myc pathways and leads to the activation of hypertrophic remodeling. ROS also induce cardiac hypertrophy through the opening of mPTP channel, release of cytochrome C and induction of apoptosis of myocardial muscles. Additionally, ROS induces inhibition of P13K, Akt and GSK-3β. All these pathways induce cardiac hypertrophy, where ET-1: Endothelin-1, mPTP: Mitochondrial Permeability Transition Pore, ASK-1: Apoptosis signal-regulating kinase-1, MMP. TIMP: Matrix metalloproteinase/Tissue inhibitors of metalloproteinases, AP-1: Activator protein 1, NF-κβ: Nuclear factor-κ Beta, KATP; ATP-sensitive potassium, NADPH oxidase: Nicotinamide dinucleotide phosphate reduced, p38MAPK; p38 mitogen-activated protein kinases, HIFA-α; Hypoxia-inducible factor 1-alpha, FOXO1; Fork-head box transcription factors, PDK: Protein 3-phosphoinositide-dependent protein kinase, NLRP: Nucleotide-binding oligomerization domain, MCP: Monocyte Chemo-attractant Protein, TNF-α:Tumor necrosis factor alpha, IL-1β: Interleukin-1 beta.CC BY · PubMed Central
Figure 7 The diagram shows the involvement of reactive oxygen species and amyloid β in Alzheimer’s disease, where Aβ; amyloid plaques, NFT: neurofibrillary tangles; AD: Alzheimer’s disease, SOD: superoxide dismutase, CAT: Catalase, APP: Amyloid β (Aβ) precursor protein, GSK3β: Glycogen synthase kinase-3, Wnt-1: Wingless and Int-1, Cdk5: Cyclin-dependent kinase-5, PRx: peroxiredoxin, RCAN1: regulator of calcineurin 1.
Figure 7 The diagram shows the involvement of reactive oxygen species and amyloid β in Alzheimer’s disease, where Aβ; amyloid plaques, NFT: neurofibrillary tangles; AD: Alzheimer’s disease, SOD: superoxide dismutase, CAT: Catalase, APP: Amyloid β (Aβ) precursor protein, GSK3β: Glycogen synthase kinase-3, Wnt-1: Wingless and Int-1, Cdk5: Cyclin-dependent kinase-5, PRx: peroxiredoxin, RCAN1: regulator of calcineurin 1.CC BY · PubMed Central
Figure 8 The diagram shows the role of ROS in Parkinson’s disease through the of dopaminergic neurons. ROS exerts oxidative stress on DNA leads to modification in base and causes fragmentation in DNA. Peroxidative damage in lipids, loss of fatty acids, changes in plasma membrane and degradation of proteins. All these changes damage the dopaminergic neurons, where H2O2: Hydrogen peroxide; ROS: Reactive oxygen species, GSH: Reduced glutathione, GSSG: Oxidized glutathione.
Figure 8 The diagram shows the role of ROS in Parkinson’s disease through the of dopaminergic neurons. ROS exerts oxidative stress on DNA leads to modification in base and causes fragmentation in DNA. Peroxidative damage in lipids, loss of fatty acids, changes in plasma membrane and degradation of proteins. All these changes damage the dopaminergic neurons, where H2O2: Hydrogen peroxide; ROS: Reactive oxygen species, GSH: Reduced glutathione, GSSG: Oxidized glutathione.CC BY · PubMed Central
Figure 9 This diagram represents the role of ROS in the pathogenesis of cardiovascular cardiovascular diseases and contrast-induced nephropathy. Over produced reactive oxygen species such as H2O2, ONOO−, *OH induces oxidative damage on lipids (OxLDL) and CM and leads in the production of Endothelin-1. Endothelin-1along with ROS-mediated inflammation causes arterial stiffness, atherosclerosis, endothelial damage, tissue injury. Among the renal complications it causes renal microcirculation dysfunction, renal medullary ischemia, tubular necrosis and damages glomerular injury. Were, OxLDL: Oxidized low-density lipoproteins, CM: Cell membrane, NO: Nitric oxide, NADPH ox: nicotinamide adenine dinucleotide phosphate oxidase. Note: Upward arrows indicate increase and downward arrows indicate decrease.
Figure 9 This diagram represents the role of ROS in the pathogenesis of cardiovascular cardiovascular diseases and contrast-induced nephropathy. Over produced reactive oxygen species such as H2O2, ONOO−, *OH induces oxidative damage on lipids (OxLDL) and CM and leads in the production of Endothelin-1. Endothelin-1along with ROS-mediated inflammation causes arterial stiffness, atherosclerosis, endothelial damage, tissue injury. Among the renal complications it causes renal microcirculation dysfunction, renal medullary ischemia, tubular necrosis and damages glomerular injury. Were, OxLDL: Oxidized low-density lipoproteins, CM: Cell membrane, NO: Nitric oxide, NADPH ox: nicotinamide adenine dinucleotide phosphate oxidase. Note: Upward arrows indicate increase and downward arrows indicate decrease.CC BY · PubMed Central
Figure 10 This diagram represents the role of reactive oxygen species (ROS) in cellular ageing. ROS-induced oxidative stress-induced damage in DNA (base alteration, fragmentation), peroxidative damage in lipids, protein degradation and inhibition of repair. All these abnormal changes in the cells decrease their working efficiency and causing their ageing. Were, GSH; Reduced glutathione, GSSG: Oxidized glutathione. MDA, TBARS. Note: Dot (.) designates free radical.
Figure 10 This diagram represents the role of reactive oxygen species (ROS) in cellular ageing. ROS-induced oxidative stress-induced damage in DNA (base alteration, fragmentation), peroxidative damage in lipids, protein degradation and inhibition of repair. All these abnormal changes in the cells decrease their working efficiency and causing their ageing. Were, GSH; Reduced glutathione, GSSG: Oxidized glutathione. MDA, TBARS. Note: Dot (.) designates free radical.CC BY · PubMed Central
Figure 11 The diagram reflecting the role of cisplatin and Doxorubicin in the initiation of oxidative stress and molecular changes. Cisplatin activates the CTR1 and OCT2, damage in mitochondria (perforations), release of cytochrome, apoptosis and fragmentation in DNA. Doxorubicin induces the production of superoxides and peroxide production; ROS inhibit the enzymatic activities. Doxorubicin directly binds to the aconitase enzymes, enters into the nucleus and leads the ROS-induced DNA damage, where CRT1: The copper transporter CTR1 regulates1, OCT2; Organic cation transporter 2, PARP: poly (ADP-ribose) polymerase, APf-1: Apoptotic protease factor 1, Cyt C: Cytochrome C, Casp3, 9: Caspase3 and 9, and DSBs: Double-stranded breaks.NH3, Cl, CSE. Note: Dot (.) designates free radical.
Figure 11 The diagram reflecting the role of cisplatin and Doxorubicin in the initiation of oxidative stress and molecular changes. Cisplatin activates the CTR1 and OCT2, damage in mitochondria (perforations), release of cytochrome, apoptosis and fragmentation in DNA. Doxorubicin induces the production of superoxides and peroxide production; ROS inhibit the enzymatic activities. Doxorubicin directly binds to the aconitase enzymes, enters into the nucleus and leads the ROS-induced DNA damage, where CRT1: The copper transporter CTR1 regulates1, OCT2; Organic cation transporter 2, PARP: poly (ADP-ribose) polymerase, APf-1: Apoptotic protease factor 1, Cyt C: Cytochrome C, Casp3, 9: Caspase3 and 9, and DSBs: Double-stranded breaks.NH3, Cl, CSE. Note: Dot (.) designates free radical.CC BY · PubMed Central

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  1. Hajam, 2017, Retrieval of reproductive complications by exogenous melatonin treatment in streptozotocin induced diabetic rat model, Res. Rev. J. Zool. Sci., 5, 96

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Metadata

Authors
Hajam, Y. A., Rani, R., Ganie, S. Y., Sheikh, T. A., Javaid, D., Qadri, S. S., Pramodh, S., Alsulimani, A., Alkhanani, M. F., Harakeh, S., Hussain, A., Haque, S., & Reshi, M. S.
Affiliations
  • Career Point University (IN)
  • Baba Ghulam Shah Badshah University (IN)
  • Zayed University (AE)
  • Jazan University (SA)
  • Almaarefa University (SA)
  • King Abdulaziz University (SA)
  • Manipal Academy of Higher Education, Dubai (AE)
  • Bursa Uludağ Üni̇versi̇tesi̇ (TR)
Corresponding author
  • Hussain, Arif
  • Haque, Shafiul
  • Reshi, Mohd Salim
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-02-05
Volume
11
Issue
3
Pages
552
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11030552
PMC
PMC8833991
OpenAlex
W4210796776
Cited by
915
References
218
Citations by year
2026: 165 · 2025: 330 · 2024: 226 · 2023: 150 · 2022: 44
FWCI
16.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bursa Uludag University - AVESIS (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Funders
  • Jazan University
  • University Grants Commission (/2018)
Topics
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Keywords
oxidative stress, reactive oxygen species, reactive nitrogen species, antioxidants, aging, age-related diseases, cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, cancer, antioxidant enzymes, oxidative stress signaling
MeSH terms
Aging, Humans, Reactive Oxygen Species, Oxidative Stress

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