The overexpression of Tipe2 in CRC cells suppresses survival while endogenous Tipe2 accelerates AOM/DSS induced-tumor initiation

AbstractAging is a natural and progressive process characterized by an increased frequency of age-related diseases such as cancer. But its mechanism is unclear. TNFAIP8L2 (Tipe2) is an important negative regulator for homeostasis through inhibiting TLR and TCR signaling. Our work reveals that Tipe2 might have dual function by regulating senescence. One side, the overexpression of Tipe2 in CRC cells could induce typical senescent phenotype, especially exposure to oxidative stress. Tipe2 inhibits telomerase activity by regulating c-Myc and c-Est-2 binding to the hTERT promotor. Interestingly, Tipe2 KO mice treated with D-Gal showed a less serious inverse of CD4:CD8 ratio, a lower percentage of Treg compared to WT. Besides, Tipe2 KO mice were more tolerant to the initiation of AOM/DSS-induced CRC, accompanied by a lower level of Treg within IEL. Therefore, specific antibodies against CD25 effectively ameliorate tumorigenesis. These data suggest strongly that the overexpressed Tipe2 suppresses tumor cells proliferation and survival, but endogenous Tipe2 promotes the initiation of tumorigenesis when exposure to dangerous environment such as AOM/DSS-related inflammation.

Download Full-text

Thioredoxin Binding Protein-2 Regulates Autophagy of Human Lens Epithelial Cells under Oxidative Stress via Inhibition of Akt Phosphorylation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/4856431 ◽

2016 ◽

Vol 2016 ◽

pp. 1-17 ◽

Cited By ~ 5

Author(s):

Jiaojie Zhou ◽

Ke Yao ◽

Yidong Zhang ◽

Guangdi Chen ◽

Kairan Lai ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Cell Viability ◽

Binding Protein ◽

Negative Regulator ◽

Human Lens ◽

Lens Epithelial Cells ◽

Human Lens Epithelial Cells ◽

Age Related

Oxidative stress plays an essential role in the development of age-related cataract. Thioredoxin binding protein-2 (TBP-2) is a negative regulator of thioredoxin (Trx), which deteriorates cellular antioxidant system. Our study focused on the autophagy-regulating effect of TBP-2 under oxidative stress in human lens epithelial cells (LECs). Human lens epithelial cells were used for cell culture and treatment. Lentiviral-based transfection system was used for overexpression of TBP-2. Cytotoxicity assay, western blot analysis, GFP/mCherry-fused LC3 plasmid, immunofluorescence, and transmission electronic microscopy were performed. The results showed that autophagic response of LECs with increased LC3-II, p62, and GFP/mCherry-LC3 puncta (P<0.01) was induced by oxidative stress. Overexpression of TBP-2 further strengthens this response and worsens the cell viability (P<0.01). Knockdown of TBP-2 attenuates the autophagic response and cell viability loss induced by oxidative stress. TBP-2 mainly regulates autophagy in the initiation stage, which is mTOR-independent and probably caused by the dephosphorylation of Akt under oxidative stress. These findings suggest a novel role of TBP-2 in human LECs under oxidative stress. Oxidative stress can cause cell injury and autophagy in LECs, and TBP-2 regulates this response. Hence, this study provides evidence regarding the role of TBP-2 in lens and the possible mechanism of cataract development.

Download Full-text

Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-020-00053-4 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Tetsuya Oishi ◽

Daisuke Matsumaru ◽

Nao Ota ◽

Hiroshi Kitamura ◽

Tianxiang Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Target Genes ◽

Negative Regulator ◽

Nrf2 Pathway ◽

Expression Levels ◽

Age Related ◽

Pathway Activation ◽

Brainstem Response ◽

Age Related Hearing Loss

AbstractAge-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.

Download Full-text

α2-Antiplasmin as a potential regulator of the spatial memory process and age-related cognitive decline

Molecular Brain ◽

10.1186/s13041-020-00677-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Eri Kawashita ◽

Keiichi Ishihara ◽

Haruko Miyaji ◽

Yu Tanishima ◽

Akiko Kiriyama ◽

...

Keyword(s):

Oxidative Stress ◽

Spatial Memory ◽

Cognitive Decline ◽

Brain Aging ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Negative Regulator ◽

Memory Process ◽

Age Related ◽

Brain Oxidative Stress

Abstract α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is also expressed in several parts of the brain, including the hippocampus and cerebral cortex. Our previous study demonstrated that α2AP knockout mice exhibit spatial memory impairment in comparison to wild-type mice, suggesting that α2AP is necessary for the fetal and/or neonatal development of the neural network for spatial memory. However, it is still unclear whether α2AP plays a role in the memory process. The present study demonstrated that adult hippocampal neurogenesis and remote spatial memory were enhanced by the injection of an anti-α2AP neutralizing antibody in WT mice, while the injection of α2AP reduced hippocampal neurogenesis and impaired remote spatial memory, suggesting that α2AP is a negative regulator in memory processing. The present study also found that the levels of α2AP in the brains of old mice were higher than those in young mice, and a negative correlation between the α2AP level and spatial working memory. In addition, aging-dependent brain oxidative stress and hippocampal inflammation were attenuated by α2AP deficiency. Thus, an age-related increase in α2AP might cause cognitive decline accompanied by brain oxidative stress and neuroinflammation. Taken together, our findings suggest that α2AP is a key regulator of the spatial memory process, and that it may represent a promising target to effectively regulate healthy brain aging.

Download Full-text

Senescent Phenotype of Astrocytes Leads to Microglia Activation and Neuronal Death

10.21203/rs.3.rs-1186816/v1 ◽

2021 ◽

Author(s):

You Wen Zhang ◽

Xuehan Yang ◽

Jingyue Liu ◽

Yichen Pan ◽

Ming Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Brain Aging ◽

Cell Model ◽

Neurological Diseases ◽

Ion Homeostasis ◽

Senescent Phenotype ◽

Age Related ◽

The Central Nervous System ◽

Aged Subjects

Abstract Astrocyte, the most abundant cell type in the central nervous system, is increasingly recognized and is thought to depend on curial and diverse roles in maintaining brain homeostasis, the blood-brain barrier, ion homeostasis, secrete neurotrophic factors and regulate synaptic transmission which is essential to tune individual-to-network neuronal activity. Senescence in astrocytes has been discovered to be an important contributor to several age-related neurological diseases like Alzheimer's and Parkinson's disease. However, the latest research about astrocytes from aged subjects or aged astrocytes in vitro is not yet adequate to be well elucidated on their curial process in the regulation of brain function. In this study, an in vitro cell model of aged astrocytes was constructed by serial passaging until passage 20-25, and those passages within 1-5 were used as young astrocytes. Meanwhile, oxidative induced astrocyte senescence model was also constructed by H2O2 induction. Our results indicate that after serial passaging or oxidative stress-induced astrocytes, all showed manifest changes in several established markers of cellular senescence like P53, P21, the release of inflammatory cytokine IL-6 and SA-β-gal positive cells. Results also showed mitochondrial dysfunction in the oxidative stress-induced astrocyte senescence model and treatment of berberine could reverse these alterations. What’s more interests us is that those two types of senescent astrocytes’ conditioned medium co-cultured with neuronal cells could do impact on neuron apoptosis no matter in direct or indirect ways. This study may help us better understand the fundamental role of astrocyte senescence on the regulation of normal and pathological brain aging.

Download Full-text

Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain

Molecules ◽

10.3390/molecules26164794 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4794

Author(s):

Tarek Benameur ◽

Raffaella Soleti ◽

Maria Antonietta Panaro ◽

Maria Ester La Torre ◽

Vincenzo Monda ◽

...

Keyword(s):

Oxidative Stress ◽

Positive Impact ◽

Curcuma Longa ◽

Telomerase Activity ◽

Modern Medicine ◽

Low Grade ◽

Age Related ◽

Reduce Tumor Growth ◽

External Stimuli ◽

The Brain

The nutrients and their potential benefits are a new field of study in modern medicine for their positive impact on health. Curcumin, the yellow polyphenolic compound extracted from Curcuma longa species, is widely used in traditional Ayurvedic medicine to prevent and contrast many diseases, considering its antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephron-protective, hepato-protective, anti-neoplastic, and anti-rheumatic proprieties. In recent years, the investigations of curcumin have been focused on its application to aging and age-associated diseases. Aging is a physiological process in which there is a decreasing of cellular function due to internal or external stimuli. Oxidative stress is one of the most important causes of aging and age-related diseases. Moreover, many age-related disorders such as cancer, neuroinflammation, and infections are due to a low-grade chronic systemic inflammation. Curcumin acting on different proteins is able to contrast both oxidative stress than inflammation. In the brain, curcumin is able to modulate inflammation induced by microglia. Finally in brain tumors curcumin is able to reduce tumor growth by inhibition of telomerase activity. This review emphasizes the anti-aging role of curcumin focusing on its mechanism to counteract aging in the brain. Moreover, new formulations to increase the bioavailability of curcumin are discussed.

Download Full-text

Age-Related Changes in Activation of Mitogen-Activated Protein Kinase Cascades by Oxidative Stress

Journal of Investigative Dermatology ◽

10.1038/jidsp.1998.7 ◽

1998 ◽

Vol 3 (1) ◽

pp. 23-27 ◽

Cited By ~ 9

Author(s):

Kathryn Z Guyton ◽

Myriani Gorospe ◽

Xiantao Wang ◽

Yolanda D Mock ◽

Gertrude C Kokkonen ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Age Related ◽

Mitogen Activated Protein ◽

Age Related Changes

Download Full-text

Oxidative Stress, Ocular Disease and Diabetes Retinopathy

Current Pharmaceutical Design ◽

10.2174/1381612825666190115121531 ◽

2019 ◽

Vol 24 (40) ◽

pp. 4726-4741 ◽

Cited By ~ 8

Author(s):

Orathai Tangvarasittichai ◽

Surapon Tangvarasittichai

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Cell Death ◽

Protein Modification ◽

Morphological Changes ◽

Corneal Dystrophy ◽

Age Related Macular Degeneration ◽

Ocular Diseases ◽

Retinal Light Damage ◽

Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

Download Full-text

Zone-specific damage of the olfactory epithelium under protein restriction

Scientific Reports ◽

10.1038/s41598-020-79249-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ayinuer Tuerdi ◽

Shu Kikuta ◽

Makoto Kinoshita ◽

Teru Kamogashira ◽

Kenji Kondo ◽

...

Keyword(s):

Oxidative Stress ◽

Olfactory Epithelium ◽

Control Diet ◽

Intervention Strategy ◽

Protein Restriction ◽

Outer Hair Cells ◽

Basal Cells ◽

Cell Dynamics ◽

Age Related ◽

Positive Effect

AbstractOxidative stress causes tissue damage, affecting age-related pathologies. Protein restriction (PR) provides a powerful intervention strategy for reducing oxidative stress, which may have a positive effect on individual organs. However, it is unknown whether PR intervention influences the olfactory system. Here, we investigated how 10 months of PR could affect the cell dynamics of the olfactory epithelium (OE) in mice. We found that PR reduced age-related loss of outer hair cells in the cochlea, providing preventive effects against age-related hearing loss. In contrast, PR resulted in reduced mature olfactory sensory neurons (OSNs), increased proliferative basal cells, and increased apoptotic OSNs in zone 1 (the only area containing neurons expressing NQO1 [quinone dehydrogenase 1]) of the OE in comparison with animals given a control diet. Substantial oxidative stress occurred in NQO1-positive cells and induced apoptotic OSNs in zone 1. These results indicate that in contrast to the positive effect on the auditory system, PR induces oxidative stress and structurally and functionally negative effects on OSNs in zone 1, which is probably involved in the bioactivation of NQO1.

Download Full-text

Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview

Antioxidants ◽

10.3390/antiox10040507 ◽

2021 ◽

Vol 10 (4) ◽

pp. 507

Author(s):

Rosaria Meccariello ◽

Stefania D’Angelo

Keyword(s):

Oxidative Stress ◽

Food Sources ◽

Preventive Action ◽

Nutritional Interventions ◽

Beneficial Effects ◽

Age Related ◽

Macromolecular Damage ◽

And Oxidative Stress

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.

Download Full-text

Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽

10.3390/antiox10010025 ◽

2020 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Lara Macchioni ◽

Davide Chiasserini ◽

Letizia Mezzasoma ◽

Magdalena Davidescu ◽

Pier Luigi Orvietani ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factor ◽

Nuclear Factor ◽

Rpe Cells ◽

Age Related ◽

Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

Download Full-text