Age-Related Nuclear Translocation of P2X6 Subunit Modifies Splicing Activity Interacting with Splicing Factor 3A1

Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys–Drash syndrome and pre-eclampsia). Administration of recombinant VEGF165b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGFxxxb isoforms to the pro-angiogenic VEGFxxx isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGFxxxb isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.

Download Full-text

Longevity strategies in response to light in the reef coral Stylophora pistillata

Scientific Reports ◽

10.1038/s41598-020-76925-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Alexandre Ottaviani ◽

Rita Eid ◽

Didier Zoccola ◽

Mélanie Pousse ◽

Jean-Marc Dubal ◽

...

Keyword(s):

Healthy Aging ◽

Nuclear Translocation ◽

Human Fibroblasts ◽

Reef Coral ◽

Biological Response ◽

Skin Aging ◽

Stylophora Pistillata ◽

Reef Corals ◽

Effective Interventions ◽

Age Related

AbstractAging is a multifactorial process that results in progressive loss of regenerative capacity and tissue function while simultaneously favoring the development of a large array of age-related diseases. Evidence suggests that the accumulation of senescent cells in tissue promotes both normal and pathological aging. Oxic stress is a key driver of cellular senescence. Because symbiotic long-lived reef corals experience daily hyperoxic and hypoxic transitions, we hypothesized that these long-lived animals have developed specific longevity strategies in response to light. We analyzed transcriptome variation in the reef coral Stylophora pistillata during the day–night cycle and revealed a signature of the FoxO longevity pathway. We confirmed this pathway by immunofluorescence using antibodies against coral FoxO to demonstrate its nuclear translocation. Through qPCR analysis of nycthemeral variations of candidate genes under different light regimens, we found that, among genes that were specifically up- or downregulated upon exposure to light, human orthologs of two “light-up” genes (HEY1 and LONF3) exhibited anti-senescence properties in primary human fibroblasts. Therefore, these genes are interesting candidates for counteracting skin aging. We propose a large screen for other light-up genes and an investigation of the biological response of reef corals to light (e.g., metabolic switching) to elucidate these processes and identify effective interventions for promoting healthy aging in humans.

Download Full-text

Flavonoid-Rich Ethanol Extract from the Leaves of Diospyros kaki Attenuates D-Galactose-Induced Oxidative Stress and Neuroinflammation-Mediated Brain Aging in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8938207 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Yingjuan Ma ◽

Bin Ma ◽

Yuying Shang ◽

Qingqing Yin ◽

Dejie Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Nuclear Translocation ◽

Brain Aging ◽

Ethanol Extract ◽

Neurological Impairment ◽

Diospyros Kaki ◽

Neuroprotective Effects ◽

Age Related ◽

Y Maze

Aging is a major factor that contributes to neurological impairment and neuropathological changes, such as inflammation, oxidative stress, neuronal apoptosis, and synaptic dysfunction. Flavonoids act as protective antioxidant and anti-inflammatory agents against various age-related neurodegenerative diseases. Here, we investigated the protective effect and mechanisms of the flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FELDK) in the cortex and hippocampus of D-galactose- (gal-) aged mice. Our results showed that FELDK treatment restored memory impairment in mice as determined by the Y-maze and Morris water maze tests. FELDK decreased oxidative stress levels via inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production and elevating antioxidative enzymes. FELDK also alleviated D-gal-induced neuroinflammation via suppressing the expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) and activating microgliosis and astrocytosis, nuclear factor kappa B (NF-κB) nuclear translocation, and downstream inflammatory mediators. Moreover, FELDK inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and C-jun N-terminal kinase (JNK) apoptotic signaling pathways and ameliorated the impairment of synapse-related proteins. Hence, these results indicate that FELDK exerts neuroprotective effects on D-gal-induced brain aging. Thus, FELDK may be a potential therapeutic strategy for preventing and treating age-related neurodegenerative diseases such as Alzheimer’s disease.

Download Full-text

Estrogen receptor-β regulates mechanical signaling in primary osteoblasts

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00458.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. E937-E944 ◽

Cited By ~ 20

Author(s):

Alesha B. Castillo ◽

Jason W. Triplett ◽

Fredrick M. Pavalko ◽

Charles H. Turner

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptors ◽

Fluid Shear Stress ◽

Nuclear Translocation ◽

Estrogen Receptor Α ◽

Bone Adaptation ◽

Mitogen Activated Protein Kinase ◽

Prostaglandin E ◽

Mechanical Signaling ◽

Age Related

Mechanical loading is an important regulator in skeletal growth, maintenance, and aging. Estrogen receptors have a regulatory role in mechanically induced bone adaptation. Estrogen receptor-α (ERα) is known to enhance load-induced bone formation, whereas ERβ negatively regulates this process. We hypothesized that ERβ regulates mechanical signaling in osteoblasts. We tested this hypothesis by subjecting primary calvarial cells isolated from wild-type and ERβ-knockout mice (BERKO) to oscillatory fluid flow in the absence or presence of estradiol (E2). We found that the known responses to fluid shear stress, i.e., phosphorylation of the mitogen-activated protein kinase ERK and upregulation of COX-2 expression, were inhibited in BERKO cells in the absence of E2. Flow-induced increase in prostaglandin E2 (PGE2) release was not altered in BERKO cells in the absence of E2, but was increased when E2 was present. Additionally, immunofluorescence analysis and estrogen response element luciferase assays revealed increased ERα expression and flow- and ligand-induced nuclear translocation as well as transcriptional activity in BERKO cells in both the presence and absence of E2. Taken together, these data suggest that ERβ plays both ligand-dependent and ligand-independent roles in mechanical signaling in osteoblasts. Furthermore, our data suggest that one mechanism by which ERβ regulates mechanotransduction in osteoblasts may result from its inhibitory effect on ERα expression and function. Targeting estrogen receptors (e.g., inhibiting ERβ) may represent an effective approach for prevention and treatment of age-related bone loss.

Download Full-text

Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8067592 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 15

Author(s):

Caterina Miceli ◽

Yohan Santin ◽

Nicola Manzella ◽

Raffaele Coppini ◽

Andrea Berti ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Monoamine Oxidase A ◽

Autophagic Flux ◽

Cytotoxic Effects ◽

Beneficial Effects ◽

Age Related ◽

Autophagy Induction ◽

Mao A ◽

Potential Use

Age-associated diseases such as neurodegenerative and cardiovascular disorders are characterized by increased oxidative stress associated with autophagy dysfunction. Oleuropein aglycone (OA), the main polyphenol found in olive oil, was recently characterized as an autophagy inducer and a promising agent against neurodegeneration. It is presently unknown whether OA can have beneficial effects in a model of cardiac stress characterized by autophagy dysfunction. Here, we explored the effects of OA in cardiomyocytes with overexpression of monoamine oxidase-A (MAO-A). This enzyme, by degrading catecholamine and serotonin, produces hydrogen peroxide (H2O2), which causes oxidative stress, autophagic flux blockade, and cell necrosis. We observed that OA treatment counteracted the cytotoxic effects of MAO-A through autophagy activation, as displayed by the increase of autophagic vacuoles and autophagy-specific markers (Beclin1 and LC3-II). Moreover, the decrease in autophagosomes and the increase in autolysosomes, indicative of autophagosome-lysosome fusion, suggested a restoration of the defective autophagic flux. Most interestingly, we found that the ability of OA to confer cardioprotection through autophagy induction involved nuclear translocation and activation of the transcriptional factor EB (TFEB). Our data provide strong evidence of the beneficial effects of OA, suggesting its potential use as a nutraceutical agent against age-related pathologies involving autophagy dysfunction, including cardiovascular diseases.

Download Full-text

FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Protects against Oxidative Stress-Mediated Neuronal Cell Apoptosis and Scopolamine-Induced Cognitive Impairment by Activating Nrf2/HO-1 Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8239642 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21 ◽

Cited By ~ 5

Author(s):

Ting Wan ◽

Zihao Wang ◽

Yi Luo ◽

Yifan Zhang ◽

Wei He ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Caffeic Acid ◽

Cell Apoptosis ◽

Nuclear Translocation ◽

Neurodegenerative Disorder ◽

Neuronal Cell ◽

Caffeic Acid Phenethyl Ester ◽

Therapeutic Drug ◽

Age Related

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4-O-glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H2O2-induced apoptosis in SH-SY5Y and PC12 cells and suppresses H2O2-induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD.

Download Full-text

Gosha-jinki-Gan (GJG) shows anti-aging effects through suppression of TNF-α production by Chikusetsusaponin V

10.21203/rs.3.rs-189204/v1 ◽

2021 ◽

Author(s):

Keisuke Hagihara ◽

Kazuto Nunomura ◽

Bangzhong Lin ◽

Megumi Fumimoto ◽

Junko Watanabe ◽

...

Keyword(s):

Chronic Pain ◽

Nuclear Translocation ◽

Horse Serum ◽

Digital Pcr ◽

C2c12 Cells ◽

Raw264.7 Cells ◽

Aging Effects ◽

Age Related ◽

Tnf Α ◽

Nervous System Function

Abstract Frailty develops due to multiple factors, such as sarcopenia, chronic pain, and dementia. Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine used for age-related symptoms. We have reported that GJG improved sarcopenia, chronic pain, and central nervous system function through suppression of TNF-α production. In the present study, GJG was found to reduce the production of TNF-α in the soleus muscle of senescence-accelerated mice at 12 weeks and 36 weeks. GJG did not change the differentiation of C2C12 cells with 2% horse serum. GJG significantly decreased the expression of MAFbx induced by TNF-α in C2C12 cells on real-time PCR. TNF-α significantly decreased the expression of PGC-1α and negated the enhancing effect of GJG for the expression of PGC-1α on digital PCR. Examining 20 chemical compounds derived from GJG, cinnamaldehyde from cinnamon bark and Chikusetsusaponin V (CsV) from Achyrantes Root dose-dependently decreased the production of TNF-⍺ in RAW264.7 cells stimulated by LPS. CsV inhibited the nuclear translocation of NF-κB p65 in RAW264.7 cells. CsV showed low permeability using Caco-2 cells. However, the plasma concentration of CsV was detected from 30 minutes to 6 h and peaked at 1 h in the CD1 (ICR) mice after a single dose of GJG. In 8-week-old SAMP8 mice fed 4% (w/w) GJG from one week to four weeks, the plasma CsV concentration ranged from 0.0500 to 10.0 ng/mL. The evidence that CsV plays an important role in various anti-aging effects of GJG via suppression of TNF-⍺ expression is presented.

Download Full-text

Piceatannol Protects Human Retinal Pigment Epithelial Cells against Hydrogen Peroxide Induced Oxidative Stress and Apoptosis through Modulating PI3K/Akt Signaling Pathway

Nutrients ◽

10.3390/nu11071515 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1515 ◽

Cited By ~ 5

Author(s):

Yiming Hao ◽

Jie Liu ◽

Ziyuan Wang ◽

Liangli (Lucy) Yu ◽

Jing Wang

Keyword(s):

Hydrogen Peroxide ◽

Nuclear Translocation ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Pigment Epithelium Cell ◽

Retinal Pigment Epithelial Cells ◽

Age Related Macular Degeneration ◽

Ros Generation ◽

Related Factor ◽

Age Related

This study investigated the protective effect and the molecular mechanism of piceatannol on hydrogen peroxide (H2O2)-induced retinal pigment epithelium cell (ARPE-19) damage. Piceatannol treatment significantly inhibited H2O2-induced RPE cell death and reactive oxygen species (ROS) generation by 64.4% and 75.0%, respectively. Results of flow cytometry showed that H2O2-induced ARPE-19 cells apoptosis was ameliorated by piceatannol supplementation, along with decreased relative protein expressions of Bax/Bcl-2, Cleave-Caspase-3, and Cleave-PARP. Moreover, piceatannol treatment induced NF-E2-related factor 2 (Nrf2) signaling activation, which was evidenced by increased transcription of anti-oxidant genes, glutamate-cysteine ligase catalytic subunit (GCLc), SOD, and HO-1. Knockdown of Nrf2 through targeted siRNA alleviated piceatannol-mediated HO-1 transcription, and significantly abolished piceatannol-mediated cytoprotection. LY294002 (PI3K inhibitor) dramatically blocked piceatannol-mediated increasing of Nrf2 nuclear translocation, HO-1 expression, and cytoprotective activity, indicating the involvement of PI3K/Akt pathway in the cytoprotective effect of piceatannol. The results from this suggest the potential of piceatannol in reducing the risk of age-related macular degeneration.

Download Full-text

Silencing of lncRNA AK045490 Promotes Osteoblast Differentiation and Bone Formation via β-Catenin/TCF1/Runx2 Signaling Axis

International Journal of Molecular Sciences ◽

10.3390/ijms20246229 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6229 ◽

Cited By ~ 5

Author(s):

Dijie Li ◽

Ye Tian ◽

Chong Yin ◽

Ying Huai ◽

Yipu Zhao ◽

...

Keyword(s):

Bone Formation ◽

Osteogenic Differentiation ◽

Noncoding Rna ◽

Osteoblast Differentiation ◽

Nuclear Translocation ◽

Mice Model ◽

Structural Deterioration ◽

Age Related

Osteoporosis, a disease characterized by both loss of bone mass and structural deterioration of bone, is the most common reason for a broken bone among the elderly. It is known that the attenuated differentiation ability of osteogenic cells has been regarded as one of the greatest contributors to age-related bone formation reduction. However, the effects of current therapies are still unsatisfactory. In this study we identify a novel long noncoding RNA AK045490 which is correlated with osteogenic differentiation and enriched in skeletal tissues of mice. In vitro analysis of bone-derived mesenchymal stem cells (BMSCs) showed that AK045490 inhibited osteoblast differentiation. In vivo inhibition of AK045490 by its small interfering RNA rescued bone formation in ovariectomized osteoporosis mice model. Mechanistically, AK045490 inhibited the nuclear translocation of β-catenin and downregulated the expression of TCF1, LEF1, and Runx2. The results suggest that Lnc-AK045490 suppresses β-catenin/TCF1/Runx2 signaling and inhibits osteoblast differentiation and bone formation, providing a novel mechanism of osteogenic differentiation and a potential drug target for osteoporosis.

Download Full-text