scholarly journals Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

2020 ◽  
Vol 22 (1) ◽  
pp. 37
Author(s):  
Rizwan Qaisar ◽  
Gavin Pharaoh ◽  
Shylesh Bhaskaran ◽  
Hongyang Xu ◽  
Rojina Ranjit ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Negative Impact ◽  
The Elderly ◽  
Mapk Signaling ◽  
Age Related ◽  
Mitochondrial Ros ◽  
Significant Negative Impact ◽  
Cellular Energetics ◽  
Gastrocnemius Muscles

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.

scholarly journals Species-Specific Impact of Fusarium Infection on the Root and Shoot Characteristics of Asparagus

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 509 ◽  
Author(s):  
Roxana Djalali Farahani-Kofoet ◽  
Katja Witzel ◽  
Jan Graefe ◽  
Rita Grosch ◽  
Rita Zrenner
Keyword(s):  
Negative Impact ◽  
Fusarium Species ◽  
Asparagus Officinalis ◽  
Root Characteristics ◽  
Disease Symptoms ◽  
Flight Mass Spectrometry ◽  
Significant Negative Impact ◽  
Species Specific ◽  
Specific Impact

Soil-borne pathogens can have considerable detrimental effects on asparagus (Asparagus officinalis) growth and production, notably caused by the Fusarium species F. oxysporum f.sp. asparagi, F. proliferatum and F. redolens. In this study, their species-specific impact regarding disease severity and root morphological traits was analysed. Additionally, various isolates were characterised based on in vitro physiological activities and on protein extracts using matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). The response of two asparagus cultivars to the different Fusarium species was evaluated by inoculating experiments. Differences in aggressiveness were observed between Fusarium species and their isolates on roots, while no clear disease symptoms became visible in ferns eight weeks after inoculation. F. redolens isolates Fred1 and Fred2 were the most aggressive strains followed by the moderate aggressive F. proliferatum and the less and almost non-aggressive F. oxysporum isolates, based on the severity of disease symptoms. Fungal DNA in stem bases and a significant induction of pathogenesis-related gene expression was detectable in both asparagus cultivars. A significant negative impact of the pathogens on the root characteristics total root length, volume, and surface area was detected for each isolate tested, with Fred1 causing the strongest effects. No significant differences between the tested asparagus cultivars were observed.

scholarly journals Glycation and Oxidative Stress Increase Autoantibodies in the Elderly

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3675
Author(s):  
Mohd W.A. Khan ◽  
Ahmed Al Otaibi ◽  
Subuhi Sherwani ◽  
Wahid A. Khan ◽  
Eida M. Alshammari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
The Elderly ◽  
Significant Inhibition ◽  
Group Iv ◽  
Blood Proteins ◽  
Age Related ◽  
Direct Binding ◽  
Asymptomatic Individuals ◽  
Immune Imbalance

Aging causes gradual changes in free radicals, antioxidants, and immune-imbalance in the elderly. This study aims to understand links among aging, gluco-oxidative stress, and autoantibodies in asymptomatic individuals. In vitro glycation of human serum albumin (Gly-HSA) induces appreciable biochemical changes. Significant inhibition of advanced glycation end products (AGEs) formation was achieved using garlic extract (53.75%) and epigallocatechin-3-gallate from green tea (72.5%). Increased amounts of serum carbonyl content (2.42 ± 0.5) and pentosidine (0.0321 ± 0.0029) were detected in IV-S (S represent smokers) vs. IV group individuals. Direct binding ELISA results exhibited significantly high autoantibodies against Gly-HSA in group IV-S (0.55 ± 0.054; p < 0.001) and III-S (0.40 ± 0.044; p < 0.01) individuals as compared to the age matched subjects who were non-smokers (group IV and III). Moreover, high average percent inhibition (51.3 ± 4.1%) was obtained against Gly-HSA in IV-S group individuals. Apparent association constant was found to be high for serum immunoglobulin-G (IgG) from group IV-S (1.18 × 10−6 M) vs. serum IgG from IV group (3.32 × 10−7 M). Aging induced gluco-oxidative stress and AGEs formation may generate neo-epitopes on blood-proteins, contributing to production of autoantibodies in the elderly, especially smokers. Use of anti-glycation natural products may reduce age-related pathophysiological changes.

scholarly journals Age-dependent effect of oxidative stress on cardiac sarcoplasmic reticulum vesicles

2008 ◽  
pp. S49-S54
Author(s):  
E Babušíková ◽  
M Jeseňák ◽  
D Dobrota ◽  
N Tribulová ◽  
P Kaplán
Keyword(s):  
Oxidative Stress ◽  
Sarcoplasmic Reticulum ◽  
Oxidative Damage ◽  
Structural Changes ◽  
Membrane Surface ◽  
Thiobarbituric Acid ◽  
Surface Hydrophobicity ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Age Related

The oxidative stress hypothesis of aging suggests that accumulation of oxidative damage is a key factor of the alterations in physiological function during aging. We studied age-related sensitivity to oxidative modifications of proteins and lipids of cardiac sarcoplasmic reticulum (SR) isolated from 6-, 15- and 26-month-old rats. Oxidative stress was generated in vitro by exposing SR vesicles to 0.1 mmol/l FeSO4/EDTA + 1 mmol/l H2O2 at 37 degrees C for 60 min. In all groups, oxidative stress was associated with decreased membrane surface hydrophobicity, as detected by 1-anilino-8-naphthalenesulfonate as a probe. Structural changes in SR membranes were accompanied by degradation of tryptophan and significant accumulation of protein dityrosines, protein conjugates with lipid peroxidation products, conjugated dienes and thiobarbituric acid reactive substances. The sensitivity to oxidative damage was most pronounced in SR of 26-month-old rat. Our results indicate that aging and oxidative stress are associated with accumulation of oxidatively damaged proteins and lipids and these changes could contribute to cardiovascular injury.

scholarly journals HGG-15. THE IMIPRIDONE ONC201 IN COMBINATION WITH THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD HAS A SYNERGISTIC EFFECT IN PRECLINICAL MODELS OF PHGGS AND DMGS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i20-i20
Author(s):  
Daniel de la Nava ◽  
Iker Ausejo-Mauleon ◽  
Virginia Laspidea ◽  
Lucía Marrodán ◽  
Marta Zalacain ◽  
...  
Keyword(s):  
Overall Survival ◽  
Negative Impact ◽  
Pediatric Brain Tumors ◽  
Therapeutic Benefit ◽  
In Vitro Cytotoxicity ◽  
Preclinical Models ◽  
Poor Overall Survival ◽  
Significant Negative Impact

Abstract Pediatric High Grade Gliomas (pHGGs), including Diffuse Midline Gliomas (DMGs), are aggressive pediatric tumors with a poor overall survival. In the last years, ONC201 has emerged as a promising agent in the field of pediatric brain tumors. Another interesting approach is virotherapy; Delta-24-RGD, which is an oncolytic virus, has demonstrated safety and effectiveness in different preclinical models and in clinical trials. Therefore, in this work we set to evaluate whether the combination of ONC201 with Delta-24-RGD could result in an increased therapeutic benefit in pHGGs and DMGs. Given that ONC201 targets mitochondrial metabolism in a preclinical setting, we assessed potential negative interactions of the combination therapy. While ONC201 treatment resulted in decreased viral protein load (E1A and fiber), there was no significant negative impact on the viral replication (measured by hexon staining). ONC201 did not disrupt the activation of mTORC1 pathway by the adenovirus. Furthermore, Delta-24-RGD did not affect the decrease in basal oxygen consumption rate induced by ONC201. Our results suggested that ONC201 and Delta-24-RGD are not antagonistic. Evaluation of the in vitro cytotoxicity in different human pHGG (CHLA-03-AA and SF188) and DMG (TP-54 and SU-DIPG-IV) cell lines showed that the combination treatment was significantly better that either agent alone. In vivo, a single local injection of Delta-24-RGD followed by a weekly ONC201 of mice bearing CHLA-03-AA cell line orthotopically significantly increased the median overall survival (PBS: 48 days; ONC201: 54.5 days; Delta-24-RGD: 62 days; ONC201+Delta-24-RGD: 95 days (P=0.0008)) of these mice leading to 20% long-term survivors, free of disease. Currently, we are evaluating the effect of the combination in immunosuppressed and immunocompetent models of DMGs. In summary, our data indicate ONC201 in combination with Delta-24-RGD could be a potential therapeutic choice for patients affected by pHGGs and DMGs.

scholarly journals MicroRNA-182-5p protects human lens epithelial cells against oxidative stress-induced apoptosis by inhibiting NOX4 and p38 MAPK signalling

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhao-Na Li ◽  
Ming-Xu Ge ◽  
Zhong-Fang Yuan
Keyword(s):  
Epithelial Cells ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Luciferase Reporter Gene ◽  
Age Related ◽  
Induced Apoptosis

Abstract Background MicroRNAs (miRNAs) are abnormally expressed in various ocular diseases, including age-related cataract. However, the role of miR-182-5p in the progression of age-related cataract remains unclear. Methods The expression of miR-182-5p in HLE-B3 cells was detected by qRT-PCR. HLE-B3 cells were transfected with miR-182-5p mimics. CCK-8, EdU, flow cytometry, 2′,7′-dichlorodihydrofluorescein diacetate, JC-1 kit, and western blot were used to assess the cell viability, proliferation, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and protein expression, respectively, in vitro. The relationship between miR-182-5p and NOX4 was confirmed using the dual-luciferase reporter gene analysis. Results We found that miR-182-5p expression was significantly decreased by the H2O2 exposure. Overexpression of miR-182-5p promoted cell proliferation and inhibited ROS production and apoptosis in H2O2-induced HLE-B3 cells. Moreover, p-p-38, p-ERK, and p-JNK were up-regulated in H2O2-treated HLE-B3 cells, and overexpression of miR-182-5p reversed the effects of H2O2 on HLE-B3 cells. In addition, dual-luciferase reporter assay substantiated that NOX4 was a direct target and downregulated by miR-182-5p. Conclusions We concluded that miR-182-5p inhibited lens epithelial cells apoptosis through regulating NOX4 and p38 MAPK signaling, providing a novel biomarker for treatment of age-related cataract.

scholarly journals Ageing and the border between health and disease

2014 ◽  
Vol 44 (5) ◽  
pp. 1332-1352 ◽  
Author(s):  
William MacNee ◽  
Roberto A. Rabinovich ◽  
Gourab Choudhury
Keyword(s):  
Negative Impact ◽  
Inflammatory Diseases ◽  
The Elderly ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Progressive Degeneration ◽  
Age Related ◽  
Chronic Pulmonary Diseases ◽  
Health And Disease ◽  
And Function

Ageing is associated with a progressive degeneration of the tissues, which has a negative impact on the structure and function of vital organs and is among the most important known risk factors for most chronic diseases. Since the proportion of the world’s population aged >60 years will double in the next four decades, this will be accompanied by an increased incidence of chronic age-related diseases that will place a huge burden on healthcare resources.There is increasing evidence that many chronic inflammatory diseases represent an acceleration of the ageing process. Chronic pulmonary diseases represents an important component of the increasingly prevalent multiple chronic debilitating diseases, which are a major cause of morbidity and mortality, particularly in the elderly. The lungs age and it has been suggested that chronic obstructive pulmonary disease (COPD) is a condition of accelerated lung ageing and that ageing may provide a mechanistic link between COPD and many of its extrapulmonary effects and comorbidities. In this article we will describe the physiological changes and mechanisms of ageing, with particular focus on the pulmonary effects of ageing and how these may be relevant to the development of COPD and its major extrapulmonary manifestations.

scholarly journals Immunosenescence of Polymorphonuclear Neutrophils

2010 ◽  
Vol 10 ◽  
pp. 145-160 ◽  
Author(s):  
Inga Wessels ◽  
Judith Jansen ◽  
Lothar Rink ◽  
Peter Uciechowski
Keyword(s):  
Molecular Mechanisms ◽  
Adaptive Immune System ◽  
The Elderly ◽  
Polymorphonuclear Neutrophils ◽  
Traditional Role ◽  
Functional Changes ◽  
The Public ◽  
Age Related

All immune cells are affected by aging, contributing to the high susceptibility to infections and increased mortality observed in the elderly. The effect of aging on cells of the adaptive immune system is well documented. In contrast, knowledge concerning age-related defects of polymorphonuclear neutrophils (PMN) is limited. During the past decade, it has become evident that in addition to their traditional role as phagocytes, neutrophils are able to secrete a wide array of immunomodulating molecules. Their importance is underlined by the finding that genetic defects that lead to neutropenia increase susceptibility to infections. Whereas there is consistence about the constant circulating number of PMN throughout aging, the abilities of tissue infiltration, phagocytosis, and oxidative burst of PMN from aged donors are discussed controversially. Furthermore, there are numerous discrepancies betweenin vivoandin vitroresults, as well as between results for murine and human PMN. Most of the reported functional changes can be explained by defective signaling pathways, but further research is required to get a detailed insight into the underlying molecular mechanisms. This could form the basis for drug development in order to prevent or treat age-related diseases, and thus to unburden the public health systems.

scholarly journals AB0031 METABOLIC ADAPTATION OF HUMAN NEUTROPHILS TO GLUCOSE DEPRIVATION IS IMPAIRED WITH INCREASING AGE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1049.1-1049
Author(s):  
M. Pfeiffenberger ◽  
P. L. Krauß ◽  
T. Buttgereit ◽  
Y. Chen ◽  
A. Damerau ◽  
...  
Keyword(s):  
Age Groups ◽  
Glucose Deprivation ◽  
The Elderly ◽  
Basal Respiration ◽  
Metabolic Adaptation ◽  
Human Neutrophils ◽  
Spare Capacity ◽  
Respiratory Capacity ◽  
Age Related

Background:Age-related impairment of classical neutrophil functions is well described (Fortin, McDonald et al. 2008). However, experimental evidence for age-related alterations of neutrophil metabolic adaptation towards nutrient deprivation -a feature of neutrophil battlefields- remains elusive. Moreover, age-related differences in neutrophil metabolic adaptation may contribute to age-related pathologies such as atherosclerosis, cancer, and autoimmune diseases including rheumatoid arthritis.Objectives:Therefore, we hypothesized that metabolic adaptation of human neutrophils to glucose deprivation is impaired with increasing age.Methods:We isolated human peripheral CD15+ neutrophils from four healthy young donors (mean age: 23.4 ± 2.7) and four healthy donors with a mean age of 58.7 ± 2.4. First, we analyzed the survival of neutrophils either stimulated with PMA or left untreated and subsequently incubated for 0 h and 6 h under varying glucose concentrations (0, 0.5, 1, 5, and 10 mM). To address this, we used 7-AAD staining and flow cytometry. Using Seahorse™ technology, we determined basal respiration, ATP-bound respiration, and maximal and spare capacity.Results:We show that neutrophils (purity > 95%) survived for 6 hours in vitro, independent of treatment with PMA or concentrations of glucose in the culture medium. With negligible differences between the various concentrations of glucose used, the percentage of living cells after 6 h was 95% ± 2.5 without PMA and 75% ± 4.7 with PMA stimulation. No differences were uncovered in this respect between the two age groups. However, Seahorse™ technology revealed significant differences in basal, maximal, and spare respiratory capacity. Briefly, OCR (pmol/min/cell count) with respect to basal, maximal and reserve respiratory capacity was lower in the elderly donors compared to the young donors. For instance, with a concentration of 5 mM glucose, the basal respiration (OCR) was 17 ± 0.7 in elderly donors compared to 22.5 ± 1 in young donors, while the maximal respiration was 25 ± 0.8 in elderly and 41 ± 0.6 in the young donor group. Interestingly, these differences were independent of glucose concentration in the medium.Conclusion:Our data show that basal metabolic parameters differ between neutrophils from young and older donors. Further experiments are needed to understand in detail the mechanisms and effects of age-related differences in metabolism on neutrophil functions.References:[1]Fortin, C. F., P. P. McDonald, O. Lesur and T. Fülöp, Jr. (2008). “Aging and neutrophils: there is still much to do.” Rejuvenation Res11(5): 873-882.Disclosure of Interests:None declared

scholarly journals Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

2020 ◽  
Author(s):  
Francesco Nicoli ◽  
Mariela P. Cabral-Piccin ◽  
Laura Papagno ◽  
Eleonora Gallerani ◽  
Victor Folcher ◽  
...  
Keyword(s):  
T Cells ◽  
Lipid Metabolism ◽  
T Cell ◽  
De Novo ◽  
The Elderly ◽  
Influenza Viruses ◽  
Emerging Pathogens ◽  
Cell Compartment ◽  
Age Related

ABSTRACTAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We identified an age-related link between altered basal lipid metabolism and impaired antigen responsiveness in the naive CD8+ T cell compartment. These abnormalities were associated with an enhanced susceptibility to activation-induced apoptosis and could be recapitulated in vitro by exposure to the homeostatic cytokine interleukin (IL)-7. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the functional capabilities of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens, such as seasonal influenza viruses and SARS-CoV-2.

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