scholarly journals Redox signalling and ageing: insights from Drosophila

2020 ◽  
Vol 48 (2) ◽  
pp. 367-377 ◽  
Author(s):  
Claudia Lennicke ◽  
Helena M. Cochemé
Keyword(s):  
Biological Effects ◽  
Fruit Fly ◽  
Model Organisms ◽  
Redox Signalling ◽  
Age Related ◽  
The Social ◽  
Low Levels ◽  
Specific Species

Ageing and age-related diseases are major challenges for the social, economic and healthcare systems of our society. Amongst many theories, reactive oxygen species (ROS) have been implicated as a driver of the ageing process. As by-products of aerobic metabolism, ROS are able to randomly oxidise macromolecules, causing intracellular damage that accumulates over time and ultimately leads to dysfunction and cell death. However, the genetic overexpression of enzymes involved in the detoxification of ROS or treatment with antioxidants did not generally extend lifespan, prompting a re-evaluation of the causal role for ROS in ageing. More recently, ROS have emerged as key players in normal cellular signalling by oxidising redox-sensitive cysteine residues within proteins. Therefore, while high levels of ROS may be harmful and induce oxidative stress, low levels of ROS may actually be beneficial as mediators of redox signalling. In this context, enhancing ROS production in model organisms can extend lifespan, with biological effects dependent on the site, levels, and specific species of ROS. In this review, we examine the role of ROS in ageing, with a particular focus on the importance of the fruit fly Drosophila as a powerful model system to study redox processes in vivo.

scholarly journals Enhancing autophagy by redox regulation extends lifespan in Drosophila

2019 ◽  
Author(s):  
Helena M. Cochemé ◽  
Ivana Bjedov ◽  
Sebastian Grönke ◽  
Katja E. Menger ◽  
Andrew M. James ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Model Organism ◽  
Fruit Fly ◽  
Cysteine Residue ◽  
Lifespan Extension ◽  
Post Translational Modification ◽  
Redox Signalling ◽  
Age Related

Redox signalling is an important modulator of diverse biological pathways and processes, and operates through specific post-translational modification of redox-sensitive thiols on cysteine residues 1–4. Critically, redox signalling is distinct from irreversible oxidative damage and functions as a reversible ‘redox switch’ to regulate target proteins. H2O2 acts as the major effector of redox signalling, both directly and through intracellular thiol redox relays 5,6. Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself, however the underlying mechanisms remain largely unclear 7,8. To study redox signalling by H2O2in vivo and explore its involvement in metabolic health and longevity, we used the fruit fly Drosophila as a model organism, with its tractable lifespan and strong evolutionary conservation with mammals 9. Here we report that inducing an endogenous redox-shift, by manipulating levels of the H2O2-degrading enzyme catalase, improves health and robustly extends lifespan in flies, independently of oxidative stress resistance and dietary restriction. We find that the catalase redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, a major effector of autophagy, we show that the lifespan extension in response to catalase requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings demonstrate that redox regulation of autophagy can extend lifespan, confirming the importance of redox signalling in ageing and as a potential pro-longevity target.

scholarly journals Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donita L. Garland ◽  
Eric A. Pierce ◽  
Rosario Fernandez-Godino
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Deposit Formation ◽  
Genetic Ablation ◽  
Age Related ◽  
Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

scholarly journals Circular RNA hsa_circ_101555 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-145-5p and regulating CDCA3 expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Xiaoguang Gu ◽  
Jianan Zhang ◽  
Yajuan Ran ◽  
Hena Pan ◽  
JinHong Jia ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Biological Effects ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Casein Kinase 1 ◽  
Mouse Xenograft Model ◽  
Hcc Cells

AbstractCircular RNAs have been reported to play significant roles in regulating pathophysiological processes while also guiding clinical diagnosis and treatment of hepatocellular carcinoma (HCC). However, only a few circRNAs have been identified thus far. Herein, we investigated the role of a specific closed-loop structure of hsa_circ_101555 that was generated by back-splicing of the host gene casein kinase 1 gamma 1 (CSNK1G1) in the development and proliferation of HCC. We investigated the expression of Hsa_circ_101555 in HCC and normal tissues using bioinformatics. The expression level of hsa_circ_101555 was further detected by fluorescence in situ hybridization and qRT-PCR in ten HCC patients. Transwell, migration, WST-1 assays, and colony formation assays were used to evaluate the role of hsa_circ_101555 in HCC development and proliferation. The regulatory mechanisms of hsa_circ_101555 in miR-145-5p and CDCA3 were determined by dual luciferase reporter assay. A mouse xenograft model was also used to determine the effect of hsa_circ_101555 on HCC growth in vivo. hsa_circ_101555 showed greater stability than the linear RNA; while in vitro and in vivo results demonstrated that hsa_circ_101555 silencing significantly suppressed cell proliferation, migration, and invasion of HCC cells. Rescue experiments further demonstrated that suppression of miR-145-5p significantly attenuated the biological effects of hsa_circ_101555 knockdown in HCC cells. We also identified a putative oncogene CDCA3 as a potential miR-145-5p target. Thus, our results demonstrated that hsa_circ_101555 might function as a competing endogenous RNA of miR-145-5p to upregulate CDCA3 expression in HCC. These findings suggest that hsa_circ_101555 may be a potential therapeutic target for patients with HCC.

Carbonic anhydrase in the midgut of larvalAedes aegypti: cloning, localization and inhibition

2002 ◽  
Vol 205 (5) ◽  
pp. 591-602 ◽  
Author(s):  
Maria del Pilar Corena ◽  
Theresa J. Seron ◽  
Herm K. Lehman ◽  
Judith D. Ochrietor ◽  
Andrea Kohn ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Aedes Aegypti ◽  
Fruit Fly ◽  
Cellular Heterogeneity ◽  
Carbonic Anhydrases ◽  
Larval Midgut ◽  
Posterior Midgut

SUMMARYThe larval mosquito midgut exhibits one of the highest pH values known in a biological system. While the pH inside the posterior midgut and gastric caeca ranges between 7.0 and 8.0, the pH inside the anterior midgut is close to 11.0. Alkalization is likely to involve bicarbonate/carbonate ions. These ions are produced in vivo by the enzymatic action of carbonic anhydrase. The purpose of this study was to investigate the role of this enzyme in the alkalization mechanism, to establish its presence and localization in the midgut of larval Aedes aegypti and to clone and characterize its cDNA. Here, we report the physiological demonstration of the involvement of carbonic anhydrase in midgut alkalization. Histochemistry and in situ hybridization showed that the enzyme appears to be localized throughout the midgut, although preferentially in the gastric caeca and posterior regions with specific cellular heterogeneity. Furthermore, we report the cloning and localization of the first carbonic anhydrase from mosquito larval midgut. A cDNA clone from Aedes aegypti larval midgut revealed sequence homology to α-carbonic anhydrases from vertebrates. Bioinformatics indicates the presence of at least six carbonic anhydrases or closely related genes in the genome of another dipteran, the fruit fly Drosophila melanogaster. Molecular analyses suggest that the larval mosquito may also possess multiple forms.

Oestrogens in breast tumours and fat

1989 ◽  
Vol 95 ◽  
pp. 161-168
Author(s):  
J. H. H. Thijssen ◽  
M. A. Blankenstein
Keyword(s):  
Biological Effects ◽  
Plasma Concentrations ◽  
Normal Breast ◽  
Malignant Tumours ◽  
Breast Tumours ◽  
Two Parameters ◽  
Breast Tissues

SynopsisThe levels of endogenous steroids in the target tissues are thought to be more closely related to the biological effects than their concentrations in plasma. Therefore studies on oestrogen levels in malignant and non-malignant breast tissues (expressed per g wet weight) were conducted and the following conclusions were drawn:(1) malignant tumours contained higher oestradiol levels than normal or benign breast tissues, whereas oestrone levels were more comparable;(2) in contrast to the large decrease in plasma concentrations after menopause, the levels of oestradiol in tumours and in normal breast tissue did not change with advancing age;(3) the oestradiol levels in breast tissues were lower than in uterine tissues, particularly in women before menopause; oestrone levels were very similar in all tissues studied;(4) the mean oestradiol level was higher in oestrogen-receptor-positive tumours, but no correlation between the two parameters was found;(5) preliminary results indicated lower oestradiol levels in tumours obtained from countries with a lower incidence of breast cancer;(6) as far as available, oestrone levels were comparable and those of oestradiol were lower in fat tissues than in breast tumours;(7) neither in vitro studies with breast tumours, nor in vivo results using myometrial tissues support a prominent role of the metabolism of oestrogens at the 16α-position in the development of tumours;(8) the role of local factors in the production, retention and metabolism of oestradiol in the breast remains to be elucidated.

scholarly journals Impact of GPR1 signaling on maternal high-fat feeding and placenta metabolism in mice

2019 ◽  
Vol 316 (6) ◽  
pp. E987-E997 ◽  
Author(s):  
Binbin Huang ◽  
Chen Huang ◽  
Huashan Zhao ◽  
Wen Zhu ◽  
Baobei Wang ◽  
...  
Keyword(s):  
Biological Effects ◽  
Negative Control ◽  
Feedback Mechanism ◽  
High Fat ◽  
Fatty Acid Binding ◽  
Maternal Metabolism ◽  
Phosphorylated Akt

Chemerin and G protein-coupled receptor 1 (GPR1) are increased in serum and placenta in mice during pregnancy. Interestingly, we observed increased serum chemerin levels and decreased GPR1 expression in placenta of high-fat-diet-fed mice compared with chow-fed mice at gestational day 18. GPR1 protein and gene levels were significantly decreased in gestational diabetes mellitus (GDM) patient placentas. Therefore, we hypothesized that chemerin/GPR1 signaling might participate in the pathogenic mechanism of GDM. We investigated the role of GPR1 in carbohydrate homeostasis during pregnancy using pregnant mice transfected with small interfering RNA for GPR1 or a negative control. GPR1 knockdown exacerbated glucose intolerance, disrupted lipid metabolism, and decreased β-cell proliferation and insulin levels. Glucose transport protein-3 and fatty acid binding protein-4 were downregulated with reducing GPR1 in vivo and in vitro via phosphorylated AKT pathway. Taken together, our findings first demonstrate the expression of GPR1, the characterization of its direct biological effects in humans and mice, as well as the molecular mechanism that indicates the role of GPR1 signaling in maternal metabolism during pregnancy, suggesting a novel feedback mechanism to regulate glucose balance during pregnancy, and GPR1 could be a potential target for the detection and therapy of GDM.

scholarly journals Platelet storage at 22 degrees C: role of gas transport across plastic containers in maintenance of viability

Blood ◽  
1975 ◽  
Vol 46 (2) ◽  
pp. 209-218 ◽  
Author(s):  
S Murphy ◽  
FH Gardner
Keyword(s):  
Platelet Count ◽  
Lactate Concentration ◽  
Platelet Concentrates ◽  
Pasteur Effect ◽  
Platelet Storage ◽  
Low Levels ◽  
Microscopic Morphology ◽  
Plastic Containers

Abstract Containers constructed of polyvinylchloride (PVC) are used for the storage of platelet concentrates (PC) for transfusion, At 22 degrees C, pH often falls to such low levels (pH is less that 6.0) that viability is lost. Far lesser degrees of pH fall are observed in bags constructed of polyethylene (PE). In this study, pH, PO2, PCO2, platelet count, lactate concentration, microscopic morphology, and viability after 51- chromium labeling were evaluated during storage at 22 degrees C under a variety of circumstances. The results indicate that (1) pH falls because of the generation of lactic acid by platelet glycolysis and, under some circumstances, the retention of CO2. (2) Rate of pH fall is, therefore, roughly proportional to the platelet count. (3) PE is more permeable to gases, thereby allowing CO2 escape from and easier O2 entry into the stored PC; the higher O2 tensions suppress glycolysis by the Pasteur effect. (4) Adequate agitation and container size are critical if the beneficial effect of PE is to be obtained. (5) In general, platelets stored in PE containers have excellent viability in vivo although CO2 escape can result in elevations in pH which are deleterious. (6) Storage in a 10% CO2 atmosphere prevents these deletrrious pH elevations without otherwise impairing platelet viability; (7) Results similar to those achieved with PE can be achieved with PVC if this material is made thinner to allow easier penetration of gases.

Impaired CD163-mediated hemoglobin-scavenging and severe toxic symptoms in patients treated with gemtuzumab ozogamicin

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1510-1514 ◽  
Author(s):  
Maciej Bogdan Maniecki ◽  
Henrik Hasle ◽  
Lennart Friis-Hansen ◽  
Birgitte Lausen ◽  
Ove Juul Nielsen ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
High Plasma ◽  
Gemtuzumab Ozogamicin ◽  
Intravascular Hemolysis ◽  
Soluble Cd163 ◽  
Plasma Hemoglobin ◽  
Monocytes And Macrophages ◽  
Low Levels

Abstract We describe a novel syndrome of severe toxic symptoms during intravascular hemolysis due to impaired hemoglobin scavenging in 2 children with acute myeloid leukemia undergoing CD33-directed therapy with the immunotoxin gemtuzumab ozogamicin (GO). A simultaneous high plasma hemoglobin, haptoglobin, and low bilirubin after septicemia-induced intravascular hemolysis indicated abrogated clearance of haptoglobin-hemoglobin complexes. This was further supported by low levels of plasma soluble CD163 and a concordant low number of CD163-expressing monocytes. We show that CD163 positive monocytes and macrophages from liver, spleen, and bone marrow coexpress CD33, thus suggesting that the GO-induced cellular cytotoxicity of CD33 positive cells eradicates a significant part of the CD163 positive monocytes and macrophages. The risk of severe toxic symptoms from plasma hemoglobin should be considered after CD33-targeted chemotherapy when the disease is complicated by a pathologic intravascular hemolysis. Furthermore, the cases provide further circumstantial evidence of a key role of (CD163-expressing) monocytes/macrophages in plasma hemoglobin clearance in vivo.

scholarly journals The Role of Free Radicals in Autophagy Regulation: Implications for Ageing

2018 ◽  
Vol 2018 ◽  
pp. 1-19 ◽  
Author(s):  
M. Pajares ◽  
A. Cuadrado ◽  
N. Engedal ◽  
Z. Jirsova ◽  
M. Cahova
Keyword(s):  
Control Systems ◽  
Redox Homeostasis ◽  
Biological Macromolecules ◽  
Complex Relationship ◽  
Cellular Functions ◽  
Related Disorder ◽  
Redox Signalling ◽  
Age Related ◽  
Integral Role

Reactive oxygen and nitrogen species (ROS and RNS, resp.) have been traditionally perceived solely as detrimental, leading to oxidative damage of biological macromolecules and organelles, cellular demise, and ageing. However, recent data suggest that ROS/RNS also plays an integral role in intracellular signalling and redox homeostasis (redoxtasis), which are necessary for the maintenance of cellular functions. There is a complex relationship between cellular ROS/RNS content and autophagy, which represents one of the major quality control systems in the cell. In this review, we focus on redox signalling and autophagy regulation with a special interest on ageing-associated changes. In the last section, we describe the role of autophagy and redox signalling in the context of Alzheimer’s disease as an example of a prevalent age-related disorder.

Changes in Labor Accident Risk with Aging

2011 ◽  
Vol 6 (2) ◽  
pp. 253-257 ◽  
Author(s):  
Takahiro Nakamura ◽  
◽  
Motoya Takagi ◽  
Shinnosuke Usui ◽  
◽  
...  
Keyword(s):  
Older Workers ◽  
Social Role ◽  
Well Being ◽  
The Elderly ◽  
Worker Safety ◽  
Accident Risk ◽  
Older Worker ◽  
Age Related ◽  
The Social

As we age, we change physically and mentally. As society ages, the birthrate decreases and the older worker’s social role increases in importance. The social role of the elderly is, however, threatened by the potential increase in age-related accidents. This research used 34,217 cases to explore and clarify the features of age-related accidents, classified by type, victim age –10 to 30s, 40 to 50s, and those aged 60 and over– and the number of absentee days due to accidents. Our results show that more time is needed for an older worker to return to the job after an accident than for a young worker. The importance of accident prevention for older workers is growing throughout industry. Ensuring such safety improves safety for workers of all ages. Issues involving age-related worker safety thus are related to the safety and well-being of workers of all generation.

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