scholarly journals Cellular factors required for protection from hyperoxia toxicity in Saccharomyces cerevisiae

2005 ◽  
Vol 388 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Caryn E. OUTTEN ◽  
Robert L. FALK ◽  
Valeria C. CULOTTA
Keyword(s):  
Prolonged Exposure ◽  
Reduced Form ◽  
Cellular Functions ◽  
Mitochondrial Redox State ◽  
Cellular Factors ◽  
Two Factors ◽  
Cytosolic Glutathione ◽  
Yeast Deletion Library ◽  
Mitochondrial Glutathione ◽  
Cellular Components

Prolonged exposure to hyperoxia represents a serious danger to cells, yet little is known about the specific cellular factors that affect hyperoxia stress. By screening the yeast deletion library, we have identified genes that protect against high-O2 damage. Out of approx. 4800 mutants, 84 were identified as hyperoxia-sensitive, representing genes with diverse cellular functions, including transcription and translation, vacuole function, NADPH production, and superoxide detoxification. Superoxide plays a significant role, since the majority of hyperoxia-sensitive mutants displayed cross-sensitivity to superoxide-generating agents, and mutants with compromised SOD (superoxide dismutase) activity were particularly vulnerable to hyperoxia. By comparison, factors known to guard against H2O2 toxicity were poorly represented amongst hyperoxia-sensitive mutants. Although many cellular components are potential targets, our studies indicate that mitochondrial glutathione is particularly vulnerable to hyperoxia damage. During hyperoxia stress, mitochondrial glutathione is more susceptible to oxidation than cytosolic glutathione. Furthermore, two factors that help maintain mitochondrial GSH in the reduced form, namely the NADH kinase Pos5p and the mitochondrial glutathione reductase (Glr1p), are critical for hyperoxia resistance, whereas their cytosolic counterparts are not. Our findings are consistent with a model in which hyperoxia toxicity is manifested by superoxide-related damage and changes in the mitochondrial redox state.

scholarly journals IMAGING REDOX STATE HETEROGENEITY WITHIN INDIVIDUAL EMBRYONIC STEM CELL COLONIES

2011 ◽  
Vol 04 (03) ◽  
pp. 279-288 ◽  
Author(s):  
HE N. XU ◽  
RUSSELL C. ADDIS ◽  
DAVIDA F. GOINGS ◽  
SHOKO NIOKA ◽  
BRITTON CHANCE ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Redox State ◽  
Embryonic Stem ◽  
Reduced Form ◽  
Significant Heterogeneity ◽  
Imaging Data ◽  
Mitochondrial Redox State ◽  
Reduced State

Redox state mediates embryonic stem cell (ESC) differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells. NADH redox ratio (NADH/(Fp + NADH)), where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidized flavoproteins, has been established as a sensitive indicator of mitochondrial redox state. In this paper, we report our redox imaging data on the mitochondrial redox state of mouse ESC (mESC) colonies and the implications thereof. The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonic fibroblasts (MEFs) on glass cover slips. The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies (size: ~200–440 μm), exhibiting a core with a more reduced state than the periphery. This more reduced state positively correlates with the expression pattern of Oct4, a well-established marker of pluripotency. Our observation is the first to show the heterogeneity in the mitochondrial redox state within a mESC colony, suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.

The Effect of Low Magnesium Concentration on Ictal Discharges In A Non-Synaptic Model

2020 ◽  
pp. 2050070
Author(s):  
Antônio Márcio Rodrigues ◽  
Delmo Benedito Silva ◽  
Maísa Ferreira Miranda ◽  
Silvia Cristina Braga da Silva ◽  
Luiz Eduardo Canton Santos ◽  
...  
Keyword(s):  
Computer Simulations ◽  
Prolonged Exposure ◽  
Joint Effect ◽  
Magnesium Concentration ◽  
Neuronal Cultures ◽  
Electrochemical Characteristics ◽  
Cellular Functions ◽  
Physiological Concentration ◽  
Low Magnesium ◽  
Epileptiform Discharges

Magnesium (Mg[Formula: see text] is an essential mineral for several cellular functions. The concentration of this ion below the physiological concentration induces recurrent neuronal discharges both in slices of the hippocampus and in neuronal cultures. These epileptiform discharges are initially sensitive to the application of [Formula: see text]-methyl-D-aspartate (NMDA) receptor antagonists, but these antagonists may lose their effectiveness with prolonged exposure to low [Mg[Formula: see text]], when extracellular Ca[Formula: see text] reduction occurs, typical of ictal periods, indicating the absence of synaptic connections. The study herein presented aimed at investigating the effect of reducing the [Mg[Formula: see text]] during the induction of Nonsynaptic Epileptiform Activities (NSEA). As an experimental protocol, NSEA were induced in rat hippocampal dentate gyrus (DG), using a bath solution containing high-K[Formula: see text] and zero-added-Ca[Formula: see text]. Additionally, computer simulations were performed using a mathematical model that represents electrochemical characteristics of the tissue of the DG granular layer. The experimental results show that the reduction of [Mg[Formula: see text]] causes an increase in the duration of the ictal period and a reduction in the interictal period, intensifying epileptiform discharges. The computer simulations suggest that the reduction of the Mg[Formula: see text] level intensifies the epileptiform discharges by a joint effect of reducing the surface charge screening and reducing the activity of the Na/K pump.

scholarly journals Perspectives on the use of lipoic acid in the support of disease treatment*

2019 ◽  
Vol 73 ◽  
pp. 483-490
Author(s):  
Beata Skibska ◽  
Anna Gorąca
Keyword(s):  
Diabetes Mellitus ◽  
Lipoic Acid ◽  
Heart Diseases ◽  
Reduced Form ◽  
Oxidative Decarboxylation ◽  
Multienzyme Complexes ◽  
Antioxidant Agents ◽  
Cytosolic Glutathione ◽  
Treatment Of Diabetes ◽  
Obesity Hypertension

Lipoic acid (LA) is a natural compound present in food and used as a dietary supplement. LA is endogenously synthetized in small amounts from octanoid acid in the mitochondria. This compound occurs naturally in vegetables such as spinach, broccoli and in animal tissues, in the kidneys, heart and liver. It has been shown that LA is a cofactor in the multienzyme complexes that are responsible for oxidative decarboxylation of α- ketoacids. LA and its reduced form, dihydrolipoic acid (DHLA), have many biological functions leading to a wide variety of actions such as anti-inflammation and antioxidant protection, scavenging of reactive oxygen species, regenerating other antioxidant agents, such as vitamins C and E, and cytosolic glutathione, chelating the transitional metal ions (e.g. iron and copper), and modulating the signal transduction of nuclear factor. Many authors regard LA as a potentially useful agent in the treatment and/or prevention of many diseases such as diabetes mellitus, overweight, obesity, hypertension, heart diseases, inflammation. This review concentrates on the role of LA in the treatment of diabetes mellitus, obesity, inflammation and blood pressure regulation. LA can be considered as a potentially useful drug in treatment of many diseases, particularly those related to excessive production of free radicals.

scholarly journals Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

2020 ◽  
Vol 21 (12) ◽  
pp. 4405 ◽  
Author(s):  
Jean Nakhle ◽  
Anne-Marie Rodriguez ◽  
Marie-Luce Vignais
Keyword(s):  
Intracellular Signaling ◽  
Metabolic Diseases ◽  
Tca Cycle ◽  
Target Cells ◽  
Intercellular Signaling ◽  
Cellular Functions ◽  
Mitochondrial Dysfunctions ◽  
Metabolic Functions ◽  
Transport Chain ◽  
Cellular Components

Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

scholarly journals Paradoxical arteriole constriction compromises cytosolic and mitochondrial oxygen delivery in the isolated saline-perfused heart

2018 ◽  
Vol 315 (6) ◽  
pp. H1791-H1804 ◽  
Author(s):  
Abigail V. Giles ◽  
Junhui Sun ◽  
Armel N. Femnou ◽  
Sarah Kuzmiak-Glancy ◽  
Joni L. Taylor ◽  
...  
Keyword(s):  
Oxygen Delivery ◽  
Isolated Heart ◽  
Rabbit Heart ◽  
Reduced Form ◽  
Common Finding ◽  
Perfused Heart ◽  
Mitochondrial Redox State ◽  
Species Specific

The isolated saline-perfused heart is used extensively to study cardiac physiology. Previous isolated heart studies have demonstrated lower tissue oxygenation compared with in vivo hearts based on myoglobin oxygenation and the mitochondrial redox state. These data, consistent with small anoxic regions, suggest that the homeostatic balance between work and oxygen delivery is impaired. We hypothesized that these anoxic regions are caused by inadequate local perfusion due to a paradoxical arteriole constriction generated by a disrupted vasoregulatory network. We tested this hypothesis by applying two exogenous vasodilatory agents, adenosine and cromakalim, to relax vascular tone in an isolated, saline-perfused, working rabbit heart. Oxygenation was monitored using differential optical transmission spectroscopy and full spectral fitting. Increases in coronary flow over control with adenosine (27 ± 4 ml/min) or cromakalim (44 ± 4 ml/min) were associated with proportional spectral changes indicative of myoglobin oxygenation and cytochrome oxidase (COX) oxidation, consistent with a decrease in tissue anoxia. Quantitatively, adenosine decreased deoxymyoglobin optical density (OD) across the wall by 0.053 ± 0.008 OD, whereas the reduced form of COX was decreased by 0.039 ± 0.005 OD. Cromakalim was more potent, decreasing deoxymyoglobin and reducing the level of COX by 0.070 ± 0.019 OD and 0.062 ± 0.019 OD, respectively. These effects were not species specific, as Langendorff-perfused mouse hearts treated with adenosine demonstrated similar changes. These data are consistent with paradoxical arteriole constriction as a major source of regional anoxia during saline heart perfusion. We suggest that the vasoregulatory network is disrupted by the washout of interstitial vasoactive metabolites in vitro. NEW & NOTEWORTHY Regional tissue anoxia is a common finding in the ubiquitous saline-perfused heart but is not found in vivo. Noninvasive optical techniques confirmed the presence of regional anoxia under control conditions and demonstrated that anoxia is diminished using exogenous vasodilators. These data are consistent with active arteriole constriction, occurring despite regional anoxia, generated by a disrupted vasoregulatory network. Washout of interstitial vasoactive metabolites may contribute to the disruption of normal vasoregulatory processes in vitro.

Cellular functions of ascorbic acid

1990 ◽  
Vol 68 (10) ◽  
pp. 1166-1173 ◽  
Author(s):  
Harish Padh
Keyword(s):  
Ascorbic Acid ◽  
Reduced Form ◽  
Enzymatic Reactions ◽  
Cellular Functions ◽  
Animal Cells ◽  
Major Function ◽  
Collagen Formation ◽  
Oxidative Products ◽  
Catalytic Cycles

It has long been suspected that ascorbic acid is involved in many cellular reactions. This is evident from the multitude of seemingly unrelated symptoms seen in scurvy. However, until recently, our understanding of its involvement was confined to its role in the synthesis of collagen. Studies in the past few years have unveiled mechanisms of its actions in collagen formation and many other enzymatic reactions. In addition, numerous physiological responses are reportedly affected by ascorbic acid. From the well-characterized enzymatic reactions involving ascorbic acid, it has become clear that in animal cells the ascorbate does not seem to be directly involved in catalytic cycles. Rather its major function seems to keep prosthetic metal ions in their reduced form. The role of ascorbate as a reductant in these enzymatic reactions complements its other antioxidant functions which have been recently appreciated, including that as a scavenger of free radicals. Therefore, it seems that the major function of ascorbate is to protect tissues from harmful oxidative products and to keep certain enzymes in their required reduced forms. However, it remains unclear how the deficiency of ascorbate leads to the pathological symptoms found in scurvy.Key words: ascorbic acid, vitamin C, biochemical functions, antioxidant, recommended dietary allowances, hydroxylation.

scholarly journals CHOP THERAPY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS

2013 ◽  
Vol 06 (02) ◽  
pp. 1350011 ◽  
Author(s):  
H. N. XU ◽  
H. ZHAO ◽  
T. A. MIR ◽  
S. C. LEE ◽  
M. FENG ◽  
...  
Keyword(s):  
Redox State ◽  
Statistical Significance ◽  
B Cell Lymphoma ◽  
Treated Group ◽  
Reduced Form ◽  
Control Group ◽  
Growth And Survival ◽  
Mitochondrial Redox State ◽  
Treatment Responses ◽  
Chop Therapy

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival. The redox state can be imaged by the redox scanner that collects the fluorescence signals from both the oxidized-flavoproteins (Fp) and the reduced form of nicotinamide adenine dinucleotide (NADH) in snap-frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses. Here, with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B-cell lymphoma cell line (DLCL2). The mice were treated with CHOP therapy, i.e., cyclophosphamide (C) + hydroxydoxorubicin (H) + Oncovin (O) + prednisone (P) with CHO administration on day 1 and prednisone administration on days 1–5. The Fp content of the treated group was significantly decreased (p = 0.033) on day 5, and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group (p = 0.048). The decrease of the Fp heterogeneity (measured by the mean standard deviation) had a border-line statistical significance (p = 0.071). The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

Renal metabolism of the oxidized form of ascorbic acid (dehydro-L-ascorbic acid)

1989 ◽  
Vol 256 (1) ◽  
pp. F52-F56
Author(s):  
R. C. Rose
Keyword(s):  
Ascorbic Acid ◽  
Reduced Form ◽  
Gel Chromatography ◽  
Dialysis Tubing ◽  
Renal Metabolism ◽  
Glomerular Filtrate ◽  
Metabolic Properties ◽  
Enzyme Functions ◽  
Cellular Components ◽  
Acid Reduction

We evaluated whether specific transport and metabolic properties exist in rat and guinea pig kidney for handling the immediate oxidative product of ascorbic acid, dehydro-L-ascorbic acid. Isolated tubules were used to measure uptake of 10 microM [14C]-dehydro-L-ascorbic acid over an 8-min incubation period. Uptake did not show dependence on the bathing media electrolyte composition but was inhibited to some extent by glucose. In tubules of both animal species the majority of 14C label present in the tissue extract was in the reduced form. No degredative enzymatic effect on dehydro-L-ascorbic acid is evident. Thirty-six percent of the [14C]dehydro-L-ascorbic acid reduced by the tubules was released during an 8-min incubation. Recently formed ascorbic acid is not substantially bound to cellular components. A factor necessary for dehydro-L-ascorbic acid reduction in renal cortex was found primarily in the 55-70% ammonium sulfate fraction. It is retained by mol wt 12,000 dialysis tubing, is heat labile, pH sensitive, inhibited by thiol reagents, and is most active in the presence of NADPH and glutathione. It has a molecular weight between that of blue dextran and cytochrome c as indicated by gel chromatography. We suggest that a cytosolic enzyme functions in reduction of dehydro-L-ascorbic acid and thereby is important in maintaining the redox state of ascorbic acid derived from the glomerular filtrate or from peritubular fluid.

scholarly journals Systematic binding analysis of the insulin gene transcription control region: insulin and immunoglobulin enhancers utilize similar transactivators.

1988 ◽  
Vol 8 (6) ◽  
pp. 2620-2627 ◽  
Author(s):  
L G Moss ◽  
J B Moss ◽  
W J Rutter
Keyword(s):  
Sequence Similarity ◽  
Regulatory Region ◽  
Insulin Gene ◽  
Nuclear Factor ◽  
Cell Type ◽  
Transcription Control ◽  
Enhancer Activity ◽  
Cellular Factors ◽  
Gene Enhancer ◽  
Two Factors

The 5' regulatory region (-345 to +1) of the rat insulin I gene (Ins-I) was examined for binding to cellular factors with short oligodeoxynucleotide probes. Over 40 binding species were detected. The binding profiles were specific for each cell type studied. We characterized the factors binding two elements crucial for enhancer activity (the Nir and Far boxes) which bear sequence similarity to the microE1, microE2, and microE3 elements of the immunoglobulin heavy-chain enhancer. The Nir box binds three cellular factors that display preferential affinities for microE1, microE2, or microE3, and the Far box binds two factors related to microE2 or microE3. The insulin gene enhancer was mutated at the Nir box element to reflect the sequences of microE1, microE2, or microE3. Ins-microE2 was fully active, Ins-microE3 was partially active, and Ins-microE1 was inactive. Thus, factors similar or identical to nuclear factor NF-microE1, NF-microE2, or NF-microE3 may play a role in the activity of the insulin gene enhancer.

scholarly journals The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 324
Author(s):  
Bo Meng ◽  
Andrew M. L. Lever
Keyword(s):  
Life Cycle ◽  
Surface Proteins ◽  
Cellular Functions ◽  
Enveloped Viruses ◽  
Endosomal Sorting ◽  
Diverse Families ◽  
Enveloped Virus ◽  
Virus Life Cycle ◽  
Obligate Parasites ◽  
Cellular Factors

Viruses are obligate parasites that rely on host cellular factors to replicate and spread. The endosomal sorting complexes required for transport (ESCRT) system, which is classically associated with sorting and downgrading surface proteins, is one of the host machineries hijacked by viruses across diverse families. Knowledge gained from research into ESCRT and viruses has, in turn, greatly advanced our understanding of many other cellular functions in which the ESCRT pathway is involved, e.g., cytokinesis. This review highlights the interplay between the ESCRT pathway and the viral factors of enveloped viruses with a special emphasis on retroviruses.

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