scholarly journals Redox regulation by TXNRD3 during epididymal maturation underlies capacitation-associated mitochondrial activation and sperm motility in mice

2021 ◽  
Author(s):  
Huafeng Wang ◽  
Qianhui Dou ◽  
Kyung Jo Jung ◽  
Jungmin Choi ◽  
Vadim N. Gladyshev ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox Status ◽  
Male Reproduction ◽  
Sperm Maturation ◽  
Epididymal Maturation ◽  
Sperm Development ◽  
Sheath Formation

During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of the redox regulation in sperm development and maturation remain largely elusive. In this study, we report thioredoxin reductase 3 (TXNRD3) - a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation - contributes to regulate redox homeostasis in male reproduction. Using Txnrd3-/- mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility in absence of TXNRD3. Absence of TXNRD3 alters redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization.

Proteasome Inhibitors in Cancer Therapy and their Relation to Redox Regulation

2019 ◽  
Vol 24 (44) ◽  
pp. 5252-5267
Author(s):  
Gulce Sari ◽  
Zehra Okat ◽  
Ali Sahin ◽  
Betul Karademir
Keyword(s):  
Signaling Pathways ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Proteasome Inhibitors ◽  
Redox System ◽  
Redox Balance ◽  
Redox Status ◽  
Signaling Molecules ◽  
Cancer Therapies

Redox homeostasis is important for the maintenance of cell survival. Under physiological conditions, redox system works in a balance and involves activation of many signaling molecules. Regulation of redox balance via signaling molecules is achieved by different pathways and proteasomal system is a key pathway in this process. Importance of proteasomal system on signaling pathways has been investigated for many years. In this direction, many proteasome targeting molecules have been developed. Some of them are already in the clinic for cancer treatment and some are still under investigation to highlight underlying mechanisms. Although there are many studies done, molecular mechanisms of proteasome inhibitors and related signaling pathways need more detailed explanations. This review aims to discuss redox status and proteasomal system related signaling pathways. In addition, cancer therapies targeting proteasomal system and their effects on redox-related pathways have been summarized.

102. CHARACTERISATION OF THE GTPase DYNAMIN THROUGHOUT MURINE SPERM MATURATION

2010 ◽  
Vol 22 (9) ◽  
pp. 20
Author(s):  
A. T. Reid ◽  
S. D. Roman ◽  
R. Aitken ◽  
B. Nixon
Keyword(s):  
Protein Trafficking ◽  
Molecular Mechanisms ◽  
Protein Translocation ◽  
Morphological Changes ◽  
Sperm Maturation ◽  
The Novel ◽  
Epididymal Maturation ◽  
Distinct Cell ◽  
Molecular Machinery

Throughout sperm maturation distinct remodelling events occur that imbue the cells with both the ability to bind the zona pellucida and undergo the acrosome reaction. Of long standing interest to our laboratory is the elucidation of the molecular mechanisms that underpin the attainment of these key functional attributes. This process begins with a complex range of morphological changes that accompany spermatogenesis, and is continued through post-testicular phases of maturation in both the male (epididymal maturation) and female (capacitation) reproductive tracts. However, among these changes only those occurring during the initial stages of spermatogenesis are intrinsically driven. The fact that the majority of sperm remodelling is extrinsically stimulated, and occurs in the absence of new protein synthesis, highlights the potential importance of processes such as intracellular protein trafficking. This has directed our focus towards the dynamin family of protein traffickers. The GTPase dynamin exists in three isoforms, namely Dnm1, Dnm2 and Dnm3 and is an integral part of the molecular machinery required for vesicle mediated protein translocation. Recent research from our laboratory has demonstrated the presence of these three isoforms in distinct, cell-specific locations during murine spermatogenesis. Immunofluorescence on mouse testis revealed that both Dnm1 and 2 are present within a region corresponding to the developing acrosome in maturing sperm, whilst Dnm3 appears to reside solely within pre-meiotic germ cells. Interestingly, Dnm1 and Dnm2 are both retained within the peri-acrosomal region of the sperm head in mature spermatozoa. Additionally, upon the induction of capacitation in vitro, staining for both Dnm1 and 2 becomes significantly reduced. Collectively these data support the novel hypothesis that dynamin not only participates in sperm remodelling events during spermatogenesis but may also have a previously unappreciated role in capacitation-associated priming of the sperm surface for interaction with the oocyte.

scholarly journals Expression of the trxC Gene of Rhodobacter capsulatus: Response to Cellular Redox Status Is Mediated by the Transcriptional Regulator OxyR

2006 ◽  
Vol 188 (21) ◽  
pp. 7689-7695 ◽  
Author(s):  
Tanja Zeller ◽  
Kuanyu Li ◽  
Gabriele Klug
Keyword(s):  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Rhodobacter Capsulatus ◽  
Transcriptional Regulator ◽  
Redox Status ◽  
Cellular Functions ◽  
Cellular Redox

ABSTRACT Despite the importance of thioredoxins in cellular functions, little is known about the regulation of trx genes. To understand the molecular mechanisms involved in the regulation of the Rhodobacter capsulatus trxC gene, the expression of this gene was investigated. We describe OxyR-dependent redox regulation of the trxC gene that adjusts the levels of thioredoxins in the cell.

scholarly journals TXNRD3 supports male fertility via the redox control of spermatogenesis

2021 ◽  
Author(s):  
Qianhui Dou ◽  
Anton A Turanov ◽  
Marco Mariotti ◽  
Jae Yeon Hwang ◽  
Huafeng Wang ◽  
...  
Keyword(s):  
Critical Role ◽  
Thioredoxin Reductase ◽  
Redox Status ◽  
Fertilization Rate ◽  
Male Reproduction ◽  
Redox Control ◽  
Thiol Redox ◽  
Knockout Animals

Thioredoxin/glutathione reductase (TGR, TXNRD3) is a thiol oxidoreductase of unknown function composed of thioredoxin reductase and glutaredoxin domains. This NADPH-dependent enzyme evolved by gene duplication within the Txnrd family, is expressed in the testes and can reduce both thioredoxin and glutathione in vitro. To characterize the function of TXNRD3 in vivo, we generated a strain of mice with the deletion of Txnrd3 gene. We show that Txnrd3 knockout mice are viable and without discernable gross phenotypes, but TXNRD3 deficiency leads to fertility impairment in male mice. Txnrd3 knockout animals exhibit a lower fertilization rate in vitro, a sperm movement phenotype and an altered redox status of thiols. Proteomic analyses revealed a broad range of substrates reduced by TXNRD3 during sperm maturation, presumably as a part of quality control. The results show that TXNRD3 plays a critical role in male reproduction via the thiol redox control of spermatogenesis.

H2S signaling in redox regulation of cellular functions

2013 ◽  
Vol 91 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Youngjun Ju ◽  
Weihua Zhang ◽  
Yanxi Pei ◽  
Guangdong Yang
Keyword(s):  
Mammalian Cells ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Therapeutic Interventions ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Future Design ◽  
Cellular Effects

Hydrogen sulfide (H2S) is traditionally recognized as a toxic gas with a rotten-egg smell. In just the last few decades, H2S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H2S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H2S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H2S can promote an antioxidant effect and is cytoprotective; on the other side, H2S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H2S through S-sulfhydration and the role of H2S in glutathione generation is also recapitulated. A better understanding of H2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.

scholarly journals Redox Systems in Botrytis cinerea: Impact on Development and Virulence

2014 ◽  
Vol 27 (8) ◽  
pp. 858-874 ◽  
Author(s):  
Anne Viefhues ◽  
Jens Heller ◽  
Nora Temme ◽  
Paul Tudzynski
Keyword(s):  
Botrytis Cinerea ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox System ◽  
Redox Status ◽  
Redox Systems ◽  
Gene Encoding ◽  
Cellular Redox ◽  
Thioredoxin System ◽  
The Impact

The thioredoxin system is of great importance for maintenance of cellular redox homeostasis. Here, we show that it has a severe influence on virulence of Botrytis cinerea, demonstrating that redox processes are important for host-pathogen interactions in this necrotrophic plant pathogen. The thioredoxin system is composed of two enzymes, the thioredoxin and the thioredoxin reductase. We identified two genes encoding for thioredoxins (bctrx1, bctrx2) and one gene encoding for a thioredoxin reductase (bctrr1) in the genome of B. cinerea. Knockout mutants of bctrx1 and bctrr1 were severely impaired in virulence and more sensitive to oxidative stress. Additionally, Δbctrr1 showed enhanced H2O2 production and retarded growth. To investigate the impact of the second major cellular redox system, glutathione, we generated deletion mutants for two glutathione reductase genes. The effects were only marginal; deletion of bcglr1 resulted in reduced germination and, correspondingly, to retarded infection as well as reduced growth on minimal medium, whereas bcglr2 deletion had no distinctive phenotype. In summary, we showed that the balanced redox status maintained by the thioredoxin system is essential for development and pathogenesis of B. cinerea, whereas the second major cellular redox system, the glutathione system, seems to have only minor impact on these processes.

scholarly journals Oxidative remote induction of type 3 deiodinase impacts nonthyroidal illness syndrome

2020 ◽  
Vol 246 (3) ◽  
pp. 237-246
Author(s):  
Tatiana Ederich Lehnen ◽  
Rafael Marschner ◽  
Fernanda Dias ◽  
Ana Luiza Maia ◽  
Simone Magagnin Wajner
Keyword(s):  
Reductase Activity ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Coronary Artery Occlusion ◽  
Redox Status ◽  
Artery Occlusion ◽  
Antioxidant Defenses ◽  
Nonthyroidal Illness ◽  
Male Wistar Rats ◽  
Type 3

Imbalances in redox status modulate type 3 deiodinase induction in nonthyroidal illness syndrome. However, the underlying mechanisms that lead to D3 dysfunction under redox imbalance are still poorly understood. Here we evaluated D3 induction, redox homeostasis, and their interrelationships in the liver, muscle, and brain in an animal model of NTIS. Male Wistar rats were subjected to left anterior coronary artery occlusion and randomly separated into two groups and treated or not (placebo) with the antioxidant N-acetylcysteine. Sham animals were used as controls. Animals were killed 10 or 28 days post-MI induction and tissues were immediately frozen for biochemical analysis. D3 activity, protein oxidation and antioxidant defenses were measured in liver, muscle, and brain. Compared to those of the sham group, the levels of D3 expression and activity were increased in the liver (P = 0.002), muscle (P = 0.03) and brain (P = 0.01) in the placebo group. All tissues from the placebo animals showed increased carbonyl groups (P < 0.001) and diminished sulfhydryl levels (P < 0.001). Glutathione levels were decreased and glutathione disulfide levels were augmented in all examined tissues. The liver and muscle showed augmented levels of glutathione peroxidase, glutathione reductase and thioredoxin reductase activity (P = 0.001). NAC prevented all the alterations described previously. D3 dysfunction in all tissues correlates with post-MI-induced protein oxidative damage and altered antioxidant defenses. NAC treatment prevents D3 dysfunction, indicating that reversible redox-related remote D3 activation explains, at least in part, the thyroid hormone derangements of NTIS.

scholarly journals Role of Selenoproteins in Redox Regulation of Signaling and the Antioxidant System: A Review

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 383 ◽  
Author(s):  
Ying Zhang ◽  
Yeon Jin Roh ◽  
Seong-Jeong Han ◽  
Iha Park ◽  
Hae Min Lee ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Lipid Peroxides ◽  
Lipid Hydroperoxides ◽  
Cellular Processes ◽  
System A ◽  
Catalytic Role ◽  
Er Membrane

Selenium is a vital trace element present as selenocysteine (Sec) in proteins that are, thus, known as selenoproteins. Humans have 25 selenoproteins, most of which are functionally characterized as oxidoreductases, where the Sec residue plays a catalytic role in redox regulation and antioxidant activity. Glutathione peroxidase plays a pivotal role in scavenging and inactivating hydrogen and lipid peroxides, whereas thioredoxin reductase reduces oxidized thioredoxins as well as non-disulfide substrates, such as lipid hydroperoxides and hydrogen peroxide. Selenoprotein R protects the cell against oxidative damage by reducing methionine-R-sulfoxide back to methionine. Selenoprotein O regulates redox homeostasis with catalytic activity of protein AMPylation. Moreover, endoplasmic reticulum (ER) membrane selenoproteins (SelI, K, N, S, and Sel15) are involved in ER membrane stress regulation. Selenoproteins containing the CXXU motif (SelH, M, T, V, and W) are putative oxidoreductases that participate in various cellular processes depending on redox regulation. Herein, we review the recent studies on the role of selenoproteins in redox regulation and their physiological functions in humans, as well as their role in various diseases.

scholarly journals Thioredoxin Reductase 2 (TXNRD2) Mutation Associated With Familial Glucocorticoid Deficiency (FGD)

2014 ◽  
Vol 99 (8) ◽  
pp. E1556-E1563 ◽  
Author(s):  
Rathi Prasad ◽  
Li F. Chan ◽  
Claire R. Hughes ◽  
Juan P. Kaski ◽  
Julia C. Kowalczyk ◽  
...  
Keyword(s):  
Cell Line ◽  
Redox Regulation ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Antioxidant Systems ◽  
Homozygous Mutation ◽  
Inherited Disease ◽  
Knockout Mouse Model ◽  
Disease Trait ◽  
Glucocorticoid Deficiency

Context: Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis. Objective: We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD. Design: Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis. Setting: The study was conducted on patients from three pediatric centers in the United Kingdom. Patients: Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study. Interventions: There were no interventions. Main Outcome Measure: Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured. Results: A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line. Conclusion: In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

scholarly journals Cytotoxicity of Gymnopilus purpureosquamulosus extracts on hematologic malignant cells through activation of the SAPK/JNK signaling pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0252541
Author(s):  
Rich Milton Dulay ◽  
Benigno C. Valdez ◽  
Yang Li ◽  
Seemanti Chakrabarti ◽  
Braham Dhillon ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Thioredoxin Reductase ◽  
Annexin V ◽  
Hematologic Malignancies ◽  
Myeloma Cell ◽  
Redox Status ◽  
Multiple Myeloma Cell ◽  
Protein Levels ◽  
Formidable Challenge

Treatment of hematologic malignancies is a formidable challenge for hematologists and there is an urgent need to identify safe and efficacious agents either via synthesis in the laboratory or isolation from natural products. Here, we report the cytotoxicity of extracts from mushroom Gymnopilus purpureosquamulosus Høil (G. pps) and describe its molecular mechanisms. Using leukemia, lymphoma and multiple myeloma cell lines, 28–35 ppm G. pps extract inhibited cell proliferation by ~46–79%, which correlates with activation of apoptosis as indicated by increase in annexin V-positive cells (~5–8-fold), production of reactive oxygen species (~2–3-fold), cells in sub G0/G1 phase (~3–13-fold), caspase 3 enzymatic activity (~1.6–2.9-fold), DNA fragmentation, PARP1 cleavage and down-regulation of prosurvival proteins. Mitochondrial membrane potential decreased and leakage of pro-apoptotic factors to cytoplasm was observed, consistent with the activation of intrinsic apoptosis. Western blot analysis showed activation of the ASK1-MEK-SAPK/JNK and ASK1-P38 MAPK pathways possibly due to changes in the cellular redox status as suggested by decreased protein levels of peroxiredoxin, thioredoxin and thioredoxin reductase. Moreover, antioxidant N-acetylcysteine alleviated the cytotoxicity of G. pps. Pharmacological inhibition of SAPK/JNK and P38 alleviated the G. pps-mediated cytotoxicity. The extract activated apoptosis in leukemia and lymphoma patient cell samples but not in mononuclear cells from healthy donors further supporting the therapeutic values of G. pps for hematologic malignancies.

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