Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Wang S et al. (2020) Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders..... Expression of this gene decreases in aging granulosa cells. //////////////////
Functional analysis by Jin et al. (1997) showed that PRDX4 protected glutamine synthetase (GLUL; 138290) from inactivation. Regulatory role for a novel human thioredoxin peroxidase in NF-kappaB activation. Jin DY et al. (1998) Reduction-oxidation (redox) plays a critical role in NF-kappaB activation. Diverse stimuli appear to utilize reactive oxygen species (e.g. hydrogen peroxide) as common effectors for activating NF-kappaB. Antioxidants govern intracellular redox status, and many such molecules can reduce H2O2. However, functionally, it does appear that different antioxidants are variously selective for redox regulation of certain transcription factors such as NF-kappaB. For NF-kappaB, thioredoxin has been described to be a more potent antioxidant than either glutathione or N-acetylcysteine. Thioredoxin peroxidase is the immediate enzyme that links reduction of H2O2 to thioredoxin. Several putative human thioredoxin peroxidases have been identified using recursive sequence searches/alignments with yeast or prokaryotic enzymes. None has been characterized in detail for intracellular function(s). Here, we describe a new human thioredoxin peroxidase, antioxidant enzyme AOE372, identified by virtue of its protein-protein interaction with the product of a proliferation association gene, pag, which is also a thiol-specific antioxidant. In human cells, AOE372 defines a redox pathway that specifically regulates NF-kappaB activity via a modulation of IkappaB-alpha phosphorylation in the cytoplasm. We show that AOE372 activity is regulated through either homo- or heterodimerization with other thiol peroxidases, implicating subunit assortment as a mechanism for regulating antioxidant specificities. AOE372 function suggests thioredoxin peroxidase as an immediate regulator of H2O2-mediated activation of NF-kappaB.////////////////// ///////////
NCBI Summary:
The protein encoded by this gene is an antioxidant enzyme and belongs to the peroxiredoxin family. The protein is localized to the cytoplasm. Peroxidases of the peroxiredoxin family reduce hydrogen peroxide and alkyl hydroperoxides to water and alcohol with the use of reducing equivalents derived from thiol-containing donor molecules. This protein has been found to play a regulatory role in the activation of the transcription factor NF-kappaB. [provided by RefSeq, Jul 2008]
General function
Enzyme
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Luteolysis
Comment
Changes in the expression of steroidogenic and antioxidant genes in the mouse corpus luteum during luteolysis Foyouzi N, ET AL .
Luteal cell death plays a key role in the regulation of the reproductive process in all mammals. It is also known that prostaglandin (PG) F(2alpha) is one of the main factors that cause luteal demise; still, the effects of PGF(2alpha) on luteal gene transcription have not been fully explored. Using microarray and reverse transcription-polymerase chain reaction, we have profiled gene expression in the corpus luteum (CL) of wild-type and PGF(2alpha) receptor knockout mice on Day 19 of pregnancy. Western blot analysis of selected genes was also performed. Because luteolysis has been shown to be associated with increased oxygen radical production and decreased progesterone synthesis, we report here changes observed in the expression of antioxidant and steroidogenic genes. We found that luteal cells express all genes necessary for progesterone synthesis, whether or not they had undergone luteolysis; however, an increase in mRNA levels of enzymes involved in androgen production, along with a decrease in the expression of enzymes implicated in estrogen synthesis, was observed. We also identified six genes committed to the elimination of free radical species that are dramatically down-regulated in the CL of wild-type animals with respect to PGF(2alpha) receptor knockout mice. Similar changes in the expression of steroidogenic and antioxidant genes were found in the CL of wild-type animals between Days 15 and 19 of pregnancy. It is proposed that an increase in the androgen:estrogen biosynthesis ratio, along with a significantly reduced expression of free radical scavenger proteins, may play an important role in the luteolytic process.
The results also showed that the mRNA of all members of the peroxiredoxin (Prdx) family of proteins are expressed in the CL. Prdx1, Prdx2, Prdx3, and Prdx6 mRNA were found to be highly expressed, while Prdx4 and Prdx5 were found to be present at low levels (Fig. 3B, lower). Low relative expression levels of catalase (Cat) were found (Fig. 3, lower). Messenger RNA levels of Prdx6 were significantly lower in wild-type mice compared with PGF2 receptor knockout animals (Fig. 3B, top).
High luteal mRNA levels for glutathione peroxidase (Gpx) types 1, 3, and 4 were found in both wild-type and PGF2 receptor knockout mice (Fig. 3B, lower), and no differences were found in mRNA levels of these enzymes between these two groups (Fig. 3B, top).
It was also found that luteal cells express the mRNA for the -tocopherol transfer protein (Ttpa). Levels of Ttpa mRNA were 10-fold higher in luteal cells of PGF2 receptor knockout mice than in cells of wild-type animals (Fig. 3B). In wild-type mice, a significant decrease in microsomal glutathione S-transferase (Mgst) 2 mRNA levels was found compared with levels in PGF2 receptor knockout mice, but no differences were found in the expression of Mgst1 and Mgst3 (Fig. 3B, top). Mgst1 mRNA was found to be expressed at very high relative levels, whereas Mgst2 and Mgst3 were expressed at moderate and low relative levels, respectively.
Peroxiredoxin 4, a new oxidative stress marker in follicular fluid, may predict in vitro fertilization and embryo transfer outcomes. Yi Q et al. (2020) Peroxiredoxin 4 (Prdx4), a member of the Prdx family, can catalyze the reduction of reactive oxygen species. This study aims to explore whether Prdx4 can serve as an effective marker in follicular fluid (FF) for predicting in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle outcomes. In this prospective study, all participants were recruited from the center of clinical reproductive medicine from 2017 September to 2018 December. Women with tubal or male factor infertility undergoing their first IVF/ICSI cycle were recruited (n=138). FF samples from each patient were collected on the day of oocyte retrieval. Prdx4 concentrations were measured, and the correlation between Prdx4 levels and IVF outcomes was analyzed. The results showed that pregnant women had higher levels of Prdx4 than nonpregnant women. Prdx4 was positively correlated with the oocyte fertilization rate (r =0.334; P=0.011) and good quality embryo rate (r =0.326; P=0.013). Furthermore, we found that the clinical pregnancy rate was positively correlated with Prdx4 levels in a concentration-dependent manner in the Prdx4 quartiles (<13.38, 13.83-16.93, 16.93-22.93, >22.93 ng/mL). The fertilization rates, clinical pregnancy rates and live pregnancy rates were all significantly higher in the highest Prdx4 quartile group than in the lowest quartile. Moreover, the results indicated that Prdx4 had an area under the receiver operating characteristic curve (AUC) of 0.754, corresponding to an optimal cutoff point of 22.30 ng/mL. Our results provide evidence that higher expression of antioxidants, such as Prdx4, in the FF of IVF patients tends to indicate a higher likelihood of pregnancy through an oocyte quality mechanism.//////////////////
Implication of differential Peroxiredoxin 4 expression with age in ovaries of mouse and human for ovarian aging. Qian Y et al. (2016) Ovarian aging has been associated with increased levels of reactive oxygen species and the deficiencies of antioxidant defense. The antioxidant peroxiredoxin 4 (Prdx4), as a member of Prdx protein family, controls cellular oxidative stress by reducing H2O2 levels. In previous studies, we provided evidence that Prdx4 was abundantly expressed in mouse and human ovaries and expression of Prdx4 in matured follicles was higher than that in immatured follicles. Accordingly, we speculated that Prdx4 expression could be associated with follicle development and it may be as a part of the antioxidative mechanism in follicular development. In this study, we demonstrated that Prdx4 was mainly expressed in the granulosa cells of mouse ovaries and the expression levels significantly increased along development of follicles. However, the expression levels of Prdx4 decreased when mice reached the aged stage (18 months old). Likewise a similar pattern that was observed in the mice study was also found in human ovaries where Prdx4 was expressed lower in premenopausal women than young women. Subsequent in vitro experiments indicated that Prdx4 mRNA and protein levels both increased with H2O2 in a concentration-dependent manner, but decreased rapidly with high concentration of H2O2, and the changes were closely related to cell proliferation. Taken together, these findings argue our understanding on the role of oxidative stress and antioxidant in follicular development and ovarian aging.//////////////////
Downregulated Expression of Peroxiredoxin 4 in Granulosa Cells from Polycystic Ovary Syndrome. Meng Y 2013 et al.
Peroxiredoxin 4 (PRDX4), a member of Peroxiredoxin (PRDX) family, is a typical 2-Cys PRDX. PRDX4 monitors the oxidative burden within cellular compartment and reduces hydrogen peroxide and alkyl hydroperoxide related to oxidative stress and apoptosis. Antioxidant, like PRDX4, may promote follicle development and participate in the pathophysiology of PCOS. In our previous study, we found that PRDX4 was expressed in mice oocyte cumulus oophorus complex, and that PRDX4 could be associated with follicle development. In this study, we explored the expression of PRDX4 in human follicles and possible role of PRDX4 in PCOS pathophysiology. Our data showed that PRDX4 was mainly expressed in granulosa cells in human ovaries. When compared to control group, both PRDX4 mRNA level and protein level decreased in PCOS group. The lowered levels of PRDX4 may relate to oxidative stress in the pathophysiologic progress of PCOS. Furthermore, expression of PRDX4 in the granulosa cells of in vivo or in vitro matured follicles was higher than that in immatured follicles, which suggested that PRDX4 may have a close relationship with follicular development. Altogether, our findings may provide new clues of the pathophysiologic mechanism of PCOS and potential therapeutic strategy using antioxidant, like PRDX4.
/////////////////////////
Follicle stages
Corpus luteum
Comment
Peroxiredoxin 4 protects against ovarian ageing by ameliorating D-galactose-induced oxidative damage in mice. Liang X et al. (2020) Peroxiredoxin 4 (Prdx4), a member of the Prdx family, is a vital ER-resident antioxidant in cells. As revealed in our previous study, Prdx4 expression was detected in ovarian granulosa cells and was closely related to ovarian function. This research aimed to explore the effect and underlying molecular mechanism of the protective role of Prdx4 against D-gal-induced ovarian ageing in mice. The D-gal-induced ovarian ageing model has been extensively used to study the mechanisms of premature ovarian failure (POF). In this study, adult Prdx4-/- and wild-type mice were intraperitoneally injected with D-gal (150 mg/kg/day) daily for 6 weeks. Ovarian function, granulosa cell apoptosis, oxidative damage and ER stress in the ovaries were evaluated in the two groups. Ovarian weight was significantly lower, the HPO axis was more strongly disrupted, and the numbers of atretic follicles and apoptotic granulosa cells were obviously higher in Prdx4-/- mice. In addition, Prdx4-/- mice showed increased expression of oxidative damage-related factors and the ovarian senescence-related protein P16. Moreover, the levels of the proapoptotic factors CHOP and activated caspase-12 protein, which are involved in the ER stress pathway, and the level of the apoptosis-related BAX protein were elevated in the ovaries of Prdx4-/- mice. Thus, D-gal-induced ovarian ageing is accelerated in Prdx4-/- mice due to granulosa cell apoptosis via oxidative damage and ER stress-related pathways, suggesting that Prdx4 is a protective agent against POF.//////////////////