Glutaredoxin Interacts with GR and AhpC to Enhance Low-Temperature Tolerance of Antarctic Psychrophile Psychrobacter sp. ANT206.

Glutaredoxin (Grx) is an important oxidoreductase to maintain the redox homoeostasis of cells. In our previous study, cold-adapted Grx from Psychrobacter sp. ANT206 (PsGrx) has been characterized. Here, we constructed an in-frame deletion mutant of psgrx (Δpsgrx). Mutant Δpsgrx was more sensitive to low temperature, demonstrating that psgrx was conducive to the growth of ANT206. Mutant Δpsgrx also had more malondialdehyde (MDA) and protein carbonylation content, suggesting that PsGrx could play a part in the regulation of tolerance against low temperature. A yeast two-hybrid system was adopted to screen interacting proteins of 26 components. Furthermore, two target proteins, glutathione reductase (GR) and alkyl hydroperoxide reductase subunit C (AhpC), were regulated by PsGrx under low temperature, and the interactions were confirmed via bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (Co-IP). Moreover, PsGrx could enhance GR activity. trxR expression in Δpsgrx, Δahpc, and ANT206 were illustrated 3.7, 2.4, and 10-fold more than mutant Δpsgrx Δahpc, indicating that PsGrx might increase the expression of trxR by interacting with AhpC. In conclusion, PsGrx may participate in glutathione metabolism and ROS-scavenging by regulating GR and AhpC to protect the growth of ANT206. These findings preliminarily suggest the role of PsGrx in the regulation of oxidative stress, which could improve the low-temperature tolerance of ANT206.

Peroxiredoxin 1 Controls Ovulation and Ovulated Cumulus-Oocyte Complex Activity through TLR4-Derived ERK1/2 Signaling in Mice.

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus-oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 µg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors' mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation.

PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53.

Colorectal cancer is the most common gastrointestinal cancer and causes severe damage to human health. PRDX2 is a member of the peroxiredoxin family reported to have a high level of expression in colorectal cancer. However, the mechanisms by which PRDX2 promotes the proliferation of colorectal cancer are still unclear. Here, the results indicated that PRDX2 expression was upregulated in colorectal cancer and closely correlated with poor prognosis. Functionally, PRDX2 promoted the proliferation of colorectal cancer cells. Mechanistically, PRDX2 could bind RPL4, reducing the interaction between RPL4 and MDM2. These findings demonstrate that the oncogenic property of PRDX2 may be attributed to its regulation of the RPL4-MDM2-p53 pathway, leading to p53 ubiquitinated degradation.

PRDX4 Improved Aging-Related Delayed Wound Healing in Mice.

Aging-related delayed wound healing is an issue of concern worldwide. Oxidative stress is involved in wound healing. Antioxidative enzymes have various roles in this process. PRDX4, a member of the PRDX family, is upregulated after injury. To investigate the effects of PRDX4 on aging-related wound healing, we subjected C57BL/6J (wild-type), human Prdx4‒transgenic (i.e., hPrdx4+/+), Prdx4-knockout (i.e., Prdx4-/y) mice of three age groups (young, adult, and aged) to skin wound formation. The overexpression of PRDX4 accelerated wound healing in adult and aged mice but not in young mice. Aged hPrdx4+/+ mice showed reduced oxidative stress and inflammation, lower numbers of neutrophils, increased macrophage infiltration, increased angiogenesis, and increased GF levels. The granulation tissue of adult and aged hPrdx4+/+ mice was richer in fibroblasts than that in the matched wild-type mice. PRDX4 deficiency was associated with mortality in adult and aged mice. In vitro, the overexpression of PRDX4 promoted the proliferation and migration of fibroblasts derived from adult or aged mice and made fibroblasts more resistant to the cytotoxicity of hydrogen peroxide. PRDX4 is essential for wound healing and can improve the healing process from multiple aspects, suggesting that it may be very beneficial to wound treatment, especially for the elderly.

Peroxiredoxin alleviates the fitness costs of imidacloprid resistance in an insect pest of rice.

Chemical insecticides have been heavily employed as the most effective measure for control of agricultural and medical pests, but evolution of resistance by pests threatens the sustainability of this approach. Resistance-conferring mutations sometimes impose fitness costs, which may drive subsequent evolution of compensatory modifier mutations alleviating the costs of resistance. However, how modifier mutations evolve and function to overcome the fitness cost of resistance still remains unknown. Here we show that overexpression of P450s not only confers imidacloprid resistance in the brown planthopper, Nilaparvata lugens, the most voracious pest of rice, but also leads to elevated production of reactive oxygen species (ROS) through metabolism of imidacloprid and host plant compounds. The inevitable production of ROS incurs a fitness cost to the pest, which drives the increase or fixation of the compensatory modifier allele T65549 within the promoter region of N. lugens peroxiredoxin (NlPrx) in the pest populations. T65549 allele in turn upregulates the expression of NlPrx and thus increases resistant individuals' ability to clear the cost-incurring ROS of any source. The frequent involvement of P450s in insecticide resistance and their capacity to produce ROS while metabolizing their substrates suggest that peroxiredoxin or other ROS-scavenging genes may be among the common modifier genes for alleviating the fitness cost of insecticide resistance.

Peroxiredoxins couple metabolism and cell division in an ultradian cycle.

Redox cycles have been reported in ultradian, circadian and cell cycle-synchronized systems. Redox cycles persist in the absence of transcription and cyclin-CDK activity, indicating that cells harbor multiple coupled oscillators. Nonetheless, the causal relationships and molecular mechanisms by which redox cycles are embedded within ultradian, circadian or cell division cycles remain largely elusive. Yeast harbor an ultradian oscillator, the yeast metabolic cycle (YMC), which comprises metabolic/redox cycles, transcriptional cycles and synchronized cell division. Here, we reveal the existence of robust cycling of H2O2 and peroxiredoxin oxidation during the YMC and show that peroxiredoxin inactivation disrupts metabolic cycling and abolishes coupling with cell division. We find that thiol-disulfide oxidants and reductants predictably modulate the switching between different YMC metabolic states, which in turn predictably perturbs cell cycle entry and exit. We propose that oscillatory H2O2-dependent protein thiol oxidation is a key regulator of metabolic cycling and its coordination with cell division.

Testis-specific peroxiredoxin 4 variant is not absolutely required for spermatogenesis and fertility in mice.

PRDX4, a member of peroxiredoxin family, is largely concentrated in the endoplasmic reticulum (ER) and plays a pivotal role in the redox relay during oxidative protein folding as well as in peroxidase reactions. A testis-specific PRDX4 variant transcript (PRDX4t) lacks the conventional exon 1, which encodes the signal peptide that is required for entry into the ER lumen, but instead carries alternative exon 1, which is transcribed from the upstream promoter in a testis-specific manner and results in the PRDX4t protein being localized in the cytosol. However, the potential roles of PRDX4t in male genital action remain unknown. Using a CRISPR/Cas9 system, we first disrupted the testis-specific promoter/exon 1 and generated mice that were specifically deficient in PRDX4t. The resulting PRDX4t knockout (KO) mice underwent normal spermatogenesis and showed no overt abnormalities in the testis. Mating PRDX4t KO male mice with wild-type (WT) female mice produced normal numbers of offspring, indicating that a PRDX4t deficiency alone had no effect on fertility in the male mice. We then generated mice lacking both PRDX4 and PRDX4t by disrupting exon 2, which is communal to these variants. The resulting double knockout (DKO) mice were again fertile, and mature sperm isolated from the epididymis of DKO mice exhibited a normal fertilizing ability in vitro. In the meantime, the protein levels of glutathione peroxidase 4 (GPX4), which plays an essential role in the disulfide bond formation during spermatogenesis, were significantly increased in the testis and caput epididymis of the DKO mice compared with the WT mice. Based on these results, we conclude that the disruption of the function of PRDX4t in the spermatogenic process appears to be compensated by other factors including GPX4.

Peroxiredoxin 2 deficiency reduces white adipogenesis due to the excessive ROS generation.

Reactive oxygen species (ROS) act as signaling molecules to regulate various cell functions. Numerous studies have demonstrated ROS to be essential for the differentiation of adipocytes. Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes in mammalian cells. Prx2 is present in the cytoplasm and cell membranes and demonstrates ROS scavenging activity. We focused on Prx2 involvement in regulating adipogenesis and lipid accumulation and demonstrated that Prx2 expression was upregulated during adipocyte differentiation. In addition, the silencing of Prx2 (shPrx2) inhibited adipogenesis by modulating adipogenic gene expression, and cell death was enhanced via increased ROS production in shPrx2-3T3-L1 cells. These results demonstrate that shPrx2 triggers adipocyte cell death and weakens adipocyte function via ROS production. Taken together, our data suggest the participation of Prx2 in adipocyte function and differentiation. Our results also imply that the downregulation of Prx2 activity could help prevent obesity. Overall, findings support the development of ROS-based therapeutic solutions for the treatment of obesity and obesity-related metabolic disorders.

Involvement of peroxiredoxin 2 in cumulus expansion and oocyte maturation in mice.

Peroxiredoxin 2 (Prdx2), an antioxidant enzyme, is expressed in the ovary during the ovulatory process. The aim of the present study was to examine the physiological role of Prdx2 during ovulation using Prdx2-knockout mice and mouse cumulus-oocyte complex (COC) from WT mice. Two days of treatment of immature mice (21-23 days old) with equine chorionic gonadotrophin and followed by treatment with human chorionic gonadotrophin greatly impaired cumulus expansion and oocyte maturation in Prdx2-knockout but not wild-type mice. Treatment of COCs in culture with conoidin A (50µM), a 2-cys Prdx inhibitor, abolished epiregulin (EPI)-induced cumulus expansion. Conoidin A treatment also inhibited EPI-stimulated signal molecules, including signal transducer and activator of transcription-3, AKT and mitogen-activated protein kinase 1/2. Conoidin A treatment also reduced the gene expression of EPI-stimulated expansion-inducing factors (hyaluronan synthase 2 (Has2), pentraxin 3 (Ptx3), TNF-α induced protein 6 (Tnfaip6) and prostaglandin-endoperoxide synthase 2 (Ptgs2)) and oocyte-derived factors (growth differentiation factor 9 (Gdf9) and bone morphogenetic protein 15 (Bmp15)). Furthermore, conoidin A inhibited EPI-induced oocyte maturation and the activity of connexins 43 and 37. Together, these results demonstrate that Prdx2 plays a role in regulating cumulus expansion and oocyte maturation during the ovulatory process in mice, probably by modulating epidermal growth factor receptor signalling.

PRDX2 plays an oncogenic role in esophageal squamous cell carcinoma via Wnt/ß-catenin and AKT pathways.

PURPOSE: To investigate the role of PRDX2 in esophageal carcinoma (ESCA). METHODS: The expression of PRDX2 was detected in ESCA tissues. And PRDX2 expression in two ESCA cell lines was knocked down. Cell proliferation, metastasis and invasion were detected in these cells. RESULTS: Here, we found that PRDX2 expression was significantly increased in ESCA tissues and was associated with a poor prognosis in ESCA patients. In addition, PRDX2 expression was significantly associated with pathological grading, infiltration degree and 5-year survival time in ESCA patients. Next, we knocked down PRDX2 expression by PRDX2-shRNA transfection in two ESCA cell lines, Eca-109 and TE-1. Proliferation analysis indicated that in vitro PRDX2 knockdown decreased growth and clone formation of ESCA cells. Scratch and transwell assays indicated that cell migration and invasion were significantly inhibited by PRDX2 knockdown. In addition, PRDX2 knockdown inhibited cell cycle of ESCA cells and down-regulated Cyclin D1-CDK4/6. Moreover, PRDX2 knockdown regulated proteins involved in mitochondrial-dependent apoptosis, including increased Bax and Caspase9/3 and decreased Bcl2. Mechanism investigation indicated that PRDX2 knockdown led to inactivation of Wnt/ß-catenin and AKT pathways. CONCLUSIONS: Our data suggest that PRDX2 may function as an oncogene in the development of ESCA via regulating Wnt/ß-catenin and AKT pathways. Our study fills a gap in the understanding of the role of PRDX2 in ESCA and provides a potential target for ESCA treatment.

Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles.

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1ß by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1ß generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1ß-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.

The interactome of 2-Cys peroxiredoxins in Plasmodium falciparum.

Peroxiredoxins (Prxs) are crucially involved in maintaining intracellular H2O2 homeostasis via their peroxidase activity. However, more recently, this class of proteins was found to also transmit oxidizing equivalents to selected downstream proteins, which suggests an important function of Prxs in the regulation of cellular protein redox relays. Using a pull-down assay based on mixed disulfide fishing, we characterized the thiol-dependent interactome of cytosolic Prx1a and mitochondrial Prx1m from the apicomplexan malaria parasite Plasmodium falciparum (Pf). Here, 127 cytosolic and 20 mitochondrial proteins that are components of essential cellular processes were found to interact with PfPrx1a and PfPrx1m, respectively. Notably, our data obtained with active-site mutants suggests that reducing equivalents might also be transferred from Prxs to target proteins. Initial functional analyses indicated that the interaction with Prx can strongly impact the activity of target proteins. The results provide initial insights into the interactome of Prxs at the level of a eukaryotic whole cell proteome. Furthermore, they contribute to our understanding of redox regulatory principles and thiol-dependent redox relays of Prxs in subcellular compartments.

Peroxiredoxin V Reduces ß-Lapachone-induced Apoptosis of Colon Cancer Cells.

BACKGROUND/AIM: Peroxiredoxin (Prx) V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS). Also, Prx V has been shown to mediate cell apoptosis in various cancers. However, the mechanism of Prx V-induced apoptosis in colon cancer cells remains unknown. Thus, in this study we analyzed the effects of Prx V in ß-lapachone-induced apoptosis in SW480 human colon cancer cells. MATERIALS AND METHODS: ß-lapachone-induced apoptosis was analyzed by the MTT assay, western blotting, fluorescence microscopy, Annexin V staining and flow cytometry. RESULTS: Overexpression of Prx V, significantly decreased ß-lapachone-induced cellular apoptosis and Prx V silencing increased ß-lapachone-induced cellular apoptosis via modulating ROS scavenging activity compared to mock SW480 cells. In addition, to further explore the mechanism of Prx V regulated ß-lapachone-induced SW480 cells apoptosis, the Wnt/ß-catenin signaling was studied. The Wnt/ ß-catenin signaling pathway was found to be induced by ß-lapachone. CONCLUSION: Prx V regulates SW480 cell apoptosis via scavenging ROS cellular levels and mediating the Wnt/ß-catenin signaling pathway, which was induced by ß-lapachone.

Peroxiredoxin 4 ameliorates amyloid beta oligomer-mediated apoptosis by inhibiting ER-stress in HT-22 hippocampal neuron cells.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by amyloid beta oligomers (AßO), which induce cell death by triggering oxidative stress and endoplasmic reticulum (ER) stress. Oxidative stress is regulated by antioxidant enzymes, including peroxiredoxins. Peroxiredoxins (Prx) are classified into six subtypes, based on their localization and cysteine residues, and protect cells by scavenging hydrogen peroxide (H2O2). Peroxiredoxin 4 (Prx4) is unique in being localized to the ER; however, whether Prx4 protects neuronal cells from AßO-induced toxicity remains unclear, although Prx4 expression is upregulated in AßO-induced oxidative stress and ER stress. In this study, we established HT-22 cells in which Prx4 was either overexpressed or silenced to investigate its role in AßO-induced toxicity. AßO-stimulation of HT-22 cells with overexpressed Prx4 caused decreases in both AßO-induced ROS and ER stress (followed by ER expansion). In contrast, AßO stimulation caused increases in both ROS and ER stress that were notably higher in HT-22 cells with silenced Prx4 expression than in HT-22 cells. Consequently, Prx4 overexpression decreased apoptotic cell death and ameliorated the AßO-induced increase in intracellular Ca2+. Therefore, we conclude that Prx4 has a protective effect against AßO-mediated oxidative stress, ER stress, and neuronal cell death. Furthermore, these results suggest that Prx4 may be a target for preventing AßO toxicity in AD. Graphical abstract .

Role of peroxiredoxin of the AhpC/TSA family in antioxidant defense mechanisms of Francisella tularensis.

Francisella tularensis is a Gram-negative, facultative intracellular pathogen and the causative agent of a lethal human disease known as tularemia. Due to its extremely high virulence and potential to be used as a bioterror agent, F. tularensis is classified by the CDC as a Category A Select Agent. As an intracellular pathogen, F. tularensis during its intracellular residence encounters a number of oxidative and nitrosative stresses. The roles of the primary antioxidant enzymes SodB, SodC and KatG in oxidative stress resistance and virulence of F. tularensis live vaccine strain (LVS) have been characterized in previous studies. However, very fragmentary information is available regarding the role of peroxiredoxin of the AhpC/TSA family (annotated as AhpC) of F. tularensis SchuS4; whereas the role of AhpC of F. tularensis LVS in tularemia pathogenesis is not known. This study was undertaken to exhaustively investigate the role of AhpC in oxidative stress resistance of F. tularensis LVS and SchuS4. We report that AhpC of F. tularensis LVS confers resistance against a wide range of reactive oxygen and nitrogen species, and serves as a virulence factor. In highly virulent F. tularensis SchuS4 strain, AhpC serves as a key antioxidant enzyme and contributes to its robust oxidative and nitrosative stress resistance, and intramacrophage survival. We also demonstrate that there is functional redundancy among primary antioxidant enzymes AhpC, SodC, and KatG of F. tularensis SchuS4. Collectively, this study highlights the differences in antioxidant defense mechanisms of F. tularensis LVS and SchuS4.

Effects of the Prdx2 depletion on blood pressure and life span in spontaneously hypertensive rats.

Oxidative stress is involved in the pathogenesis of hypertension and hypertensive organ damage. Our previous study suggested that stroke-prone spontaneously hypertensive rats (SHRSP) exhibited greater oxidative stress than SHR and that the stroke incidence was significantly greater in SHRSP than SHR. Therefore, we hypothesized that oxidative stress was responsible for the stroke susceptibility in SHRSP. The present study constructed Prdx2 (a gene coding an antioxidative enzyme)-knockout (KO) SHR to examine whether Prdx2 knockout would make SHR more vulnerable to hypertensive organ damage, including stroke. Prdx2-KO SHR were created using CRISPR/CAS9 for genome editing. Eight-week-old male SHR and Prdx2-KO SHR were fed 1% NaCl for 2 months to induce blood pressure (BP) changes and stroke occurrence. The baseline BP was significantly greater in KO SHR, and this difference disappeared after salt loading. The life span of KO SHR was significantly reduced compared to that of SHR despite no differences in BP under salt-loading. However, no stroke was observed in KO SHR. The severity of hypertensive renal and cardiac injuries did not differ significantly between the two strains, but oxidative stress, evaluated using urinary isoprostane excretion and DHE staining, was greater in KO SHR. These results indicated that the Prdx2-depletion caused a shorter life span and modest BP increase in SHR via increased oxidative stress. The pathophysiological roles of oxidative stress in this model should be clarified in future studies.

Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice.

BACKGROUND AND AIMS: Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4-/y) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model. MATERIALS AND METHODS: Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4-/y male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues. RESULTS: PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4-/y mice were significantly higher compared to those of WT mice. Specifically, PRDX4-/y mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4-/y compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4-/y compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4-/y compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4-/y than WT mice, which was consistent with severe ER stress under PRDX4 deficiency. CONCLUSION: Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4-/y than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation.

The multiple roles of peroxiredoxins in tick blood feeding.

Hydrogen peroxide (H2O2) and hydroxyl radicals (HO·) are generated through partial reduction of oxygen. The HO· are the most reactive and have a shorter half-life than H2O2, they are produced from comparatively stable H2O2 through Fenton reaction. Although controlling HO· is important and biologically advantageous for organisms, it may be difficult. Ticks are obligate hematophagous arthropods that need blood feeding for development. Ticks feed on vertebrate blood containing high levels of iron. Ticks also concentrate iron-containing host blood, leading to high levels of iron in ticks. Host-derived iron may react with oxygen in the tick body, resulting in high concentrations of H2O2. On the other hand, ticks have antioxidant enzymes, such as peroxiredoxins (Prxs), to scavenge H2O2. Gene silencing of Prxs in ticks affects their blood feeding, oviposition, and H2O2 concentration. Therefore, Prxs could play important roles in ticks' blood feeding and oviposition through the regulation of the H2O2 concentration. This review discusses the current knowledge of Prxs in hard ticks. Tick Prxs are also multifunctional molecules related to antioxidants and immunity like other organisms. In addition, tick Prxs play a role in regulating the host immune response for ticks' survival in the host body. Tick Prx also can induce Th2 immune response in the host. Thus, this review would contribute to the further understanding of the tick's antioxidant responses during blood feeding and the search for a candidate target for tick control.

Peroxiredoxin 5 regulates adipogenesis-attenuating oxidative stress in obese mouse models induced by a high-fat diet.

Elevated levels of reactive oxygen species (ROS) are a hallmark of obesity. Peroxiredoxin 5 (Prx5), which is a cysteine-dependent peroxidase enzyme, has an intensive ROS scavenging activity because it is located in the cytosol and mitochondria. Therefore, we focused on the role of Prx5 in regulating mitochondrial ROS and adipogenesis. We demonstrated that Prx5 expression was upregulated during adipogenesis and Prx5 overexpression suppressed adipogenesis by regulating cytosolic and mitochondrial ROS generation. Silencing Prx5 promoted preadipocytes to differentiate into adipocytes accumulating lipids by activating adipogenic protein expression. Prx5-deletion mice fed on a high-fat diet (HFD) exhibited significant increase in body weight, enormous fat pads, and adipocyte hypertrophy in comparison to wild type mice. Prx5 deletion also remarkably induced adipogenesis-related gene expression in white adipose tissue. These phenotypic changes in Prx5-deletion mice were accompanied with lipid metabolic disorders, such as excessive lipid accumulation in the liver, severe hepatic steatosis, and high levels of triglyceride in the serum. These results demonstrated that Prx5 deletion increased the susceptibility to HFD-induced obesity and several of its associated metabolic disorders. In conclusion, we suggest that Prx5 inhibits adipogenesis by modulating ROS generation and adipogenic gene expression, implying that Prx5 may serve as a potential strategy to prevent and treat obesity.

Peroxiredoxin 2 deficiency accelerates age-related ovarian failure through the reactive oxygen species-mediated JNK pathway in mice.

Reactive oxygen species (ROS) produced in biological reactions have been shown to contribute to ovarian aging. Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that protects cells by scavenging ROS; however, its effect on age-related, oxidative stress-associated ovarian failure has not been reported. Here, we investigated its role in age-related ovarian dysfunction and 4-vinylcyclohexene diepoxide (VCD)-induced premature ovarian failure using Prx2-deficient mice. Compared to those in wildtype (WT) mice, serum levels of anti-Müllerian hormone, 17ß-estradiol, and progesterone and numbers of follicles and corpora lutea were significantly lower in 18-month-old Prx2-/- mice. Moreover, levels of Bax, cytochrome c, cleaved caspase-3, and phosphorylated JNK proteins were higher and numbers of apoptotic (terminal deoxynucleotidyl transferase dUTP nick end labeling-positive) cells were considerably greater in 18-month-old Prx2-/- ovaries than WT ovaries. Furthermore, the effects of the ovarian toxicant VCD in significantly enhancing ROS levels and apoptosis through activation of JNK-mediated apoptotic signaling were more pronounced in Prx2-/- than WT mouse embryonic fibroblasts. Expression of the steroidogenic proteins StAR, CYP11A1, and 3ß-HSD and serum levels of 17ß-estradiol and progesterone were also reduced to a greater extent in Prx2-/- mice than WT mice after VCD injection. This reduced steroidogenesis was rescued by addition of the Prx mimic ebselen or JNK inhibitor SP600125. This constitutes the first report that Prx2 deficiency leads to acceleration of age-related or VCD-induced ovarian failure by activation of the ROS-induced JNK pathway. These findings suggest that Prx2 plays an important role in preventing accelerated ovarian failure by inhibiting ROS-induced JNK activation.