RESUMEN

The role of peroxiredoxin 1 (PRDX1), a crucial enzyme that reduces reactive oxygen and nitrogen species levels in HepG2 human hepatocellular carcinoma (HCC) cells, in the regulation of HCC cell stemness under oxidative stress and the underlying mechanisms remain largely unexplored. Here, we investigated the therapeutic potential of non-thermal plasma in targeting cancer stem cells (CSCs) in HCC, focusing on the mechanisms of resistance to oxidative stress and the role of PRDX1. By simulating oxidative stress conditions using the plasma-activated medium, we found that a reduction in PRDX1 levels resulted in a considerable increase in HepG2 cell apoptosis, suggesting that PRDX1 plays a key role in oxidative stress defense mechanisms in CSCs. Furthermore, we found that HepG2 cells had higher spheroid formation capability and increased levels of stem cell markers (CD133, c-Myc, and OCT-4), indicating strong stemness. Interestingly, PRDX1 expression was notably higher in HepG2 cells than in other HCC cell types such as Hep3B and Huh7 cells, whereas the expression levels of other PRDX family proteins (PRDX 2-6) were relatively consistent. The inhibition of PRDX1 expression and peroxidase activity by conoidin A resulted in markedly reduced stemness traits and increased cell death rate. Furthermore, in a xenograft mouse model, PRDX1 downregulation considerably inhibited the formation of solid tumors after plasma-activated medium (PAM) treatment. These findings underscore the critical role of PRDX 1 in regulating stemness and apoptosis in HCC cells under oxidative stress, highlighting PRDX1 as a promising therapeutic target for NTP-based treatment in HCC.

RESUMEN

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t , half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

RESUMEN

Oxidative stress plays an essential role in the progression of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer's disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we evaluated whether Peroxiredoxin 1 (Prx1) affects STZ-induced AD-like pathology and cellular toxicity. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed the STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting against oxidative stress.

Asunto(s)

Enfermedad de Alzheimer , Calcio , Calpaína , Quinasa 5 Dependiente de la Ciclina , Hipocampo , Mitocondrias , Neuronas , Peroxirredoxinas , Estreptozocina , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/etiología , Quinasa 5 Dependiente de la Ciclina/metabolismo , Quinasa 5 Dependiente de la Ciclina/genética , Estreptozocina/toxicidad , Hipocampo/metabolismo , Hipocampo/patología , Neuronas/metabolismo , Neuronas/patología , Calpaína/metabolismo , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Mitocondrias/metabolismo , Ratones , Calcio/metabolismo , Línea Celular , Estrés Oxidativo , Apoptosis , Dinaminas/metabolismo , Dinaminas/genética , Fosforilación , Proteínas tau/metabolismo , Transducción de Señal

RESUMEN

BACKGROUND: The purpose of this study was to investigate the photoprotection effect of peroxiredoxin 1 (PRDX1) protein in ultraviolet B (UVB) irradiation-induced damage of retinal pigment epithelium (RPE) and its possible molecular mechanism. METHODS: ARPE-19 cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the PRDX1 expression. The corresponding kits were employed to measure the levels or activities of lactate dehydrogenase (LDH), 8-hydroxy-2-deoxyguanosine (8-OHdG), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD). Western blotting was applied to examine PRDX1 expression and mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. RESULTS: After exposure to 20 mJ/cm2 intensity of UVB irradiation for 24 h, ARPE-19 cells viability was decreased, the leakage degree of LDH and 8-OHdG were increased, and cell apoptosis was elevated. The expression of PRDX1 was significantly down-regulated in UVB-induced ARPE-19 cells. The low expression of PRDX1 was involved in high irradiation intensity. Overexpression of PRDX1 increased cell activity, decreased cell apoptosis, and LDH as well as 8-OHdG leakage in UVB-induced ARPE-19 cells. In addition to alleviating UVB-induced cell damage, PRDX1 overexpression also inhibited UVB-induced oxidative stress (down-regulation of ROS and MDA levels, up-regulation of GSH-Px and SOD activities) and the activation of MAPK signaling pathway in ARPE-19 cells. CONCLUSION: PRDX1 exerts a photoprotection effect on RPE by attenuating UVB-induced cell damage and inhibiting oxidative stress, which can be attributed to the inhibition of MAPK signaling pathway activation.

Asunto(s)

Apoptosis , Supervivencia Celular , Estrés Oxidativo , Peroxirredoxinas , Especies Reactivas de Oxígeno , Epitelio Pigmentado de la Retina , Rayos Ultravioleta , Humanos , Epitelio Pigmentado de la Retina/efectos de la radiación , Epitelio Pigmentado de la Retina/metabolismo , Peroxirredoxinas/metabolismo , Rayos Ultravioleta/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Línea Celular , Western Blotting , Células Cultivadas , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Transducción de Señal

RESUMEN

BACKGROUND: Oral leukoplakia (OLK) is the most common oral potentially malignant disorder (OPMD), which can be malignantly transformed into oral squamous cell carcinoma (OSCC). Peroxiredoxin1(Prx1) has been predicted to bind to Prohibitin2 (PHB2), which confers to affect OLK progression; however, the mechanism of Prx1/PHB2 mediated mitophagy involved in OLK remains unclear. METHODS: This study aimed to explore the mechanism of the Prx1/PHB2 axis on senescence in OLK through mediating mitophagy. The positive rate of Ki67 and the expression of p21, p16, PHB2, and LC3 in human normal, OLK, and OSCC tissues were detected by immunohistochemical staining. The mitophagy and mitochondrial function changes were then analyzed in Prx1 knockdown and Prx1C52S mutations in dysplastic oral keratinocyte (DOK) cells treated with H2O2. In situ Proximity Ligation Assay combined with co-immunoprecipitation was used to detect the interaction between Prx1 and PHB2. RESULTS: Clinically, the positive rate of Ki67 progressively increased from normal to OLK, OLK with dysplasia, and OSCC. Higher p21, p16, PHB2, and LC3 expression levels were observed in OLK with dysplasia than in normal and OSCC tissues. In vitro, PHB2 and LC3II expression gradually increased with the degree of DOK cell senescence. Prx1/PHB2 regulated mitophagy and affected senescence in H2O2-induced DOK cells. Furthermore, Prx1C52S mutation specifically reduced interaction between Prx1 and PHB2. Prx1Cys52 is associated with mitochondrial reactive oxygen species (ROS) accumulated and cell cycle arrest. CONCLUSION: Prx1Cys52 functions as a redox sensor that binds to PHB2 and regulates mitophagy in the senescence of OLK, suggesting its potential as a clinical target.

Asunto(s)

Senescencia Celular , Leucoplasia Bucal , Mitofagia , Prohibitinas , Proteínas Represoras , Humanos , Mitofagia/fisiología , Senescencia Celular/fisiología , Leucoplasia Bucal/patología , Leucoplasia Bucal/metabolismo , Leucoplasia Bucal/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/genética

RESUMEN

Hypoxia is a key trigger in the transformation of oral leukoplakia into oral cancer. However, it is still too early to determine the role of hypoxia in the development of oral leukoplakia. Prx1, an antioxidant protein, upregulated by hypoxia, regulates cellular autophagy in leukoplakia. This study aimed to understand the mechanisms by which hypoxia induces Prx1 expression during autophagy in oral leukoplakia. We used an experimental model of tongue epithelial hyperplasia induced by 4-nitroquinoline-1-oxide (4NQO) and dysplastic oral keratinocytes. Prx1 knockdown DOK cells, Leuk-1 cells and control cells were harvested, and cell proliferation was assayed using the Cell Counting Kit-8. Several hypoxia and autophagy-related proteins were examined using quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and western blotting in cells and mouse tongue tissues. In addition, the ultrastructure of the cells was observed by transmission electron microscopy. Hypoxia induces cell proliferation, autophagic vesicles and the expression of Prx1, BNIP3, LC3II/I and Beclin-1 in DOK and Leuk-1 cells. However, these effects were all attenuated by Prx1 knockdown. Histologically, 4NQO induced epithelial hyperplasia in the tongue mucosa. The expression of proliferation marker PCNA, autophagy-related proteins LC3B and Beclin-1, as well as HIF-1α/BNIP3 was significantly lower in the tongue tissues of Prx1flox/flox:Cre+ mice compared with Prx1flox/flox mice. In Prx1flox/flox:Cre+ mice, an increased expression of HIF-1α/BNIP3, LC3B and Beclin-1 was detected in epithelial hyperplasia tongue tissues compared to normal tissues. The current study suggests that Prx1 may promotes cell proliferation and autophagy in oral leukoplakia cells via the HIF-1α/BNIP3 pathway.

Asunto(s)

Autofagia , Proliferación Celular , Subunidad alfa del Factor 1 Inducible por Hipoxia , Leucoplasia Bucal , Peroxirredoxinas , Transducción de Señal , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Leucoplasia Bucal/patología , Leucoplasia Bucal/metabolismo , Leucoplasia Bucal/genética , Ratones , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Humanos , Lengua/patología , Lengua/metabolismo , Hipoxia de la Célula , Línea Celular , Proteínas Mitocondriales

RESUMEN

Microenvironment and transcriptional plasticity generate subpopulations within the tumor, and the use of BRAF inhibitors (BRAFis) contributes to the rise and selection of resistant clones. We stochastically isolated subpopulations (C1, C2, and C3) from naïve melanoma and found that the clones demonstrated distinct morphology, phenotypic, and functional profiles: C1 was less proliferative, more migratory and invasive, less sensitive to BRAFis, less dependent on OXPHOS, more sensitive to oxidative stress, and less pigmented; C2 was more proliferative, less migratory and invasive, more sensitive to BRAFis, less sensitive to oxidative stress, and more pigmented; and C3 was less proliferative, more migratory and invasive, less sensitive to BRAFis, more dependent on OXPHOS, more sensitive to oxidative stress, and more pigmented. Hydrogen peroxide plays a central role in oxidative stress and cell signaling, and PRDXs are one of its main consumers. The intrinsically resistant C1 and C3 clones had lower MITF, PGC-1α, and PRDX1 expression, while C1 had higher AXL and decreased pigmentation markers, linking PRDX1 to clonal heterogeneity and resistance. PRDX2 is depleted in acquired BRAFi-resistant cells and acts as a redox sensor. Our results illustrate that decreased pigmentation markers are related to therapy resistance and decreased antioxidant defense.

RESUMEN

Peroxiredoxin 1 (Prx1) is an antioxidant protein that may promote the carcinogenesis in oral leukoplakia (OLK). To investigate the effect of Prx1 on the oral mucosal epithelium of OLK, we generated a Prx1 conditional knockout (cKO) mouse model. The mRNA and gRNA were generated using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) technique. An infusion cloning method was used to construct a homologous recombination vector. To obtain the F0 generation mice, fertilized eggs of C57BL/6J mice were microinjected with Cas9 mRNA, gRNA, and a donor vector. Polymerase chain reaction (PCR) amplification and sequencing were used to identify F1 generation mice. Using the cyclization recombination-enzyme-locus of the X-overP1 (Cre-loxP) system, we created a Prx1 cKO mouse model, and the effectiveness of the knockout was confirmed through immunohistochemistry. We examined the influence of Prx1 knockout on the occurrence of OLK in mice by constructing a model of tongue mucosa carcinogenesis induced by 4-nitroquinoline-1-oxide (4NQO). Prx1 modification was present in the F1 generation, as evidenced by PCR amplification and sequencing. Prx1flox/flox: Cre + mice exhibited normal growth and fertility. Immunohistochemical analysis revealed that tongue epithelial cells in Prx1flox/flox: Cre + mice displayed a distinct deletion of Prx1. An examination of the heart, liver, spleen, lung, and kidney tissues revealed no visible histological changes. Histological analysis showed a reduction in the occurrence of the malignant transformation of OLK in the tongue tissues of Prx1flox/flox: Cre + mice. Ki67 immunostaining showed that Prx1 knockout significantly inhibited cell proliferation in the tongue epithelial. Our research developed a conditional knockout mouse model for Prx1. The obtained results provide insights into the function of Prx1 in the development of oral cancer and emphasize its potential as a therapeutic target for precancerous oral lesions.

RESUMEN

Ischemic stroke ranks among the leading causes of death and disability in humans and is accompanied by motor and cognitive impairment. However, the precise mechanisms underlying injury after stroke and effective treatment strategies require further investigation. Peroxiredoxin-1 (PRDX1) triggers an extensive inflammatory cascade that plays a pivotal role in the pathology of ischemic stroke, resulting in severe brain damage from activated microglia. In the present study, we used molecular dynamics simulation and nuclear magnetic resonance to detect the interaction between PRDX1 and a specific interfering peptide. We used behavioral, morphological, and molecular experimental methods to demonstrate the effect of PRDX1-peptide on cerebral ischemia-reperfusion (I/R) in mice and to investigate the related mechanism. We found that PRDX1-peptide bound specifically to PRDX1 and improved motor and cognitive functions in I/R mice. In addition, pretreatment with PRDX1-peptide reduced the infarct area and decreased the number of apoptotic cells in the penumbra. Furthermore, PRDX1-peptide inhibited microglial activation and downregulated proinflammatory cytokines including IL-1ß, IL-6, and TNF-α through inhibition of the TLR4/NF-κB signaling pathway, thereby attenuating ischemic brain injury. Our findings clarify the precise mechanism underlying PRDX1-induced inflammation after ischemic stroke and suggest that the PRDX1-peptide can significantly alleviate the postischemic inflammatory response by interfering with PRDX1 amino acids 70-90 and thereby inhibiting the TLR4/NF-κB signaling pathway. Our study provides a theoretical basis for a new therapeutic strategy to treat ischemic stroke.

RESUMEN

Peroxiredoxin 1 (PRDX1) is an important member of the peroxiredoxin family (PRDX) and is upregulated in a variety of tumors. Previous studies have found that high PRDX1 expression is closely related to the metastasis of oral squamous cell carcinoma (OSCC), but the specific molecular mechanism is elusive. To elucidate the role of PRDX1 in the metastasis process of OSCC, we evaluated the expression of PRDX1 in OSCC clinical specimens and its impact on the prognosis of OSCC patients. Then, the effect of PRDX1 on OSCC metastasis and cytoskeletal reconstruction was explored in vitro and in nude mouse tongue cancer models, and the molecular mechanisms were also investigated. PRDX1 can directly interact with the actin-binding protein Cofilin, inhibiting the phosphorylation of its Ser3 site, accelerating the depolymerization and turnover of actin, promoting OSCC cell movement, and aggravating the invasion and metastasis of OSCC. In clinical samples and mouse tongue cancer models, PRDX1 also increased lymph node metastasis of OSCC and was negatively correlated with the phosphorylation of Cofilin; PRDX1 also reduced the overall survival rate of OSCC patients. In summary, our study identified that PRDX1 may be a potential therapeutic target to inhibit OSCC metastasis.

Asunto(s)

Carcinoma de Células Escamosas , Ratones Desnudos , Neoplasias de la Boca , Peroxirredoxinas , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Factores Despolimerizantes de la Actina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/secundario , Línea Celular Tumoral , Movimiento Celular , Cofilina 1/metabolismo , Regulación Neoplásica de la Expresión Génica , Metástasis Linfática , Ratones Endogámicos BALB C , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/genética , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Fosforilación , Pronóstico , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/genética

RESUMEN

BACKGROUND: Some studies confirmed that erythroblast transformation-specific-related gene (ERG) may be a pathogenic factor of oral squamous cell carcinoma (OSCC). However, the undergoing molecular mechanism has not been elucidated yet. OBJECTIVE: In this study, the investigation will focus on how the transcription factor ERG modulates the biological behaviors of OSCC. METHODS: In this study, cancer tissue specimens and corresponding paracancer tissues were collected from 54 patients. Real-time polymerase chain reaction analysis and Western blots were employed to detect the expression of multiple genes. Cell proliferation assays, Transwell, and flow cytometry assay were utilized to detect the proliferation, invasion, and apoptosis of OSCC cell, respectively. Dual luciferase reporter gene and chromatin immunoprecipitation assays were conducted to verify the regulation of ERG on PRDX1. RESULTS: ERG exhibits high expression levels in OSCC. Inhibition of ERG has been shown to effectively suppress the malignant growth of OSCC cells. Moreover, ERG has been found to transcriptionally upregulate the expression of PRDX1. The knockdown of PRDX1 has demonstrated its ability to inhibit the malignant growth of OSCC cells. Interestingly, when PRDX1 is overexpressed, it attenuates the inhibitory effect of si-ERG on the malignant growth of OSCC cells. This suggests that PRDX1 may play a crucial role in mediating the impact of ERG on malignancy in OSCC cells. CONCLUSION: The transcription factor ERG promotes the expression of PRDX1, which could enhance the proliferation and invasion while inhibiting the apoptosis of OSCC cells.

Asunto(s)

Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias de la Boca , Peroxirredoxinas , Regulador Transcripcional ERG , Regulación hacia Arriba , Humanos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Invasividad Neoplásica , Activación Transcripcional , Femenino , Masculino

RESUMEN

Peroxiredoxin-1 (Prdx1) is a thiol-specific antioxidant enzyme that detoxifies reactive oxygen species (ROS) and regulates the redox status of cells. In this study, the Prdx1 cDNA sequence was isolated from the pre-established Amphiprion clarkii (A. clarkii) (AcPrdx1) transcriptome database and characterized structurally and functionally. The AcPrdx1 coding sequence comprises 597 bp and encodes 198 amino acids with a molecular weight of 22.1 kDa and a predicted theoretical isoelectric point of 6.3. AcPrdx1 is localized and functionally available in the cytoplasm and nucleus of cells. The TXN domain of AcPrdx1 comprises two peroxiredoxin signature VCP motifs, which contain catalytic peroxidatic (Cp-C52) and resolving cysteine (CR-C173) residues. The constructed phylogenetic tree and sequence alignment revealed that AcPrdx1 is evolutionarily conserved, and its most closely related counterpart is Amphiprion ocellaris. Under normal physiological conditions, AcPrdx1 was ubiquitously detected in all tissues examined, with the most robust expression in the spleen. Furthermore, AcPrdx1 transcripts were significantly upregulated in the spleen, head kidney, and blood after immune stimulation by polyinosinic:polycytidylic acid (poly (I:C)), lipopolysaccharide (LPS), and Vibrio harveyi injection. Recombinant AcPrdx1 (rAcPrdx1) demonstrated antioxidant and DNA protective properties in a concentration-dependent manner, as evidenced by insulin disulfide reduction, peroxidase activity, and metal-catalyzed oxidation (MCO) assays, whereas cells transfected with pcDNA3.1(+)/AcPrdx1 showed significant cytoprotective function under oxidative and nitrosative stress. Overexpression of AcPrdx1 in fathead minnow (FHM) cells led to a lower viral copy number following viral hemorrhagic septicemia virus (VHSV) infection, along with upregulation of several antiviral genes. Collectively, this study provides insights into the function of AcPrdx1 in defense against oxidative stressors and its role in the immune response against pathogenic infections in A. clarkii.

Asunto(s)

Proteínas de Peces , Peroxirredoxinas , Filogenia , Vibriosis , Animales , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/inmunología , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Proteínas de Peces/inmunología , Vibriosis/inmunología , Poli I-C/inmunología , Enfermedades de los Peces/inmunología , Inmunidad Innata , Vibrio/inmunología , Vibrio/fisiología , Clonación Molecular , Secuencia de Aminoácidos , Perciformes/inmunología , Lipopolisacáridos/inmunología , Alineación de Secuencia , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

BACKGROUND/AIM: Nasopharyngeal carcinoma (NPC), a common cancer in Southern China, is associated with Epstein-Barr Virus (EBV) infection. Although many therapies for NPC have been established, the definite role of EBV in NPC remains unclear. Therefore, this work focuses on LMP2A, a latent EBV gene, and investigates whether LMP2A is related to peroxiredoxin 1 (PRDX1) in EBV-positive NPC. MATERIALS AND METHODS: The mRNA and protein expression levels of LMP2A, PRDX1, and beta-catenin were compared in patient samples. To identify molecular mechanisms, EBV-negative NP69 and EBV-positive C666-1 NPC cell lines were used. After making an agar cell block for cell slides, the intensity of LMP2A expression was observed visually. To measure the level of reactive oxygen species, both fluorescence microscope and flow cytometry were used. To investigate the intracellular signaling molecular mechanisms with and without the LMP2A gene, reverse transcription polymerase chain reaction and western blotting were used. RESULTS: Both patient samples and cells of nasopharyngeal carcinoma infected with EBV had increased expression of LMP2A compared with controls, and high ROS levels were identified. Cell viability assay showed that LMP2A promoted cell growth by regulating gene expression. Furthermore, LMP2A induced the expression of PRDX1 and beta-catenin. LMP2A also increased the expression of both cyclin B1 and cyclin D1. CONCLUSION: In NPC cells, PRDX1 and beta-catenin were regulated through LMP2A expression, which reduced cell growth through cell cycle-related gene expression. This study suggests that LMP2A could be a target molecule for inhibiting cancer progression in NPC cells infected with EBV.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , beta Catenina/metabolismo , Neoplasias Nasofaríngeas/patología

RESUMEN

In this study, we have investigated the chemopreventive role of 6-shogaol (6-SGL) on benzopyrene (BaP) exposed lung carcinogenesis by modulating PRDX1-associated oxidative stress, inflammation, and proliferation in Swiss albino mouse models. Mice were exposed to BaP (50 mg/kg b.wt) orally twice a week for four consecutive weeks and maintained for 16 weeks, respectively. 6-SGL (30 mg/kg b.wt) were orally administered to mouse 1 h before BaP exposure for 16 weeks. After the experiment's termination, 6-SGL (30 mg/kg b.wt) prevented the loss in body weight, increased lung weight, and the total number of tumors in the mice. Moreover, we observed that 6-SGL treatment reverted the activity of BaP-induced lipid peroxidation and antioxidants in mice. Also, 6-SGL impeded the phosphorylation of MAPK family proteins such as Erk1, p38, and Jnk1 in BaP-exposed mice. PRDX1 is an essential antioxidant protein that scavenges toxic radicals and enhances several antioxidant proteins. Overexpression of PRDX1 substantially inhibits MAPKs, proliferation, and inflammation signaling axis. Hence, PRDX1 is thought to be a novel targeting protein for preventing BaP-induced lung cancer. In this study, we have obtained the 6-SGL treatment in a mouse model that reverted BaP-induced depletion of PRDX1 expression. Moreover, pretreatment of 6-SGL (30 mg/kg b.wt) significantly inhibited enhanced proinflammatory cytokines (TNF-α, IL-6, IL-ß1, IL-10) and proliferative markers (Cyclin-D1, Cyclin-D2, and PCNA) in BaP-exposed mice. The histopathological studies also confirmed that 6-SGL effectively protected the cells with less damage. Thus, the study demonstrated that 6-SGL could be a potential phytochemical and act as a chemopreventive agent in BaP-induced lung cancer by enhancing PRDX1 expression.

Asunto(s)

Antioxidantes , Neoplasias Pulmonares , Ratones , Animales , Antioxidantes/metabolismo , Benzo(a)pireno/toxicidad , Estrés Oxidativo , Pulmón , Carcinogénesis , Inflamación/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/metabolismo , Modelos Animales de Enfermedad , Proliferación Celular , Ciclinas/metabolismo , Ciclinas/farmacología

RESUMEN

Tumour cells often display an active metabolic profile, leading to the intracellular accumulation of reactive oxygen species. As a member of the peroxidase family, peroxiredoxin 1 (PRDX1) functions generally in protecting against cell damage caused by H2O2. Additionally, PRDX1 plays a role as a molecular chaperone in various malignant tumours, exhibiting either tumour-promoting or tumour-suppressing effects. Currently, PRDX1-targeting drugs have demonstrated in vitro anticancer effects, indicating the potential of PRDX1 as a molecular target. Here we discussed the diverse functions of PRDX1 in tumour biology and provided a comprehensive analysis of the therapeutic potential of targeting PRDX1 signalling across various types of cancer.

Asunto(s)

Neoplasias , Peroxirredoxinas , Humanos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Peróxido de Hidrógeno , Oxidación-Reducción , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica

RESUMEN

Acute liver injury (ALI) is a significant causative factor for multiple hepatic diseases. The excessive inflammatory response triggers proinflammatory immune cells recruitment, infiltration and differentiation, further contributing to inflammatory injuries in liver. As a proinflammatory factor, circulating Peroxiredoxin 1 (Prdx1) is elevated in ALI patients and mice. In this study, through carbon tetrachloride (CCl4) and cecal puncture and ligation (CLP)-induced liver injury mice model, we found hepatocytes-derived Prdx1 expression was increased in ALI. After AAV8-Prdx1-mediated Prdx1 knockdown, CCl4 and CLP-induced ALI was alleviated, along with the reduced proinflammatory cytokines, suppressed myeloid cells recruitment, decreased proportions of hepatic macrophages and neutrophils, restrained proinflammatory macrophage differentiation and infiltration. Mechanistically, hepatocyte-derived Prdx1 regulated macrophages through paracrine activation of the TLR4 signal. Our data support the immune and inflammatory regulatory role of Prdx1 in ALI pathological process to suggest its potential therapeutic application and clinical value.

Asunto(s)

Peroxirredoxinas , Receptor Toll-Like 4 , Animales , Humanos , Ratones , Hepatocitos/metabolismo , Hígado/patología , Macrófagos/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Fenotipo , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo

RESUMEN

Peroxiredoxin1(Prx1), also known as natural killer enhancing factor A (NKEF-A), is a crucial antioxidant involving in various cellular activities and immune response against bacterial and viral infection in fish. In the present study, a full-length Prx1 cDNA sequence (TfPrx1) was firstly cloned from roughskin sculpin (Trachidermus fasciatus), which was composed of 1044 bp nucleotides encoding a peptide of 199 amino acids with a molecular weight of 22.35 kDa and a theoretical pI of 6.42, respectively. The predicted peptide was a typical 2-cys Prx containing two conserved characteristic motifs 43FYPLDFTFVCPTEI56 and 170GEVCPA175 with the two conserved peroxidatic and resolving cysteine residuals forming disulfide bond. Quantitative real-time PCR analysis showed that TfPrx1 was ubiquitously expressed in all tested tissues with the highest expression in the intestine. It could be significantly induced following LPS injection and heavy metal exposure. Recombinant TfPrx1 (rTfPrx1) displayed insulin disulfide reduction and ROS-scavenging activity in a concentration-dependent manner, and further exhibited DNA and cytoprotective effects under oxidative stress. These results suggested that TfPrx1 protein may play an important role in fish immune protection from oxidative damage.

Asunto(s)

Perciformes , Peroxirredoxinas , Animales , Secuencia de Aminoácidos , Secuencia de Bases , Alineación de Secuencia , Peroxirredoxinas/genética , Peroxirredoxinas/química , Perciformes/genética , Peces/genética , Péptidos/genética , Disulfuros , Filogenia

RESUMEN

Objectives: Cerebral ischemia/reperfusion (I/R) injury inevitably aggravates the initial cerebral tissue damage following a stroke. Peroxiredoxin 1 (Prdx1) is a representative protein of the endogenous antioxidant enzyme family that regulates several reactive oxygen species (ROS)-dependent signaling pathways, whereas the JNK/caspase-3 proapoptotic pathway has a prominent role during cerebral I/R injury. This study aimed to examine the potential mechanism of Prdx1 in Neuro 2A (N2a) cells following oxygen-glucose deprivation and reoxygenation (OGD/R) injury. Materials and Methods: N2a cells were exposed to OGD/R to simulate cerebral I/R injury. Prdx1 siRNA transfection and the JNK inhibitor (SP600125) were used to interfere with their relative expressions. CCK-8 assay, flow cytometry, and lactate dehydrogenase (LDH) assay were employed to determine the viability and apoptosis of N2a cells. The intracellular ROS content was assessed using ROS Assay Kit. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses were conducted to detect the expression levels of Prdx1, JNK, phosphorylated JNK (p-JNK), and cleaved caspase-3. Results: Firstly, Prdx1, p-JNK, and cleaved caspase-3 expression were significantly induced in OGD/R-exposed N2a cells. Secondly, the knockdown of Prdx1 inhibited cell viability and increased apoptosis rate, expression of p-JNK, and cleaved caspase-3 expression. Thirdly, SP600125 inhibited the JNK/caspase-3 signaling pathway and mitigated cell injury following OGD/R. Finally, SP600125 partially reversed Prdx1 down-regulation-mediated cleaved caspase-3 activation and OGD/R damage in N2a cells. Conclusion: Prdx1 alleviates the injury to N2a cells induced by OGD/R via suppressing JNK/caspase-3 pathway, showing promise as a potential therapeutic for cerebral I/R injury.

RESUMEN

BACKGROUND: Pulmonary fibrosis is a major category of end-stage changes in lung diseases, characterized by lung epithelial cell damage, proliferation of fibroblasts, and accumulation of extracellular matrix. Peroxiredoxin 1 (PRDX1), a member of the peroxiredoxin protein family, participates in the regulation of the levels of reactive oxygen species in cells and various other physiological activities, as well as the occurrence and development of diseases by functioning as a chaperonin. METHODS: Experimental methods including MTT assay, morphological observation of fibrosis, wound healing assay, fluorescence microscopy, flow cytometry, ELISA, western blot, transcriptome sequencing, and histopathological analysis were used in this study. RESULTS: PRDX1 knockdown increased ROS levels in lung epithelial cells and promoted epithelial-mesenchymal transition (EMT) through the PI3K/Akt and JNK/Smad signalling pathways. PRDX1 knockout significantly increased TGF-ß secretion, ROS production, and cell migration in primary lung fibroblasts. PRDX1 deficiency also increased cell proliferation, cell cycle circulation, and fibrosis progression through the PI3K/Akt and JNK/Smad signalling pathways. BLM treatment induced more severe pulmonary fibrosis in PRDX1-knockout mice, mainly through the PI3K/Akt and JNK/Smad signalling pathways. CONCLUSIONS: Our findings strongly suggest that PRDX1 is a key molecule in BLM-induced lung fibrosis progression and acts through modulating EMT and lung fibroblast proliferation; therefore, it may be a therapeutic target for the treatment of BLM-induced lung fibrosis.

Asunto(s)

Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Transición Epitelial-Mesenquimal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Bleomicina/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Pulmón/metabolismo , Proliferación Celular , Fibroblastos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/efectos adversos , Peroxirredoxinas/metabolismo

RESUMEN

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.

Asunto(s)

Ácido Aspártico , Peroxirredoxinas , Ácido Aspártico/genética , Ácido Aspártico/metabolismo , Daño del ADN , Estrés Oxidativo/genética , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Humanos