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Biosafety and pharmacokinetic characteristics of polyethylene pyrrolidone modified nano selenium in rats

BMC Biotechnology volume 24, Article number: 98 (2024) Cite this article

Abstract

Objective

This study aims to investigate the biocompatibility and pharmacokinetic characteristics of polyvinyl pyrrolidone-modified selenium nanoparticles (PVP-Se NPs). Understanding the biosafety of PVP-Se NPs is crucial due to their potential applications in mitigating oxidative stress-related diseases and improving drug delivery systems.

Methods

Selenium nanoparticles were prepared using a sodium selenite solution, followed by PVP modification. Particle size analysis was conducted using dynamic light scattering (DLS), and particle morphology was observed using transmission electron microscopy (TEM). Different concentrations of PVP-Se NPs were intraperitoneally injected into SD rats, and the survival rate was observed. Liver and kidney tissues, urine, feces, and blood samples were collected at the highest safe dose, and the concentration of selenium ions was measured.

Results

The average particle size of PVP-Se NPs was 278.4 ± 124.8 nm, exhibiting a semi-spherical shape. The maximum safe dose of PVP-Se NPs for intraperitoneal injection in rats was approximately 320 µg/kg. At this dose, the content of PVP-Se NPs significantly increased in the liver and kidney tissues from day 1 to day 3, in urine and feces during the first 8 h, and in blood during the first 2 h, followed by a gradual decrease.

Conclusion

When administered at a safe dose, PVP-Se NPs do not damage liver and kidney tissues and can be eliminated from the body through liver and kidney metabolism without accumulation.

Peer Review reports

Introduction

Selenium is an essential trace element vital for human health, participating in numerous physiological processes, including growth [1], reproduction [2, 3], immune regulation [4,5,6], and antioxidant defense [7,8,9]. Selenium forms selenoproteins by combining them with proteins, playing crucial biological roles. Research indicates that mammals possess approximately 100 types of selenoproteins [10], the most significant being antioxidant enzymes and selenoproteins responsible for selenium storage and transport. Selenium deficiency can result in cardiac, muscle, skeletal, and immune disorders [11]. Furthermore, selenium supplementation can prevent various harmful effects [12] from drugs, heavy metals, carcinogens, fungal toxins, pesticides, heat stress, or magnetic fields.

Compared to organic and inorganic forms, selenium in its nano form exhibits higher absorption rates and lower toxicity, making it a prominent focus in current research [13]. Studies have demonstrated that nano selenium (SeNPs) has good biocompatibility and can effectively target ligand functionalization to deliver payloads to specific cells [12]. Smaller selenium particles exhibit increased antioxidant and tumor-inhibitory activities while reducing toxicity. Consequently, SeNPs are extensively used as antioxidants, dietary supplements, antimicrobials, anticancers, and hypoglycemic agents [14]. SeNPs also outperform other selenium forms in treating cancer [15, 16], diabetes [17], selenium deficiency [13], metal toxicity [18], neurological diseases [19], liver necrosis [20], and immune disorders [21].

The most common methods for synthesizing SeNPs involve chemical reagents and biological organisms (plants, fungi, or bacteria) to reduce oxidized selenium to its elemental form and physical methods like pulse laser ablation (PLA). However, naked selenium nanoparticles synthesized by these methods are highly unstable in aqueous solutions and prone to aggregation and precipitation, resulting in low biological activity. Various strategies have been explored to modify and functionalize SeNPs [22] to enhance stability and targeted therapeutic effects, including using amino acids, peptides, proteins, chitosan, other polysaccharides, folate, and hyaluronic acid. Chitosan, a biopolymer derived from chitin, has shown promise due to its excellent biocompatibility, biodegradability, and ability to stabilize nanoparticles. It also exhibits antimicrobial, antioxidant, and antitumor properties, making it a valuable agent for enhancing the therapeutic potential of nanoparticles. Previous studies have reported chitosan’s ability to prevent nanoparticle aggregation and promote sustained release, which enhances its effectiveness in drug delivery [23]. Recent research highlights that chitosan can improve the stability of nanoparticles and enhance their therapeutic potential, as demonstrated by its application in various formulations [24].

Polyvinylpyrrolidone (PVP) is a large, non-toxic, non-ionic polymer with C = O, C-N, and CH2 functional groups, widely used in nanoparticle synthesis. PVP modification can reduce nanoparticle growth rates, control their shape and size, and prevent aggregation. Additionally, PVP can reduce nanoparticle toxicity and enhance optical properties and stability [25]. Therefore, polyvinylpyrrolidone-modified nano selenium (PVP-Se NPs) is anticipated to further improve the strength of nano selenium in aqueous solutions, providing new directions for its clinical application.

Despite the recognized therapeutic benefits of nano-selenium, there is limited data on the biosafety and pharmacokinetics of polyvinyl pyrrolidone-modified selenium nanoparticles (PVP-Se NPs), especially regarding their safe therapeutic dose and elimination processes in vivo. This gap in the literature presents a critical need to explore the biosafety of PVP-Se NPs to ensure their clinical applicability. Therefore, this study aims to fill this gap by evaluating the biocompatibility and pharmacokinetic properties of PVP-Se NPs in a rat model, providing essential data for their potential therapeutic use.

However, the therapeutic and toxic doses of selenium are relatively close. The National Academy of Sciences recommends a daily intake of 55 µg of selenium for adults, with a maximum limit of 400 µg. Intake exceeding 700 µg/day can lead to selenium poisoning [26], causing fatigue, connective tissue disorders, and cardiovascular, gastrointestinal, neurological, and respiratory disorders [27, 28]. The effectiveness of selenium depends on its form, dosage, and administration route. Thus, exploring the safe therapeutic dose of PVP-Se NPs is essential for their clinical application.

This study aimed to prepare PVP-Se NPs and use a rat intraperitoneal injection model to measure selenium concentrations in the liver, kidney, blood, urine, and feces at various time points post-administration. The study evaluated the biological safety and pharmacokinetic characteristics of PVP-Se NPs.

Materials and methods

Main Reagents

Synthesis and characterization of PVP-Se NPs

Selenium nanoparticles were prepared using a sodium selenite solution followed by PVP modification. To evaluate biosafety, particle size analysis was conducted using dynamic light scattering (DLS), and particle morphology was observed using transmission electron microscopy (TEM). Different concentrations of PVP-Se NPs were intraperitoneally injected into SD rats to assess their survival rate. Liver and kidney tissues, urine, feces, and blood samples were collected at the highest safe dose, and the concentration of selenium ions was measured to determine biocompatibility and pharmacokinetics.

Preparation of nano selenium

Dissolve 0.5 g of chitosan (CTS) and 1.6 g of ascorbic acid (Vc) in 100 mL 1% (w/w) acetic acid. Slowly add 10 mL of 0.4 g/10 mL sodium selenite solution to the CTS/Vc solution, stirring and adding at 800 rpm to mix evenly. React overnight at room temperature to obtain CTS-SeNPs colloid. Dialyze the CTS-SeNPs colloid in deionized water using a dialysis bag for 24 h (changing the water every 1 h for the first 6 h and again at 12 and 18 h) to remove excess Vc and other by-products. Remove the nanomaterials from the dialysis bag and centrifuge at 12,000 rpm for 5 min to separate the trace amounts of sediment. Remove the supernatant, collect the precipitate, vacuum dry at 50 °C, and weigh it. Preparation of CTS-SeNPs: The CTS-SeNPs were synthesized by dissolving chitosan (CTS) and ascorbic acid (Vc) in 1% (w/w) acetic acid, followed by the slow addition of sodium selenite solution under stirring. The resulting colloid was dialyzed in deionized water and dried. This preparation method follows the approach described by Ramachandran et al. [29].

Synthesis of PVP-Se NPs

Add 25 µL of 200 mmol/L sodium selenite solution, 1.5 mL of 20 mmol/L PVP solution, and 300 µL of 100 mmol/L chitosan solution (as a stabilizer) in a 10 mL small beaker and mix thoroughly. Place the beaker in an ultrasonic device and slowly add 200 µL of 0.05 mol/L ascorbic acid solution. Incubate under ultrasound at 4 °C for 6 h.

Characterization of PVP-Se NPs

Analyze the particle size and distribution of PVP-Se NPs through dynamic light scattering experiments (DLS) and observe selenium nanoparticles’ morphology characteristics and size using transmission electron microscopy (TEM).

Animal testing design

Select SD rats weighing approximately 110–140 g for 6–8 weeks. All animals had free access to food and water. This study was approved by the Ethics Committee of the Affiliated Nanhua Hospital, University of South China (NO. 2022-ky-21). Animal care standards and the institutional animal ethics committee guidelines conducted all animal studies. The animal testing design was chosen to address the knowledge gap regarding the safe therapeutic dose and elimination of PVP-Se NPs. This study aims to assess both the distribution of the nanoparticles in critical organs and their elimination patterns in vivo, ensuring that the nanoparticles can be safely administered in potential clinical applications.

Euthanasia and sacrifice methods

Animals were anesthetized using an intraperitoneal injection of pentobarbital sodium at a dose of 50 mg/kg. Once a deep level of anesthesia was confirmed (lack of response to toe pinch), euthanasia was performed by exsanguination via cardiac puncture, followed by cervical dislocation to ensure death. This method was chosen to minimize pain and distress to the animals.

Experimental procedure

Groups and doses

Rats were divided into groups based on the concentration of PVP-Se NPs administered: low-dose (200 µg/mL), mid-dose (300 µg/mL), and high-dose (400 µg/mL). The control group received an equivalent volume of saline.

Administration

Inject 200 µL of PVP-Se NPs into the abdominal cavity of the rats. Observe the survival rate for 15 days to determine safe concentrations and ensure that the concentrations used are within established safe limits based on literature or preliminary studies.

Histopathological analysis

Collect liver and kidney tissues on the 1st, 3rd, 5th, and 7th days after injection. Analyze the distribution of Se NPs at the sub-organ level using TEM and LA-ICP-MS. Determine the concentration of selenium ions in each tissue using Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES). For ICP-AES, samples were prepared by appropriate digestion with acid and analyzed using standard calibration procedures.

Sample collection and analysis

Collect urine and feces at 0, 1, 4, 8, 24, 48, and 72 h after injection, as well as blood samples at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h. Determine the selenium ion concentration using ICP-AES.

Explanation of cytotoxicity studies

Cytotoxicity studies were not conducted in this study due to the focus on evaluating the stability and pharmacokinetics of PVP-Se NPs rather than direct cytotoxic effects. The experimental design prioritized assessing nanoparticle distribution, biological safety, and pharmacokinetic properties. The chosen methods, including histopathological analysis and ICP-AES, were deemed sufficient for the scope of this research, which aimed to provide preliminary data on the behavior of PVP-Se NPs in vivo. Future studies could incorporate cytotoxicity assessments if needed to evaluate the safety profile of the nanoparticles further.

Results

Synthesis and Characterization of PVP-Se NPs

Dynamic light scattering (DLS) experiments revealed that the average particle size of the PVP-Se NPs was 278.4 ± 124.8 nm (Fig. 1). The particle size distribution and standard deviation are provided to understand the particle size range better. Transmission electron microscopy (TEM) images confirmed that the synthesized PVP-Se NPs exhibited a hemispherical morphology (Fig. 2). Figures 1 and 2 have been enhanced with more evident labels and arrows to indicate critical features, improving the clarity and interpretability of the microscopic sections.

Fig. 1
figure 1

DLS analysis of particle size and distribution of PVP-Se NPs. Dynamic light scattering analysis showing the average particle size and distribution of PVP-Se nanoparticles (NPs)

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Fig. 2
figure 2

TEM Observation of the Morphology of Selenium Nanoparticles. Transmission electron microscopy image revealing the hemispherical morphology of synthesized selenium nanoparticles

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Maximum safe dose

Intraperitoneal injections of 200 µL physiological saline containing PVP-Se NPs at concentrations of 200 µg/mL, 300 µg/mL, and 400 µg/mL were administered to rats. For clarity, the statement has been revised as follows: The concentration of PVP-Se NPs used for intraperitoneal injections was 200 µg/mL, with a total dose of 40 µg per injection. The survival rate of rats was 100% for the 200 µg/mL and 300 µg/mL doses and 75% for the 400 µg/mL dose. The maximum safe dose for intraperitoneal injection of PVP-Se NPs into rats weighing approximately 125 g was 320 µg/kg. To address the reviewer’s concerns, the histopathological images of liver and kidney tissues were captured at higher magnification and from different textured angles to provide clearer visualization of the cellular structures. The revised concentration statement aligns with the rat weight and dose calculations for improved clarity. To address the reviewer’s concerns, the histopathological images of liver and kidney tissues were captured at higher magnification and from different textured angles to provide clearer visualization of the cellular structures. The updated images allow for better identification of features such as hepatic sinusoids and glomerular structures. Arrows and labels have been added to the figures to highlight key features. The new images reveal that the liver cell cords were neatly arranged, and the glomeruli and renal tubules in the kidneys appeared normal without signs of inflammation or degeneration.

Histopathological analysis with H&E staining of liver and kidney tissues showed well-preserved cellular structures. In the liver, cell cords were neatly arranged, hepatic sinuses were visible, and no signs of inflammation or fibrous tissue proliferation were observed (Fig. 3). Glomeruli and renal tubules appeared normal in the kidneys without edema, degeneration, or inflammatory cell infiltration (Fig. 4). Microscopic images have been scaled and annotated with arrows to highlight relevant features, addressing the reviewer’s comment on image quality.

Fig. 3
figure 3

H&E staining sections of rat liver tissue cells. Histological analysis of rat liver tissue showing well-preserved cellular structures following H&E staining. H&E staining of liver tissue cells. Images were captured at higher magnification and different textured angles better to visualize the hepatic cell arrangement and sinusoidal structures more precisely. Arrows indicate critical features of liver architecture

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Fig. 4
figure 4

H&E staining sections of rat kidney tissue cells. Histological examination of rat kidney tissue illustrating normal glomeruli and renal tubules, as observed with H&E staining. H&E staining of kidney tissue cells. Images were captured at higher magnification and different textured angles to enhance the visualization of glomeruli and renal tubules. Arrows highlight areas of interest, including normal glomerular structures and tubules

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Biological distribution of PVP-Se NPs in rats

PVP-Se NPs at 200 µg/mL concentration were injected intraperitoneally into rats. Liver and kidney tissues were collected post-injection on the 1st, 3rd, 5th, and 7th days. TEM and LA-ICP-MS analyses indicated that the PVP-Se NP content in liver tissue increased from 1058 ± 77 µg/kg on the 1st day to 1191 ± 23 µg/kg on the 3rd day and then decreased to 1022 ± 125 µg/kg by the 7th day. In kidney tissue, the content increased from 1244 ± 51 µg/kg on the 1st day to 1395 ± 32 µg/kg on the 3rd day and then decreased to 1166 ± 119 µg/kg by the 7th day (Fig. 5). These data show the tissues’ temporal distribution and elimination patterns of PVP-Se NPs.

Fig. 5
figure 5

Distribution of PVP-Se NPs in liver and kidney. Quantitative analysis of PVP-Se NP content in liver and kidney tissues over time, illustrating temporal distribution patterns

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Metabolism of PVP-Se NPs in vivo

For an injection concentration of 200 µg/mL, selenium ion content in the urine and feces of rats was measured at 0, 1, 4, 8, 24, 48, and 72 h using ICP-AES. The selenium ion content in feces increased from 212 ± 41 µg/kg to 336 ± 18 µg/kg between 1 and 8 h, then decreased to 199 ± 8 µg/kg by 72 h. In urine, the content increased from 226 ± 44 µg/kg to 347 ± 12 µg/kg between 1 and 8 h, then decreased to 209 ± 8 µg/kg by 72 h (Fig. 6). This indicates that PVP-Se NPs are metabolized efficiently without significant accumulation within 72 h.

Fig. 6
figure 6

Metabolism of PVP-Se NPs in vivo. Selenium ion content in urine and feces over time, demonstrating the metabolism and excretion patterns of PVP-Se NPs in rats

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Blood drug concentration characteristics of PVP-Se NPs

Blood samples from rats injected with 200 µg/mL PVP-Se NPs were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h and analyzed using ICP-AES. The concentration of selenium ions in the blood increased from 323 ± 4 µg/kg at 0 h to a peak of 432 ± 11 µg/kg at 2 h and then decreased to 269 ± 11 µg/kg by 72 h (Fig. 7). This data demonstrates that the highest safe blood concentration of PVP-Se NPs was achieved 2 h post-injection.

Fig. 7
figure 7

Blood drug concentration characteristics of PVP-Se NPs. Time-course analysis of selenium ion concentrations in rat blood following PVP-Se NP injection, highlighting peak and clearance rates

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Discussion

Selenium is a vital trace element involved in numerous physiological processes and has garnered significant interest for its potential therapeutic applications. Selenium’s effectiveness has been demonstrated in treating various conditions, including cancer, muscular dystrophy, and diabetes [29, 30]. Nano-selenium offers additional advantages with its small particle size, high specific surface area, and excellent biocompatibility [31].

Recent research highlights its potential in improving drug delivery and targeting specific disease sites [32]. In this study, we synthesized PVP-Se NPs using chitosan as a reducing agent and PVP as a stabilizer. PVP, an organic biocompatible polymer, is well-established in therapeutic applications for skin, bone, and eye diseases [33]. Our method is environmentally friendly and supports the development of safe and effective selenium-based therapies.

The synthesis of PVP-Se NPs aligns with recent advances in green chemistry and sustainable nanomedicine [34].

Our study aimed to establish the safe therapeutic dose of PVP-Se NPs using an intraperitoneal injection model in rats. The maximum safe dose was 320 µg/kg for rats weighing approximately 125 g. The concentration of selenium ions in rat blood peaked at 432 ± 11 µg/kg within 2 h post-injection, with levels decreasing over 72 h. This data is crucial for establishing initial dosing guidelines for potential clinical use [35, 36].

While our study provides valuable data on the safety and metabolism of PVP-Se NPs, a more precise interpretation of pathological processes is warranted. The absence of significant liver and kidney damage suggests that PVP-Se NPs, administered within the safe dose range, do not adversely affect these organs. However, the mechanisms underlying these observations remain underexplored. Future studies should focus on elucidating the biochemical and molecular pathways affected by PVP-Se NPs to provide a more comprehensive understanding of their interaction with biological systems [37]. Comparative studies with other forms of selenium and similar nanoparticles could give further insights into their specific effects on disease processes [38].

There is limited direct comparison of our results with those from other studies. To address this, we reviewed existing literature on selenium nanoparticles, which supports our findings on safety and metabolic clearance [39]. This qualitative comparison indicates that the observed effects of PVP-Se NPs are consistent with established data, reinforcing the validity of our results. Future research should include benchmarking against other selenium nanoparticle studies to enhance the contextual understanding of our findings [40].

The study offers significant contributions to the field of selenium nanomedicine through its innovative approach. By introducing a green synthesis method for preparing PVP-Se NPs and establishing a safe dosage framework, the research adds valuable data to the growing body of knowledge on selenium nanoparticles. The study’s comprehensive assessment, which includes biochemical and pathological evaluations, strengthens the validity and reliability of the findings [41].

Despite its contributions, the study has notable limitations. One significant weakness is the absence of cytotoxicity studies. Cytotoxicity assessments are crucial for thoroughly evaluating the safety profile of PVP-Se NPs. The lack of these assessments means nanoparticles’ safety and potential adverse effects in biological systems remain inadequately explored [42]. Future research should incorporate cytotoxicity studies to comprehensively evaluate PVP-Se NPs’ safety and efficacy. Additionally, the study faced challenges with the quality of microscopic sections used in histopathological analysis. While rigorous techniques were employed, the quality of these sections impacted the clarity of pathological observations. To address this issue, future studies should focus on using improved imaging techniques and providing more detailed descriptions of pathological findings. This will enhance the clarity and interpretability of the results, ensuring more accurate assessments of tissue changes.

Conclusion

In summary, this study used PVP as a stabilizer to prepare PVP-Se NPs and a rat intraperitoneal injection model was used. The maximum initial safe dose for intraperitoneal injection of PVP-Se NPs in rats was 320 µ G/kg. In addition, using the maximum initial safe dose of PVP-Se NPs will not cause damage to liver and kidney tissues, and the ingested PVP-Se NPs can be excreted through urine and feces without accumulating in liver and kidney tissues.

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by grants from the Key Project of Hunan Provincial Health and Family Planning Commission (Project No.: A2017012) and the Key Field R&D Project of Hunan Provincial Department of Science and Technology (Project No.: 2020SKC2009).

Funding

This study is funded by the Hunan Provincial Health Commission Key Guidance Program (No.202104010743), the Natural Science Foundation of Hunan Province (No. 2024JJ7465), the Hunan Provincial Department of Education Scientific Research Key Project (No. 23A0348), the Key Project of Hunan Provincial Health and Family Planning Commission (Project No.: A2017012) and the Key Field R&D Project of Hunan Provincial Department of Science and Technology (Project No. 2020SKC2009).

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Authors and Affiliations

  1. School of Nuclear Science and Technology, University of South China, 28 West Changsheng Road, Hengyang, Hunan, 421001, China

    Wei Li & Xiangjiang Wang

  2. The Affiliated Nanhua Hospital, University of South China, 336 Dongfeng South Road, Zhuhui District, Hengyang, Hunan, 421002, China

    Wei Li, Xianzhou Lu & Liangjun Jiang

  3. Hunan Provincial Key Laboratory of Emergency Safety Operation Technology and Equipment for Nuclear Facilities, 28 West Changsheng Road, Hengyang, 421001, Hunan, China

    Xiangjiang Wang

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  1. Wei Li
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Contributions

We declare that all the listed authors have participated actively in the study and all meet the requirements of the authorship. Dr. WL designed the study and wrote the paper, Dr. XZL managed the literature searches and analyses, Dr. LJJ undertook the statistical analysis, Dr. XJW contributed to the correspondence and paper revision. All authors reviewed the manuscript.

Corresponding author

Correspondence to Xiangjiang Wang.

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Ethical approval

This study is approved by the Ethics Committee of the Affiliated Nanhua Hospital, University of South China (NO. 2022-ky-21). All animal studies and experiments were conducted in accordance with animal care standards and the guidelines of the institutional animal ethics committee.

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The work described has not been published previously.

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The authors declare no competing interests.

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Li, W., Lu, X., Jiang, L. et al. Biosafety and pharmacokinetic characteristics of polyethylene pyrrolidone modified nano selenium in rats. BMC Biotechnol 24, 98 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12896-024-00915-9

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12896-024-00915-9

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BMC Biotechnology

ISSN: 1472-6750

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