Ameliorating and therapeutic impact of nano ferrite-chitosan-curcumin nanoparticles against nandrolone decanote induced renal toxicity, inflammation, and oxidative stress in male rats

The term ``anabolic-androgenic steroids'' (AASs) refers to a class of artificial substances that resemble the natural testosterone. The most often misused androgen, nandrolone decanoate (ND), is regarded as a public health concern that needs immediate action to raise public awareness of toxicology results on AAS usage. This study designed to investigate the therapeutics effect of nano ferrite-chitosan-curcumin nanoparticles (NF-CH-CurNPs) against ND induced renal toxicity, proliferation, inflammation, and oxidative stress in male rats. A total of 48 adult male rats were assigned randomly to 6 groups [1st group was control; 2nd group was CurNPs where rats received CurNPs (50 mg/kg BW/2 day) for two wk; 3rd group was NF-CH-CurNPs where rats received NF-CH-CurNPs (24 mg/Kg BW/2 day) for 2 wk.; 4th group was ND where rats received ND (25 mg/Kg BW/wk) for four wk; 5th group was ND + CurNPs in which rats received ND for 4 wk then treated with CurNPs for another 2 wk; 6th group was ND + NF-CH-CurNPs where rats received ND for 4 wk then treated with NF-CH-CurNPs for another 2 wk]. A significant elevation in serum Urea, creatinine, kidney damage, MDA, PCNA, TNFα and a significant depletion in sodium, potassium ions, catalase, SOD, GSH after ND administration as compared to control. On the contrary, treatment of ND with CurNPs or/and NF-CH-CurNPs induced significant enhancements of the studied parameters, kidney structure and functions, oxidative stress, PCNA and TNFα expressions with best results for the treatments with NF-CH-CurNPs that may possibly scavenge free radicals creating valuable effects in contrast to ND. Highlights ND-Induced an increase in kidney functions, oxidative stress (evidenced by elevated MDA), and inflammatory markers such as TNFα. Treatment with CurNPs demonstrated some beneficial effects, as it alleviated some of the toxic impacts caused by ND, improving kidney function, and lessening oxidative stress. NF-CH-CurNPs treatment also significantly improved kidney functions, decreased inflammatory and proliferative markers (like PCNA and TNFα). The enhanced effects of NF-CH-CurNPs may be attributed to the synergistic properties of chitosan (a biopolymer known for its antioxidant properties) and ferrite (which could provide additional antioxidant and anti-inflammatory benefits).

nandrolone decanote, nano ferrite-chitosan-curcumin nanoparticles, nephrotoxicity, oxidative stress, PCNA & TNFα

Synthetic variants of testosterone designed to increase anabolic effects and reduce androgenic ones are known as AASs.1–4 The main reasons for the restricted therapeutic use of AAS include inherited angioneurotic oedema, osteoporosis, breast cancer, different forms of anemia, endocrine dysfunction of the testis and gonadotropic axis, and issues with muscle growth.5–7 Androgens accelerate the development and stimulation of male sex characteristics. Medical professionals use injectable or oral AASs to treat hormonal imbalances in male impotence, hypogonadism, and delayed puberty in adolescent boys. They can be used to treat muscle loss in cancer patients, endometriosis, osteoporosis, and breast cancer.8–10 Athletes commonly misuse or abuse their skills to increase endurance and performance. Non-athletes abuse anabolic steroids in order to increase their weight and lean muscle mass without accumulating more body fat.11,12 In addition to being recommended for burns, radiation therapy, surgery, trauma, anemia, chronic kidney disease, and osteoporosis in postmenopausal women, nandrolone decanoate (ND) is one of the most often used injectable drugs for anabolic treatment.13 However, ND has long been misused in excess of the prescribed doses to improve athletic performance and body composition.14 According to Radwan et al.15 and Islam et al.,16 curcumin is the main polyphenol in turmeric's curcuminoid class. Although its anti-inflammatory, antioxidant, antidiabetic, hepatoprotective, antibacterial, and anticancer activities target a variety of malignancies, its solubility and bioavailability are poor.17,18 To enhance its therapeutic potential, curcumin can be loaded or encapsulated using the nanocurcumin method, which has been shown to be suitable.19–21 However, there are legitimate worries about the toxicological safety of curcumin once it enters biological pathways, and converting it into nanocurcumin form could be a workable strategy to get beyond its inherent limits.20,22 Several attempts have been made to boost curcumin's water solubility and bioavailability by encapsulating it in materials including polymeric nanoparticles, solid lipid nanoparticles, and macromolecules like gelatin. Therefore current research aims to investigate the therapeutics effect of nano ferrite-chitosan-curcumin nanoparticles (NF-CH-CurNPs) against ND induced renal toxicity, proliferation, inflammation, and oxidative stress in male rats.

Chemicals and kits All chemicals were purchased from sigma and Aldrich co. Nandrolone decanoate (ND) ND is found under the name of nandurabolin (50 mg / mL 1 ampoule of 1 mL) was perchased from El Nile company, Egypt and it has been prepared by dissolving in olive oil. Curcumin nanoparticles (CurNPs) CurNPs bought from Nawah Scientific “Research institute” catering for natural and medical sciences in Almokattam, Egypt. Nano ferrite-chitosan-curcumin nanoparticles (NF-CH-CurNPs) Preparation and characterization of nanoparticles drug (NF-CH-CurNPs) for treatments were under publication in anther manuscript (Data found in Supplementary File 1). Experimental animals and ethical considerations The study involved 48 albino rats (Rattus norvigicus; male; 175 ± 15 g weight) from Egypt, supplied by the National Research Center, housed in a Faculty's animal house for a week before starting, under code: IACUC-SCI-TU-0381 for Animal Care and Use approved and under standard conditions with a 12-h light/dark cycle. Experimental design Rats were randomly divided into 6 groups. 1st group acts as the control that received no treatment at all. 2nd group was CurNPs in which rats received CurNPs (50 mg/kg body weight/2 day) for two wk. 3rd group was NF-CH-CurNPs in which rats received NF-CH-CurNPs (24 mg/Kg body weight/2 day) for 2 wk. 4th group was ND in which rats received ND (25 mg/Kg body weight/wk) for four wk. 5th group was ND + CurNPs in which rats received ND (25 mg/Kg body weight/wk) for 4 wk then treated with CurNPs (50 mg/kg body weight/2 day) for another 2 wk. 6th group was ND + NF-CH-CurNPs in which rats received ND (25 mg/Kg body weight/wk) for 4 wk then treated with NF-CH-CurNPs (24 mg/Kg body weight/2 day) for another 2 wk. Biochemical assays Patton and Crouch's23 approach was used to estimate urea and creatinine. Using a commercial kit provided by Diamond, an Egyptian company, the amount of in the serum was measured. According to Elmasry et al.,24 commercial kits (Sensa core electrolyte, India) are used to estimate the levels of serum electrolytes. Assessment of oxidative stress indicators A biodiagnostic analyzer kit based on the production of malondialdehyde (MDA) by the thiobarbituric acid (TBAR) process described by Mesbah et al.25 was used to assess the degree of oxidative stress (lipid peroxidation (LPO) and reduced glutathione (GSH)) in kidney homogenates. The kidney homogenates' GSH activity was also assessed using the methodology described by Beutler.26 Assessment of antioxidant enzymes Using commercial kits and the methods outlined by Saggu et al.27 and Misra and Fridovich,28 respectively, the antioxidant activities were evaluated by measuring the activity of certain enzymes, such as catalase (CAT) and superoxide dismutase (SOD). Histopathological examination Following Tousson,29 kidney specimens from different groups were extracted, fixed in 10% neutral buffered formalin, paraffin embedded, and sectioned. The sections were then stained with hematoxylin and eosin, and the results were seen under a light microscope. Immuno-histochemical analysis Following Tousson et al.30 and Nofal et al.,31 immuno-labeling of PCNA and TNFα were estimated involved loading 5 μm slices of kidney onto positively charged slides. Different monoclonal anti-mouse primary antibodies were used to detect PCNA and TNFα. The correct secondary antibodies were used to localize the bound primary antibodies, and the Diaminobenzidine (DAB) stain was used in accordance with the manufacturer's protocol. For quantification, brown dye was extracted from classified cells with the usage of the Image J application, and the color threshold turned into determined. Statistical analysis Data were expressed as the significance of difference was analyzed by one – way ANOVA. Values are expressed as means ± SE. # and * significant difference from ND and from control groups respectively at P < 0.01.

Effect of NF-CH-CurNPs on kidney functions and electrolytes Table 1 revealed that; a significant (P < 0.01) elevation in the levels of urea, creatinine, sodium, potassium ions and a significant (P < 0.01) depletion in the level of calcium in ND group as compared with control. However, treatment of rats by ND with CurNPs or/and NF-CH-CurNPs showed a significant (P < 0.01) depletion in urea, creatinine, sodium, potassium ions and a significant (P < 0.01) elevation in calcium ions as compared to ND with best results for NF-CH-CurNPs treatment (Table 1). Table 1. | Creatinine (mg/dl) | Urea (mg/dl) | Na+ (mEq/L) | K+ (mEq/L) | Ca++ (mEq/L) | | |---|---|---|---|---|---| | Control | 0.538# ± 0.01 | 30.75# ± 0.25 | 135.5# ± 0.76 | 3.830# ± 0.06 | 11.83# ± 0.06 | | Cur NPs | 0.585# ± 0.01 | 31.50# ± 0.54 | 139.8 # 0.60 | 4.010# ± 0.02 | 11.50# ± 0.20 | | NF-CH-CurNPs | 0.560# ± 0.02 | 32.75# ± 0.25 | 137.8 ± # 0.17 | 3.968# ± 0.04 | 11.83# ± 0.11 | | ND | 0.825* ± 0.02 | 41.75* ± 0.72 | 145.1* ±0.88 | 4.603* ± 0.06 | 10.38* ±0.10 | | ND + Cur NPs | 0.733#* ± 0.01 | 37.55#* ± 0.69 | 140.3# ± 0.44 | 4.293#*0.02 | 10.80#* ± 0.21 | | ND+ NF-CH-CurNPs | 0.647#* ± 0.02 | 36.50#* ± 0.50 | 136.5# ± 0.76 | 4.127#* 0.02 | 11.77# ± 0.09 | The significance of difference was analyzed by one – way ANOVA using computer program. Values are expressed as means ± SEM. # and * significant difference from ND and control groups respectively at P < 0.01. Effect of NF-CH-CurNPs on kidney oxidative stress Table 2 revealed that; a significant (P < 0.01) elevation in kidney MDA and a significant (P < 0.01) depletion in GSH, CAT, SOD in ND group as compared with control. However, treatment of rats by ND with CurNPs or/and NF-CH-CurNPs showed a significant (P < 0.01) depletion in MDA and a significant (P < 0.01) elevation in GSH, CAT, SOD as compared to ND with best results for NF-CH-CurNPs treatment (Table 2). Table 2. | MDA (nmole/g tissue) | GSH (mmole/g tissue) | SOD (U/g tissue) | CAT (μmole/min/g tissue) | | |---|---|---|---|---| | Control | 27.83# ± 0.15 | 2.870# ± 0.02 | 63.16# ± 0.47 | 43.61# ± 0.68 | | Cur NPs | 29.43# ± 0.58 | 2.990# ± 0.03 | 63.71# ± 0.29 | 45.60# ± 0.37 | | NF-CH-CurNPs | 27.50# ± 0.81 | 3.090# ± 0.01 | 65.58# ± 0.39 | 48.31# ± 0.25 | | ND | 88.63* ± 1.0 | 1.333* ± 0.02 | 37.34* ± 1.29 | 25.84* ± 0.22 | | ND + Cur NPs | 60.67#* ± 0.4956 | 2.08#* ± 0.08 | 43.70#* ± 0.26 | 33.10#* ± 0.22 | | ND+ NF-CH-CurNPs | 34.70# ± 1.04 | 2.49#* ± 0.03 | 59.11# ± 1.21 | 41.09# ± 0.12 | The significance of difference was analyzed by one – way ANOVA using computer program. Values are expressed as means ± SEM. # and * significant difference from ND and from control groups respectively at P < 0.01. Histopathological examination Kidney histological evaluation of cortical and medullary part in control, CurNPs and NF-CH-CurNPs groups revealed normal architecture with normal renal tubules and glomeruli (Fig. 1A–C). Treated rats with ND showed distortion and dilatation of renal tubules with necrotic tubular cells with moderate to strong inflammatory cellular infiltration, severe atrophy in glomeruli and congestion in the blood vessels (Fig. 1D). On the other hand; treated rats with ND + CurNPs revealed moderate atrophy in glomeruli and renal tubular cells with mild inflammatory cellular infiltration while in treated rats with ND + NF-CH-CurNPs exhibited a good degree of improvement in the glomeruli and renal tubules (Fig. 1E and F). Immuno-histochemical localization (Figs 2 and 4) revealed the immuno-histochemical localization of PCNA in kidney tissues. Control, CurNPs, NF-CH-CurNPs groups revealed faint to mild reaction while strong reaction was detected in ND (Fig. 2A–D). Moderate reactions for PCNA were observed in treated rats with ND + CurNPs while mild reactions were detected in treated rats with ND + NF-CH-CurNPs (Fig. 2E and F). (Figs 3 and 4) revealed the immuno-histochemical localization of TNFα in kidney tissues. Control, CurNPs, NF-CH-CurNPs groups revealed faint to mild reaction while moderate to strong reaction was detected in ND (Fig. 3A–D). Moderate reactions for TNFα were observed in treated rats with ND + CurNPs while mild reactions were detected in treated rats with ND + NF-CH-CurNPs (Fig. 3E and F).

Athletes commonly use injectable anabolic-androgenic steroids (AASs) to enhance muscle growth and increase muscle mass. These substances are also used by women in various cosmetic treatments to improve the appearance of features like the breasts, buttocks, cheekbones, and lips.32,33 Additionally, people may be indirectly exposed to AASs by consuming meat from animals that have undergone AAS treatment. AASs not only enhance growth but also exert harmful effects on the cardiovascular, reproductive, and endocrine systems.7,34,35 Nandrolone decanoate (ND), a type of AAS, has effects on cells and kidney tissue that are still not completely understood. As a result, this study was established to explore the potential protective role of NF-CH-CurNPs against kidney damage and oxidative stress caused by ND in rats. Current results revealed that; ND induced kidney toxicity in rats by elevate the serum urea, creatinine, potassium, sodium ions and a significant (P < 0.01) depletion in calcium levels. Current findings coincide with Alsadee,36 who discovered that AAS Boldjan caused kidney damage in male rats. Our findings are consistent with those of El-Gharbawy,6 who found that Trenbolone as an AAS produced nephrotoxicity in male adult rats. Similarly, these results are consistent with previous investigations. Also; our findings are consistent with those of Tsitsimpikou et al.37 who reported that; long-term ND adminis induced renal toxicity and damage. Current findings coincide with Gabr et al.38; Tousson and Alm-Eldeen1 and Tousson et al.39 found that boldenone caused kidney damage in male weaned lambs and rabbits, respectively. Current findings coincide with Sessa et al.,40 who reported that; AASs-induced direct glomerular toxicity. Treatment of rats by ND with CurNPs or/and NF-CH-CurNPs showed a significant (P < 0.01) depletion in urea, creatinine, sodium, potassium ions and a significant (P < 0.01) elevation in calcium ions as compared to ND with best results for NF-CH-CurNPs treatment. Our results are in agreement with El-Gizawy et al.41 who reported that; CurNPs ameliorate nephrotoxicity induced by cisplatin in rats. Our results are in agreement with Anwar et al.42 who studied the role of curcumin loaded chitosan nanoparticles supplementation against cypermethrin induced renal toxicity. Our findings align with Hassanen et al.43 who reported that; oral supplementation of curcumin-encapsulated chitosan nanoconjugates improved renal toxicity by nickel. Oxidative stress disrupts the balance between antioxidants and pro-oxidants, leading to potential damage due to depletion of endogenous antioxidants, low dietary intake, and increased formation of free radicals.20,44 The toxicities caused by AASs have been directly linked to oxidative stress, which results in lipid peroxidation, glutathione depletion, and other oxidant processes that damage and kill biological macromolecules, particularly the cell.35,45 Current results revealed that; ND induced oxidative stress in rat kidney by elevate MDA and deplete catalase, GSH, SOD verify that the redox system imbalance contributes to the renal alterations brought on by ND. Treatments with CurNPs or/and NF-CH-CurNPs improved these changes in oxidative stress and have the capacity to scavenge free radicals; these results agree with Frankenfeld et al.46 who reported that; ND induced oxidative stress in liver, heart and kidney of male rats. The new findings also concur with those of Dornelles et al.,47 who found that rats' kidneys experienced oxidative stress as a result of receiving injections of anabolic steroids. Our findings concur with those of Yadav et al.,48 who discovered that CurNPs shield rats against oxidative stress brought on by fluoride and arsenic. Our findings concur with those of Ahmad et al.,49 who discovered that the chitosan-curcumin nanocomposites inhibit oxidative stress caused by the dangerous element cadmium. Current results revealed that; ND injection induced kidney injury with dilatation of renal tubules with necrotic tubular cells with moderate to strong inflammatory cellular infiltration, severe atrophy in glomeruli, elevation in PCNA and TNFα expressions while treated rats with ND + CurNPs or ND + NF-CH-CurNPs improved these histopathological changes and deplete the elevation in PCNA and TNFα expressions with best results for the treatments with NF-CH-CurNPs. Our results agree with Tousson29 who reported that; renal injury after boldenone injection in rabbits. Our results agree also with Hoseini et al.50 who reported that; ND induced kidney damage in mouse. Current findings coincide with Alsadee,36 who discovered that Boldjan induced kidney injury in male rats. Also our findings are consistent with those of El-Gharbawy,6 who found that Trenbolone induced kidney injury in male rats. Therefore, NF-CH-CurNPs is an immunomodulatory and anti-inflammatory drug that prevents the generation of associated cytokines as well as the growth and differentiation of inflammatory cells. Our current study's results are consistent with those of Radwan et al.,21 who found that; curcumin-loaded nanoparticles protect against thioacetamide-induced acute liver injury and proliferation in rats. Our results corroborate those of Hosseini et al.51 who found that administering curcumin encapsulated in nano micelles exhibited greater anti-inflammatory activity than curcumin itself in preventing the development of lung injury induced by paraquat. Due to its potential dual role in extrinsic or intrinsic apoptotic pathway activation, TNF-α intervened to impair ND in renal cells.52 Through the rupture of the mitochondrial membrane, the cytotoxic cytokine TNF-α triggers cellular death and releases cytochrome C.53 Conversely, testosterone could be involved in the release of pro-inflammatory cytokines such as TNF-α, IL-1b, and IL-6. According to Verzola et al.,54 the production of these cytokines may cause inflammation of the renal tissues and the advancement of chronic kidney disease.

The study you’ve outlined focuses on the potential therapeutic effects of nano ferrite-chitosan-curcumin nanoparticles (NF-CH-CurNPs) in alleviating the toxic effects of Nandrolone decanoate (ND)-induced toxicity in male rats. ND is a widely abused AAS, and its abuse is known to cause significant harm, particularly to the kidneys due to its effects on oxidative stress, and inflammation. Supplementary Material Contributor Information Ehab Tousson, Zoology Department, Faculty of Science, Tanta University, Tanta 31527, Egypt. Afaf El Atrash, Zoology Department, Faculty of Science, Tanta University, Tanta 31527, Egypt. Somia Zaki, Zoology Department, Faculty of Science, Tanta University, Tanta 31527, Egypt. Marwa Negm, Zoology Department, Faculty of Science, Tanta University, Tanta 31527, Egypt. Author contributions Marwa Negm: Methodology, formal analysis, writing original draft, writing-editing manuscript. Somia Zaki, Afaf El-Atrash: Formal analysis, methodology, and writing-editing manuscript. Ehab Tousson: Conceptualization, formal analysis, methodology, writing original draft, writing-editing manuscript and submitted the manuscript to Toxicology Research for publication. Funding No fund. Conflicts of interest The authors declare no competing interests. Data availability All the data and material were available. The data of this article are included within the article and its additional files.

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