Therapeutic potential of mesenchymal stem cells-derived exosomes loaded with elemental or nano selenium on diabetic nephropathy

Therapeutic potential of mesenchymal stem cells-derived exosomes loaded with elemental or nano selenium on diabetic nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Therapeutic potential of mesenchymal stem cells-derived exosomes loaded with elemental or nano selenium on diabetic nephropathy Lashin S. Ali, Maha A. Aljumaa, Dalal S. Alshaya, Fawziah A. Al-Salmi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6940168/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Endocrinologists and nephrologists continually seek new therapeutic approaches for diabetic nephropathy (DN). Lately, mesenchymal stem cells (MSCs)-derived exosomes (MSCs-EXs) have been applied as natural carriers for targeted drug delivery. Thus, we aim to estimate the therapeutic potentialities of MSCs-EXs loaded with ordinary selenium (Se) or its nanoform (NSe) as a promising cell-free therapy in diabetic nephropathy (DN). Eighty rats were randomly split into 8 groups; control, EXs, EXs + Se, EXs + NSe, diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. After 4 weeks, our results indicated renal hypolipidemic and renal ameliorating effects of unloaded or loaded EXs with Se or NSe, evidenced by the declined serum levels of urea, uric acid, and creatinine, compared to diabetic-untreated rats. Such observations might be a reflection of the observed antioxidant activity of both EXs alone or in the combined form with either Se or NSe, evidenced by decreased renal MDA, NO, H 2 O 2 levels coupled with increased GSH, SOD, CAT, and GPX, besides their anti-inflammatory and antiapoptotic effects, indicated by the decreased renal levels of IL-6, TGF-β, TNF-α, BAX, caspase-3, and P53, with Bcl-2 upregulation. Consequently, the kidney architecture in the three diabetic-treated groups was greatly improved. Likely, the EXs-loaded NSe treatment protocol highlighted the DN improvement superiority most significantly compared to the other protocols. Biological sciences/Cell biology Biological sciences/Physiology Biological sciences/Zoology Apoptosis Diabetic nephropathy Exosomes Stem cells Streptozotocin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 1. INTRODUCTION Diabetic nephropathy (DN), the primary cause of late-stage renal disease in diabetes mellitus (DM), is a leading cause of diabetic patients’ mortality globally because of the renal interstitial fibrosis progression, which involves mesangial expansion and extracellular matrix (ECM) increased deposition ( 1 – 3 ). As immune-privileged cells, self-renewing mesenchymal stem cells (MSCs) were suggested as a promising therapeutic strategy for DN since they can go home to injured kidneys rapidly, promoting their repair, preventing and reversing kidney fibrosis, and improving renal function through paracrine pathways. Numerous experimental reports have offered exosomes (EXs), a key player in the MSC-mediated repair mechanism of injured tissues, as a potential safer therapeutic delivery vehicle for DN management ( 4 – 7 ). EXs are a kind of extracellular vesicle with cup-shaped (30–150 nm) lipid bilayer membranes ( 8 , 9 ). MSCs-derived EXs (MSCs-EXs) coordinate tissue repair and intercellular communication through the transfer of exogenous miRNAs, proteins, DNA, lipids, cytokines, and growth factors between cells, which modulate the immune response and induce tissue repair and regeneration ( 10 – 12 ). Recently, research has been directed towards a new approach, including the loading of MSCs-EXs with nano drugs to enhance their therapeutic efficiency ( 9 , 13 , 14 ). Selenium (Se) is a vital trace element and micronutrient for most organisms. It does not exhibit direct antioxidant properties on its own but functions as a cofactor for antioxidant enzymes as part of the selenoproteins, crucial for the defense against oxidative stress. Since sufficient Se intake is essential for human health maintenance, it is strongly recommended globally as a food supplement to prevent or/and alleviate pathological conditions related to Se deficiency, including DM ( 15 , 16 ). Se has been revealed as an insulin-mimetic agent since two selenoproteins (GPX and SeP) are known to reduce oxidative stress besides being involved in the enzymatic regulation of insulin signaling cascade, lipogenic enzymes expression, and hepatic carbohydrate metabolism ( 17 , 18 ). Unfortunately, Se supplements have a low absorption extent with increased toxicity ( 19 ). Therefore, alternative Se nanoparticles (SeNPs) supplementation has received accumulated attention in recent years due to their decreased toxicity, enhanced absorption, and unique biological properties regarding the ordinary form of Se, which could be attributed to the interaction between –C–N–, C = O, –NH 2 , and -COO functional groups of proteins and the Se nanoparticles ( 15 , 20 ). In recent decades, colloidal SeNPs have emerged as exceptional Se species with reported chemopreventative and therapeutic properties ( 19 ). Therefore, our article was designed to investigate the renal ameliorative potential of Se and NSe-loaded MSCs-EXs in Streptozotocin (STZ)-induced type 1 diabetic rats. 2. MATERIALS & METHODS 2.1. Animal ethics and consent This study is in accordance with ARRIVE guidelines. All experiments conducted in this study were in strict accordance with relevant guidelines and regulations. This study had an approval number from the Faculty of Science, Arish University Animal Care and Use Committee, Egypt, with the registration code ARU/SF. 04, and informed owner consent was obtained. 2.2. Chemicals and biochemical examination Se or NSe particles (Sigma Aldrich Co., USA) incorporation into MSCs-EXs (500 µg/ml, NAWAH Co., EGYPT) was applied following the Haney et al. ( 21 ) Sonication-aided EXs drug loading technique. According to the instructions, all biochemical assessments were carried out using Bio Diagnostic Co. (Egypt) kits. On the other hand, the Suvarna et al . ( 22 ) method was applied to perform a routine kidney histochemical examination. 2.3. Experimental design Eighty male Wistar rats (6–8 weeks, 180–210 g) obtained from the laboratory animal facility of the National Research Center, Giza, Egypt were kept at room temperature (22 ± 2°C) with humidity of 50 ± 5%, 12/12-hours light/dark cycle, and were fed standard pellet chow (El-Nasr Chemical Co., Cairo, Egypt), where food and water were allowed ad libitum. After 2 weeks of acclimatization before dietary manipulation, 8 groups (10 rats each) were conducted for 4 weeks: Control, EXs, EXs + Se, EXs + NSe, diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. Unloaded or loaded EXs injection (0.5 ml, single dose) was carried out through the tail vein on day one. However, induction of diabetes was performed by intraperitoneal single streptozotocin (STZ, 60 mg/kg) injection. 2.4. Sample collection Overnight fasted rats were anesthetized with a combination of ketamine and xylazine with a ratio of 4:1 (160 µl ketamine 10% + 40 µl xylazine) before being dissected. The animals were euthanized through cervical dislocation. Blood sample collection was carried out via a cardiac puncture and then centrifuged for 15 minutes (1000X g) to obtain sera. In addition, kidney specimens were harvested for various biochemical, flow cytometric, and histopathological examinations. 2.5. Statistical analysis Data were analyzed using SPSS 21 software and expressed as the Mean ± standard error (SEM). A p-value of ≤ 0.05 was considered the minimum significance level. 3. RESULTS The transmission electron microscope revealed 50-150 nm circular EXs vesicles (Figure 1A), while showing 5-50 nm spherical NSe particles ( Figure 1B ), confirming both EXs and NSe morphological identity . In addition, the flow cytometric analysis of EXs revealed high expression of the surface markers CD9, CD63, and CD81, confirming their phenotype identity (Figure 1C). Figure 2 A-D recorded a marked glycemic control amelioration in all diabetic-treated groups, as proved by the clear serum levels decline of both HbA1c and glucose associated with marked insulin and C-peptide levels relative to untreated diabetic rats. EXs-loaded NSe likely showed a hypoglycemic superiority relative to other treatments. The illustrated data in Figure 3 (A-C) highlighted an obvious amelioration in both serum and renal lipid profiles in all three treated diabetic groups, indicated by the significant TL, TC, TG, and LDL-C associated with HDL-C decline in the diabetic untreated group. Notably, AD-MSCs-EXs loaded with NSe recorded the greatest hypolipidemic efficacy. Data of diabetic rats treated with unloaded EXs or EXs loaded with either Se or NSe revealed in Figure 4 highlighted serum marked urea, uric acid, and creatinine declines relative to the untreated diabetic rats. Notably, diabetic rats treated with EXs+NSe exhibited the greatest renal function ameliorating effect over other treatments. The three diabetic rats-treated groups' findings represented in Figures 5 & 6 indicated significant renal MDA, H 2 O 2 , and NO levels decline, associated with marked GSH, SOD, CAT, and GST upregulation. However, EXs+NSe treatment reflected the highest renal antioxidant potential and oxidative stress suppression excellence. Regarding diabetic-untreated rats, Figure 7 data shows a marked renal inflammatory regression of all diabetic rats’ treatment protocols, with an NSe-loaded EXs anti-inflammatory superiority. Compared to untreated diabetics, the results of Figure 8 revealed that diabetic rats injected with EXs alone or in loaded form with Se or NSe exhibited substantial relief in the renal apoptotic status. This was indicated by the significant upregulation in some apoptotic markers (caspase-3 %, BAX, and P53), with the noted Bcl-2 (anti-apoptotic) % downregulation. Interestingly, the EXs+NSe protocol revealed the most antiapoptotic potential. Figures 9A-D , representing the Control, EXs, EXs+Se, and EXs+NSe regular groups, showed normal renal glomeruli and tubules. In contrast, Figure 9E represented the diabetic (STZ-treated) group, displaying severe pathological lesions, evidenced by diffuse tubular dilation with marked hydropic degeneration in epithelial lining (thin black arrows) with few pyknotic nuclei (thick black arrows), congested intratubular capillaries (red arrows), swollen congested glomerular tuft with dilated Bowman's capsule (black arrowheads), interstitial edema (*). On the other hand, the renal section in Figure 9F , from the STZ+EXs group, shows slightly less severe pathological lesions: diffuse tubular dilation with hydropic degeneration in epithelial lining (thin black arrows), some pyknotic nuclei (thick black arrows), dilated Bowman's capsule (black arrowheads), interstitial edema (*). The renal sections in Figure 9G , from the STZ+EXs+Se group, showed decreased tubular dilation and hydropic degeneration in the epithelial lining (thin black arrows) with dilated Bowman's capsule (black arrowheads). Likely, the renal sections of the STZ+EXs+NSe (Figure 9H) revealed the greatest renal histological improvement, nearly resembling the control kidney, except for slightly dilated Bowman's capsule (black arrowheads), highlighting the renal protective and ameliorative superiority of such treatment protocol on diabetic kidney over the two other protocols. 4. DISCUSSION In DM, hyperglycemia activates DN-various renal inflammatory pathways through renal ROS overproduction and repressing the antioxidant enzymes activity, leading to oxidative stress progression, DNA fragmentation, lipid peroxidation, protein damage, promoting the infiltration of inflammatory cells, and increased profibrotic cytokines release, leading collectively to progressive podocyte fibrosis and apoptosis, renal tubular damage, and associated albuminuria ( 20 , 23 – 26 ). Accordingly, MSCs-EXs are considered a prominent approach for relieving kidney fibrosis because of their kidney regeneration therapeutic potential in the restoration of normal cell functions, immunoregulation, and homing mechanisms, which could be attributed mainly to the essential roles of their microRNAs (miRNAs) abundance, among other cargos ( 11 ). According to our results, AD-MSCs-EXs injection into STZ-diabetic mice showed an efficient anti-fibrotic effect via the suppression of podocyte apoptosis, autophagy downregulation, reversion, and DN attenuation, evidenced by diminished levels of serum creatinine (Scr), urine protein, blood urea nitrogen (BUN), and TGF-β fibrotic marker ( 27 ). AD-MSCs-EXs-dependent renal protection and amelioration against acute and chronic renal inflammation were suggested relying on the capability of their miRNAs, mRNAs, and growth and immunosuppressive factors contents, in ( 1 ) regression of destructive immune response in the kidneys, ( 2 ) increased renal tubular epithelial cells proliferation and ( 3 ) suppression of oxidative stress progression, necrosis, and apoptosis ( 28 , 29 ). Additionally, MSCs-EXs significantly alleviated renal fibrosis and inflammation in diabetic rats through miR-21 and miR-125a delivery which targeted the inflamed kidneys' TGF-β1 pro-fibrotic gene, resulting in ( 1 ) reduced Th1 and Th17 cells activation, ( 2 ) lowering the inflammatory IL-1β and TNF-α cytokines release, via the inflammatory M1 cells conversion into immunosuppressive M2 macrophages, and ( 3 ) neo-angiogenesis induction by MSCs-EXs-derived vascular endothelial growth factor (VEGF) ( 30 , 31 ). Interestingly, bone marrow stem cell-derived (BM-MSCs) exosomes can also improve diabetes-induced cognitive nephropathy. Meanwhile, miR-let-7a transported by BM-MSC-EXs inhibited the JAK2/STAT3 pathway, which resulted in decreased BUN, TGs, and TCs in rats with DN, leading to the inhibition of renal cells, oxidative stress, apoptosis, and renal tubular epithelial cells degeneration ( 18 , 32 ). According to Nagaishi et al. ( 33 , 34 ), in STZ-diabetic rats with DN, BM-MSCs-EXs delivered to the subcapsular region of the kidney markedly relieved kidney injury by ( 1 ) minimizing the infiltration of inflammatory cells, ( 2 ) the release of TGF-β, and ( 3 ) degeneration and apoptosis of renal cells. On the other hand, Zhang et al. ( 35 ) have shown that human umbilical cord-MSCs-EXs (hUC-MSCs-EXs) carried abundant miR-146a-5p, which can ( 1 ) promotes the polarization of M2 macrophage, ( 2 ) dramatically downregulated hyperglycemia-induced pro-inflammatory cytokines, and ( 3 ) transferred growth factors including EGF, FGF, HGF and VEGF, resulting in marked renal inflammation suppression and the restoration of normal renal function ( 36 ). Interestingly, a significant anti-fibrotic effect of UC-MSC-EXs injection, following unilateral ureteral obstruction (UUO)-induced renal damage, was highlighted, evidenced by the decreased secretion of TGF-β1, MDA, and ROS, kidney fibrosis marked alleviation, and suppression of renal cells apoptosis, leading to regular renal function restoration (declined Scr, uric acid, and BUN) ( 37 ). Moreover, urine-derived stem cell EXs (USC-EXs) intravenous injections alleviated albuminuria in the STZ-DN rat model through their delivery of miRNA-16-5p to the injured kidney, which attenuated the impairment of renal functions (decreased Ucr, Scr, and BUN). The renoprotection mechanism was likely attributed to ( 1 ) the downregulation of podocyte apoptosis-associated proteins (caspase-3, BAX, and P53), TNF-α, and TGF-β1, ( 2 ) cell survival and vascular regeneration promotion, ( 3 ) mesangial angiogenesis glomerular endothelial cell proliferation induction, which collectively protected diabetic rats from DN ( 38 , 39 ). All these results propose a rationale for the role of different miRNAs in inducing the amelioration of renal resident cells in the DN model treated with various EXs from various sources. Regarding Se, its antidiabetic and renoprotective actions appear to arise from its behavior as a mainly antioxidant as well as an insulin-mimetic with a tremendous free radical scavenging effect, which in turn reflects the insulin signaling and secretion role in the cellular redox modulation ( 17 ). Indeed, Se promoted renal glucose excretion in rats ( 40 ). According to Huang et al. ( 41 ), the Se contents in the plasma were significantly lower in DN patients, with a significant negative correlation with renal function and a positive correlation with HbA1c than in the healthy controls. In this line, the Bahmani et al. ( 42 ) study demonstrated that daily Se supplementation (200 µg) for 12 weeks among patients with DN had increased serum insulin levels, plasma GPX, ameliorated lipid profiles, and enhanced kidney functions. Furthermore, it was found that a Se-rich diet supplementation for 6 months activated many selenoprotein antioxidants, which was suggested to delay the onset of DN in diabetic rats ( 19 ). Nevertheless, the SeNPs insulin-mimetic activity can also mitigate the STZ-diabetic rats' hyperlipidemia and hyperglycemia, probably via improving the, since oral administration of SeNPs (0.1 mg/kg) to STZ-diabetic rats significantly decreased FBG levels while enhanced serum insulin concentration, after 28 days of treatment. Furthermore, the SeNP hypoglycemic effect significantly declines renal function markers (creatinine, urea, and uric acid), TL, TC, TG, and LDL-C levels, while increasing kidney glycogen contents and HDL-C levels, besides ameliorating the renal tissues' histological architecture ( 20 ). Consistently, oral administration of SeNPs (0.5 mg kg) daily for eight weeks to STZ-induced DN rats significantly reversed the disturbance of the renal redox status, confirmed by the significant decrease in FBG, Scr, urea, MDA, NO, IL-6, NF-κB, TNF-α, BAX, and caspase-3, while marked elevations in renal antioxidants, such as HO-1, GPX, CAT, SOD, and GSH, compared to the untreated-DN group, confirming the SeNPs’ anti-inflammatory and antiapoptotic potential renoprotective effects against DN ( 43 , 44 ). Interestingly, Lotfy et al. ( 45 ) suggested that the anti-fibrotic and ameliorative effects of the SeNPs against kidney injury caused by diabetic complications result from their inhibitory potential on TGF-β1 and its receptor gene expression in renal tissues. CONCLUSION Both unloaded and loaded EXs with either elemental or nano Se showed a renoprotective impact and minimized the risk of DN progression in type 1 diabetic rats. However, further studies are needed regarding maximizing the EXs tissue-protective abilities through loading with other therapeutic nano-drugs before MSCs-EXs can be given as a global human therapy for various inflammatory and autoimmune diseases. Abbreviations AD-MSCs: Adipose-derived mesenchymal stem cells, BUN: Blood urea nitrogen, CAT: Catalase, CD: Cluster of differentiation, D: Diabetic, DM: Diabetes mellitus, DMEM: Dulbecco's modified Eagle's medium, DN: Diabetic nephropathy, EXs: Exosomes, FBG: Fasting blood glucose, FBS: Fetal bovine serum, GPX: Glutathione peroxidase, GSH: Glutathione , HbA1c: glycosylated hemoglobin, H 2 O 2: Hydrogen peroxide, MDA: Malondialdehyde, MSCs: Mesenchymal stem cells, NSe: Nano selenium, PBS: Phosphate-buffered saline, ROS: Reactive oxygen species, Scr: Serum creatinine, Se: Selenium , SEM: Standard error of the mean , SOD: Superoxide dismutase, SPSS: Statistical Package for Social Scientists, STZ: Streptozotocin, T1DM: Type 1 diabetes mellitus. Declarations Ethics approval : Our design was approved by the Animal Ethics Committee of the Faculty of Science, Arish University, North Sinai, Egypt (ARU/SF. 04). Consent to participate: Not applicable. Consent to publish: Not applicable. Authors' Contributions: SGE, FAA, IY, LSA, MAA, DSA, EIE, FGE, AAE, ME, and EF conceived and designed the study. Experiments and lab work were done by SGE, FAA, IY, EIE, LSA, AAE, and ME; data tabulating and acquisition, searching for literature, and preparing the first draft of the manuscript were performed by SGE, FAA, IY, DYK, RYK, EIE, FAA, ME, AAE, and LSA. All authors reviewed the results and approved the final version of the manuscript. Funding : The authors extend their appreciation to the Deanship of Scientific Research and Graduate Studies at King Khalid University for funding this work through the Large Research Project under grant number RGP2/63/46. The authors extend their appreciation to the Deanship of Scientific Research of Princess Nourah bint Abdulrahman University, Researchers Supporting Project number (PNURSP2025R465), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. Acknowledgments : The authors extend their appreciation to the Deanship of Scientific Research and Graduate Studies a King Khalid University for funding this work through the Large Research Project under grant number RGP2/63/46. Y. The authors extend their appreciation to the Deanship of Scientific Research of Princess Nourah bint Abdulrahman University, Researchers Supporting Project number (PNURSP2025R465), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors would also like to express sincere gratitude to AlMaarefa University, Riyadh, Saudi Arabia, for supporting this research. Competing Interests: The authors declare that they have no competing interests. Data Availability: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References He, C., Zheng, S., Luo, Y. & Wang, B. Exosome theranostics: Biology and translational medicine. Theranostics 8 (1), 237–55. doi: 10.7150/thno.21945 (2018). He, Q., Wang, L., Zhao, R. et al. Retraction Note: Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy. Stem Cell Res. Ther. 13 , 505. DOI.org/10.1186/s13287-022-03191-6 (2022). Al-Tamimi, O., Awwad, S. H., Issa, R., Al-Qaisi, T., Abazid, H., Daraosheh, A. & Abu-Samak, M. The effect of roasting degrees on bioactive compounds levels in Coffea arabica and their associations with glycated hemoglobin levels and kidney function in diabetic rats. Journal of Applied Pharmaceutical Science DOI.org/10.7324/JAPS.2024.181047 (2024). Newton, W. C., Kim, J. W., Luo, J. Z. Q. & Luo, L. Stem cell-derived exosomes: a novel vector for tissue repair and diabetic therapy. Journal of Molecular Endocrinology 59 (4), R155–R165 (2017). Chen, J., Zhang, Q., Liu, D. & Liu Z. Exosomes: Advances, development and potential therapeutic strategies in diabetic nephropathy. Metabolism Clinical and Experimental 122, 154834, DOI.org/10.1016/j.metabol.2021.154834 (2021). Abd El‐lateef, H. M., Qahl, S., Fayad, E., Altalhi, S. A., Jafri, I., Shabana E, Darwish, M. K., et al. The potency of N, N′-diphenyl-1,4-phenylenediamine and adipose-derived stem cell co-administration in alleviating hepatorenal dysfunction complications associated with type 1 diabetes mellitus in rats. Biocell 47 (8), DOI: 10.32604/biocell.2023.030680 (2023). Abd El‐lateef, H. M., Ali, L. S., Qahl, S. H., Fayad, E., Binjawhar, D. N., Fayad, E., Alghamdi, M. A. et al. Therapeutic effect of N, N-Diphenyl-1,4-phenylenediamine and adipose‐derived stem cells coadministration on diabetic cardiomyopathy in type 1 diabetes mellitus‐rat model. Journal of Experimental Zoology Part A: Ecological and Integrative Physiology , 1–11. DOI.org/10.1002/jez.2810 (2024). Harrell, C.R., Jovicic, N., Djonov, V., Volarevic, V. Therapeutic Use of Mesenchymal Stem Cell-Derived Exosomes: From Basic Science to Clinics. Pharmaceutics 12 , 474. DOI.org/10.3390/pharmaceutics12050474 (2020). Yang, M., Chen, J. & Chen, L. The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications. Frontiers in Endocrinology . 13 , 1027686, DOI.org/10.3389/fendo.2022.1027686 (2022). Sun, Y., Tao, Q., Wu, X., Zhang, L., Liu, Q. & Wang, L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Frontiers in Endocrinology 12 , 756581, DOI.org/10.3389/fendo.2021.756581 (2021). Cao, Q., Huang, C., Chen, X., & Pollock, C. A. Mesenchymal Stem Cell-Derived Exosomes: Toward Cell-Free Therapeutic Strategies in Chronic Kidney Disease. Frontiers in Medicine 9 , 816656. DOI.org/10.3389/fmed.2022.816656 (2022). Alahmari, L. A., Ali, L. S., Fansa, H. A., Alshaya, D. S., Al‐Salmi, F. A., El‐Hallous, E.I. et al. Antioxidant and antiapoptotic effects of selenium and nano selenium-loaded exosomes on hepatic dysfunction of type 1 diabetic rats. Journal of Experimental Zoology Part A: Ecological and Integrative Physiology 1–9. DOI.org/10.1002/jez.2881 (2024). Wei, W., Ao, Q., Wang, X., Cao, Y., Liu, Y. & Tian, X. Mesenchymal Stem Cell-Derived Exosomes: A Promising Biological Tool in Nanomedicine. Frontiers in Pharmacology 11 , 590470. DOI.org/10.3389/fphar.2020.590470 (2021). Al-Samydai, A., Abu Hajleh, M. N., Al-Sahlawi, F., Nsairat, H., Khatib, A. A., Alqaraleh, M. & Ibrahim, A. K. Advancements of metallic nanoparticles: A promising frontier in cancer treatment. Science Progress 107(4):00368504241274967. DOI.org/10.1177/00368504241274967 (2024). Shahidi, S., Asl, S.S., Gholamigeravand, B., Afshar, S., Hashemi-Firouzi, N., Samzadeh-Kermani, A., Majidi, M., Amiri, K. Effect of co-treatment with mesenchymal stem cells and polyvinyl alcohol-coated selenium nanoparticles on rats with streptozotocin-induced Alzheimer's disease. Research Square , DOI.org/10.21203/rs.3.rs-2077811/v1 (2022). Moon, S. & Oh, C.M. Selenium and Risk of Diabetes. Biomarkers in Diabetes. Biomarkers in Disease: Methods, Discoveries, and Applications. Cham. DOI.org/10.1007/978-3-031-08014-255 (2023). Fontenelle, L. C., Feitosa, M. M., Morais, J. B. S., Severo, J. S., de Freitas, T. E. C., Beserra, J. B., Henriques, G. S. & Marreiro, D. N. The role of selenium in insulin resistance. Brazilian Journal of Pharmaceutical Sciences , DOI.org/10.1590/s2175-97902018000100139 9 (2018). Wang, Y., Shan, S. K., Guo, B., Li, F., Zheng, M. H., Lei, L. M., Xu, Q. S., Ullah, M. H. E., Xu, F., Lin, X. et al. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. Front. Endocrinol ., 12 , 671566 (2021). Kumar, A. & Prasad, K. S. Role of nano-selenium in health and environment. Journal of Biotechnology 325 , 152-163. DOI.org/10.1016/j.jbiotec.2020.11.004 (2021). Al-Quraishy, S., Dkhil, M. A. & Moneim, A. E. A. Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. International Journal of Nanomedicine 10 (1), 6741-6756. DOI.org/10.2147/IJN.S91377 (2015). Haney, M. J., Klyachko, N. L., Zhao, Y., Gupta, R., Plotnikova, E. G., He, Z., Patel, T., Piroyan, A., Sokolsky, M., Kabanov, A.V. et al.. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release . 207 , 18-30, DOI.10.1016/j.jconrel.2015.03.033 (2015). Suvarna, S. K., Layton, C., Bancroft, J. D. Bancroft's theory and practice of histological techniques. 7th ed. (1) online resource (2013). Ratliff, B. B., Abdulmahdi, W., Pawar, R., Wolin & M. S. Oxidant mechanisms in renal injury and disease. Antioxid. Redox. Signal . 25 , 119-146. DOI:10.1089/ars.2016.6665 (2016). El-Sawah, S. G., Althobaiti, F., Aldahahrani, A., Fayad, E. Shabana E, El-Hallous, E. I., Rashwan, H. M. AD-MSCs and BM-MSCs Ameliorating Effects on The Metabolic and Hepato-renal Abnormalities in Diabetic Rats. Saudi Journal of Biological Sciences , DOI.org/10.1016/j.sjbs.2021.09.067 (2021). El-Sawah, S. G., El-Hallous, E. I., Khalil, D. Y., Rashwan, H. M., Ameliorating effects of mesenchymal stem cells derived from adipose and bone marrow tissues on cardiomyopathy of diabetic rats: A comparative study. Egyptian Journal of Zoology , DOI: 10.21608/ejz.2022.121278.1073 (2022). Shaaban, S., El-Shamy, H., Gouda, M., Darwish, M. K., Khalaf, M. M. et al. N, N- Diphenyl-1,4-phenylenediamine Antioxidant’s Potential Role in Enhancing the Pancreatic Antioxidant, Immunomodulatory, and Anti-Apoptotic Therapeutic Capabilities of Adipose-Derived Stem Cells in Type I Diabetic Rats. Antioxidants 12 , 58. DOI.org/10.3390/antiox12010058 (2023). Jin, J., Shi, Y., Gong, J., Zhao, L., Li, Y., He, Q. et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocytes. Stem Cell Res. Ther . 10 , 95. Doi: 10.1186/s13287-019-1177-1 (2019). Bruno, S., Tapparo, M., Collino, F., Chiabotto, G., Deregibus, M. C., Lindoso, S. et al. Renal Regenerative Potential of Different Extracellular Vesicle Populations Derived from Bone Marrow Mesenchymal Stromal Cells. Tissue Eng. Part A 23 , 1262–1273 (2017). Tsuji, K., Kitamura, S. & Wada, J. Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity. Stem Cells Int. 8693137, 2018. Harrell, C. R., Jovicic, N., Djonov, V., Arsenijevic, N. & Volarevic, V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells . 8 , 1605. DOI.org/10.3390/cells8121605 (2019). Hao, Y., Miao, J., Liu, W., Cai, K., Huang, X., Peng, L. et al. Mesenchymal stem cell-derived exosomes carry MicroRNA-125a to protect against diabetic nephropathy by targeting histone deacetylase 1 and downregulating endothelin-1. Diabetes Metab. Syndr. Obes. 14 ,140518. DOI: 10.2147/DMSO.S286191 (2021). Mao, R., Shen, J. & Hu, X. BMSCs-derived exosomal microRNA-let-7a plays a protective role in diabetic nephropathy via inhibition of USP22 expression. Life Sci. 268 ,118937, Doi: 10.1016/j.lfs.2020.118937 (2021). Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M., Konari, N. et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci. Rep. 6 , 34842, Doi: 10.1038/srep34842 (2016). Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M. T. et al. Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy. Sci. Rep . 7 (1), 1-17, DOI: 10.1038/s41598-017-08921-y (2017). Zhang, Z., Mi, T., Jin, L., Li, M., Hao, C., Huang, Z. et al. Comprehensive proteomic analysis of exosome mimetic vesicles and exosomes derived from human umbilical cord mesenchymal stem cells. Stem Cell Res. Ther. 13 (1), 312. DOI: 10.1186/s13287-022-03008-6 (2022). Xiang, E., Han, B., Zhang, Q., Rao, W., Wang, Z., Chang, C. et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy by inhibiting inflammation and fibrosis. Stem Cell Res. Ther . 11 , 336. DOI: 10.1186/s13287-020-01852-y (2020). Liu, B., Hu, D., Zhou, Y., Yu, Y., Shen, L., Long, C. et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK/ERK signaling pathway. Am. J. Transl. Res. 12 , 4998–5014 (2020). Jiang, Z. Z., Liu, Y. M., Yin, J. Y., Hu, B. & Guo, S. C. Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. Stem Cell Res. Ther . 7 , 24, DOI.org/10.1186/s13287-016-0287-2 (2016). Duan, Y. R., Chen, B. P., Chen, F., Yang, S. X., Zhu, C. Y. & Ma, Y. L et al. Exosomal microRNA-16-5p from human urine-derived stem cells ameliorates diabetic nephropathy by protecting podocytes. J. Cell Mol. Med . 25 , 10798 813, DOI: 10.1111/jcmm 14558. Mueller, A. S. & Pallauf, J. Compendium of the antidiabetic effects of supranutritional selenate doses: in vivo and in vitro investigations with type II diabetic db/db mice. J. Nutr. Biochem . 17 , 548-560 (2006). Huang, F., Zhao, L., Cheng, L., Chen, Z., Fu, R. & Tian, L. Changes of selenium and selenoprotein expressions in diabetic nephropathy. Journal of Xi'an Jiaotong University (Medical Sciences) 6 , 562-566 (2018) . Bahmani, F., Kia, M., Soleimani, A., Asemi, Z. & Esmaillzadeh, A. Effect of Selenium Supplementation on Glycemic Control and Lipid Profiles in Patients with Diabetic Nephropathy. Biol Trace Elem Res . 172 (2), 282-289. doi: 10.1007/s12011-015-0600-4 (2016). Alkhudhayri, A., Al-Shaebi, E. M., Qasem, A. A., Murshed, M., Mares, M. H., Al-Quraishy, S., Dkhil, M. A. Antioxidant and anti-apoptotic effects of selenium nanoparticles against murine eimeriosis. An Acad. Bras. Cienc . 92 (2), e20191107, https://doi 10.1590/0001-3765202020191107 (2020). Zaghloul, R. A., Abdelghany, A. M. & Samra, Y. A. Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats by downregulating the Jak-2/Stat3 pathway and upregulating the Nrf-2/HO-1 pathway. Eur J Pharmacol. 933 , 175289, DOI: 10.1016/j.ejphar.2022.175289 (2022). Lotfy, M. M., Dowidar, M. F., Ali, H. A. & Ahmed, A. I. Effect of Selenium Nanoparticles and Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy. Metabolites 13 (3), 400, DOI.org/10.3390/metabo13030400 (2023). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":374498,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eA:\u003c/strong\u003e\u003c/em\u003e EXs morphology.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eB:\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eNSe morphology.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eC:\u003c/strong\u003e\u003c/em\u003e MSCs-EXs surface markers \u0026nbsp;\u0026nbsp;flow cytometric analysis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/de29b00b71ddafcdfe32ad8b.png"},{"id":91998483,"identity":"c5d792f8-a001-4229-b129-f6ff8c826871","added_by":"auto","created_at":"2025-09-23 14:08:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":170002,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(2A): Serum glucose level.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(2B): Serum HbA1c level.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003e\u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(2AC): Serum insulin level.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(2D): Serum C-peptide level.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/a1b25593b996ea1bb2b9cbfd.png"},{"id":92000982,"identity":"15d52966-2a1f-4fa3-91ed-e512c8e0488a","added_by":"auto","created_at":"2025-09-23 14:24:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":138868,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eA: Renal TL, TG \u0026amp; TC levels.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eB: Serum TL, TG \u0026amp; TC levels.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eC: Serum HDL-C \u0026amp; LDL-C levels.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eTL → \u003c/strong\u003e\u003c/em\u003etotal lipids,\u003cem\u003e\u003cstrong\u003e TG → \u003c/strong\u003e\u003c/em\u003etriglycerides,\u003cstrong\u003e \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eTC → \u003c/strong\u003e\u003c/em\u003etotal cholesterol, \u003cem\u003e\u003cstrong\u003eHDL-C → \u003c/strong\u003e\u003c/em\u003ehigh-density lipoproteins cholesterol,\u003cem\u003e\u003cstrong\u003e LDL-C → \u003c/strong\u003e\u003c/em\u003elow-density lipoproteins cholesterol.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/15debe71cd73381c57b1b0cf.png"},{"id":91998488,"identity":"8b630ee0-19d0-4079-a75b-85fa949181e6","added_by":"auto","created_at":"2025-09-23 14:08:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37302,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSerum creatinine, uric acid \u0026amp; urea levels.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eAST\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003easpartate aminotransferase,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eALT\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003ealanine aminotransferase,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eTB\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003etotal bilirubin.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/326f5c4853740a5ecd23a0f3.png"},{"id":91999697,"identity":"edc8e311-c46f-4fae-b048-50c95d76ce4f","added_by":"auto","created_at":"2025-09-23 14:16:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":39813,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eRenal MDA, NO \u0026amp; H\u003c/strong\u003e\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e\u003cstrong\u003eO\u003c/strong\u003e\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e\u003cstrong\u003e contents.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/99026d788fd730c1fcec9696.png"},{"id":92001304,"identity":"f1d39ba1-4001-427a-9db5-b2a8e0f76d89","added_by":"auto","created_at":"2025-09-23 14:32:02","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":47329,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eRenal GSH, SOD, CAT \u0026amp; GPX contents.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cem\u003e\u003cstrong\u003eMDA\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003emalondialdehyde,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eH\u003c/strong\u003e\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e\u003cstrong\u003eO\u003c/strong\u003e\u003c/em\u003e\u003csub\u003e\u003cem\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e → \u003c/em\u003ehydrogen peroxide,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNO\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enitric oxide.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cem\u003e\u003cstrong\u003eGSH\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003eglutathione,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSOD\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003esuperoxide dismutase,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eCAT\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003ecatalase,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eGPX\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eglutathione peroxidase.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/906f9955ec1f5183599c8970.png"},{"id":92000980,"identity":"1c862472-5dd4-4672-b7b4-f5257f794c7e","added_by":"auto","created_at":"2025-09-23 14:24:02","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":38141,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eHepatic TNF-α, TGF-β, \u0026amp; IL-6 contents.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/f56500e12d71044a38eb3a9d.png"},{"id":91999694,"identity":"4ac5a685-b07a-4127-9860-c53bb32121da","added_by":"auto","created_at":"2025-09-23 14:16:02","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":39626,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eRenal Caspase-3, BAX, P53 (apoptotic) \u0026amp; Bcl-2 (anti-apoptotic).\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003ea, b \u0026amp; c \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ significance relative to C, D \u0026amp; D+EXs treated groups respectively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/eb7af67258941643a7e1357f.png"},{"id":91999699,"identity":"053885ab-3a98-4d9a-ae84-6796ac22facd","added_by":"auto","created_at":"2025-09-23 14:16:02","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":1743964,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePhotomicrograph of HE-stained renal sections in different rat groups\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eLow magnification → 100X: bar 100 \u0026amp; High magnification → 400X: bar 50\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e).\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cem\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003econtrol,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eEXs\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eexosomes,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003eselenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eNSe\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e → \u003c/em\u003enano-selenium,\u003cem\u003e \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eD \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e→ \u003c/em\u003ediabetic.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/34cc9bff986c8387ce8fc4b3.png"},{"id":93024491,"identity":"bd38cd54-11a1-4bac-bc77-7d2f2673d663","added_by":"auto","created_at":"2025-10-08 09:17:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3856398,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6940168/v1/63c53eb3-e642-47d6-a475-225ccf18a0e8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Therapeutic potential of mesenchymal stem cells-derived exosomes loaded with elemental or nano selenium on diabetic nephropathy","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eDiabetic nephropathy (DN), the primary cause of late-stage renal disease in diabetes mellitus (DM), is a leading cause of diabetic patients\u0026rsquo; mortality globally because of the renal interstitial fibrosis progression, which involves mesangial expansion and extracellular matrix (ECM) increased deposition (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). As immune-privileged cells, self-renewing mesenchymal stem cells (MSCs) were suggested as a promising therapeutic strategy for DN since they can go home to injured kidneys rapidly, promoting their repair, preventing and reversing kidney fibrosis, and improving renal function through paracrine pathways. Numerous experimental reports have offered exosomes (EXs), a key player in the MSC-mediated repair mechanism of injured tissues, as a potential safer therapeutic delivery vehicle for DN management (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). EXs are a kind of extracellular vesicle with cup-shaped (30\u0026ndash;150 nm) lipid bilayer membranes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). MSCs-derived EXs (MSCs-EXs) coordinate tissue repair and intercellular communication through the transfer of exogenous miRNAs, proteins, DNA, lipids, cytokines, and growth factors between cells, which modulate the immune response and induce tissue repair and regeneration (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Recently, research has been directed towards a new approach, including the loading of MSCs-EXs with nano drugs to enhance their therapeutic efficiency (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSelenium (Se) is a vital trace element and micronutrient for most organisms. It does not exhibit direct antioxidant properties on its own but functions as a cofactor for antioxidant enzymes as part of the selenoproteins, crucial for the defense against oxidative stress. Since sufficient Se intake is essential for human health maintenance, it is strongly recommended globally as a food supplement to prevent or/and alleviate pathological conditions related to Se deficiency, including DM (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Se has been revealed as an insulin-mimetic agent since two selenoproteins (GPX and SeP) are known to reduce oxidative stress besides being involved in the enzymatic regulation of insulin signaling cascade, lipogenic enzymes expression, and hepatic carbohydrate metabolism (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Unfortunately, Se supplements have a low absorption extent with increased toxicity (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Therefore, alternative Se nanoparticles (SeNPs) supplementation has received accumulated attention in recent years due to their decreased toxicity, enhanced absorption, and unique biological properties regarding the ordinary form of Se, which could be attributed to the interaction between \u0026ndash;C\u0026ndash;N\u0026ndash;, C\u0026thinsp;=\u0026thinsp;O, \u0026ndash;NH\u003csub\u003e2\u003c/sub\u003e, and -COO functional groups of proteins and the Se nanoparticles (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In recent decades, colloidal SeNPs have emerged as exceptional Se species with reported chemopreventative and therapeutic properties (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Therefore, our article was designed to investigate the renal ameliorative potential of Se and NSe-loaded MSCs-EXs in Streptozotocin (STZ)-induced type 1 diabetic rats.\u003c/p\u003e"},{"header":"2. MATERIALS \u0026 METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Animal ethics and consent\u003c/h2\u003e\u003cp\u003eThis study is in accordance with ARRIVE guidelines. All experiments conducted in this study were in strict accordance with relevant guidelines and regulations. This study had an approval number from the Faculty of Science, Arish University Animal Care and Use Committee, Egypt, with the registration code ARU/SF. 04, and informed owner consent was obtained.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Chemicals and biochemical examination\u003c/h2\u003e\u003cp\u003eSe or NSe particles (Sigma Aldrich Co., USA) incorporation into MSCs-EXs (500 \u0026micro;g/ml, NAWAH Co., EGYPT) was applied following the \u003cb\u003eHaney et al.\u003c/b\u003e (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Sonication-aided EXs drug loading technique. According to the instructions, all biochemical assessments were carried out using Bio Diagnostic Co. (Egypt) kits. On the other hand, the \u003cb\u003eSuvarna\u003c/b\u003e \u003cb\u003eet al\u003c/b\u003e. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) method was applied to perform a routine kidney histochemical examination.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Experimental design\u003c/h2\u003e\u003cp\u003eEighty male Wistar rats (6\u0026ndash;8 weeks, 180\u0026ndash;210 g) obtained from the laboratory animal facility of the National Research Center, Giza, Egypt were kept at room temperature (22\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C) with humidity of 50\u0026thinsp;\u0026plusmn;\u0026thinsp;5%, 12/12-hours light/dark cycle, and were fed standard pellet chow (El-Nasr Chemical Co., Cairo, Egypt), where food and water were allowed ad libitum. After 2 weeks of acclimatization before dietary manipulation, 8 groups (10 rats each) were conducted for 4 weeks: Control, EXs, EXs\u0026thinsp;+\u0026thinsp;Se, EXs\u0026thinsp;+\u0026thinsp;NSe, diabetic (D), D\u0026thinsp;+\u0026thinsp;EXs, D\u0026thinsp;+\u0026thinsp;EXs\u0026thinsp;+\u0026thinsp;Se, and D\u0026thinsp;+\u0026thinsp;EXs\u0026thinsp;+\u0026thinsp;NSe groups. Unloaded or loaded EXs injection (0.5 ml, single dose) was carried out through the tail vein on day one. However, induction of diabetes was performed by intraperitoneal single streptozotocin (STZ, 60 mg/kg) injection.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Sample collection\u003c/h2\u003e\u003cp\u003eOvernight fasted rats were anesthetized with a combination of ketamine and xylazine with a ratio of 4:1 (160 \u0026micro;l ketamine 10% + 40 \u0026micro;l xylazine) before being dissected. The animals were euthanized through cervical dislocation. Blood sample collection was carried out via a cardiac puncture and then centrifuged for 15 minutes (1000X g) to obtain sera. In addition, kidney specimens were harvested for various biochemical, flow cytometric, and histopathological examinations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Statistical analysis\u003c/h2\u003e\u003cp\u003eData were analyzed using SPSS 21 software and expressed as the Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error (SEM). A p-value of \u0026le;\u0026thinsp;0.05 was considered the minimum significance level.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eThe transmission electron microscope revealed 50-150 nm circular EXs vesicles \u003cstrong\u003e\u003cem\u003e(Figure 1A),\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ewhile showing 5-50 nm spherical NSe particles \u003cstrong\u003e\u003cem\u003e(\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eFigure 1B\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e),\u0026nbsp;\u003c/em\u003e\u003c/strong\u003econfirming both EXs and NSe morphological identity\u003cem\u003e.\u003c/em\u003e In addition, the flow cytometric analysis of EXs revealed high expression of the surface markers CD9, CD63, and CD81, confirming their phenotype identity \u003cstrong\u003e\u003cem\u003e(Figure 1C).\u003c/em\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFigure 2 A-D\u0026nbsp;\u003c/em\u003e\u003c/strong\u003erecorded\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ea marked glycemic control amelioration in all diabetic-treated groups, as proved by the clear serum levels decline of both HbA1c and glucose associated with marked insulin and C-peptide levels relative to untreated diabetic rats. EXs-loaded NSe likely showed a hypoglycemic superiority relative to other treatments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe illustrated data in \u003cstrong\u003e\u003cem\u003eFigure 3 (A-C)\u003c/em\u003e\u003c/strong\u003e highlighted an obvious amelioration in both serum and renal lipid profiles in all three treated diabetic groups, indicated by the significant TL, TC, TG, and LDL-C associated with HDL-C decline in the diabetic untreated group. Notably, AD-MSCs-EXs loaded with NSe recorded the greatest hypolipidemic efficacy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData of diabetic rats treated with unloaded EXs or EXs loaded with either Se or NSe revealed in \u003cstrong\u003e\u003cem\u003eFigure 4\u003c/em\u003e\u003c/strong\u003e highlighted serum marked urea, uric acid, and creatinine declines relative to the untreated diabetic rats. Notably, diabetic rats treated with EXs+NSe exhibited the greatest renal function ameliorating effect over other treatments.\u003c/p\u003e\n\u003cp\u003eThe three diabetic rats-treated groups\u0026apos; findings represented in \u003cstrong\u003e\u003cem\u003eFigures 5 \u0026amp; 6\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eindicated significant renal MDA, H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, and NO levels decline, associated with marked GSH, SOD, CAT, and GST upregulation. However, EXs+NSe treatment reflected the highest renal antioxidant potential and oxidative stress suppression excellence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding diabetic-untreated rats, \u003cstrong\u003e\u003cem\u003eFigure 7\u003c/em\u003e\u003c/strong\u003e data shows a marked renal inflammatory regression of all diabetic rats\u0026rsquo; treatment protocols, with an NSe-loaded EXs anti-inflammatory superiority.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompared to untreated diabetics, the results of \u003cstrong\u003e\u003cem\u003eFigure 8\u0026nbsp;\u003c/em\u003e\u003c/strong\u003erevealed that diabetic rats injected with EXs alone or in loaded form with Se or NSe exhibited substantial relief in the renal apoptotic status. This was indicated by the significant upregulation in some apoptotic markers (caspase-3 %, BAX, and P53), with the noted Bcl-2 (anti-apoptotic) % downregulation. Interestingly, the EXs+NSe protocol revealed the most antiapoptotic potential.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFigures 9A-D\u003c/em\u003e\u003c/strong\u003e, representing the Control, EXs, EXs+Se, and EXs+NSe regular groups, showed normal renal glomeruli and tubules. In contrast,\u0026nbsp;\u003cstrong\u003e\u003cem\u003eFigure 9E\u003c/em\u003e\u003c/strong\u003e represented the diabetic (STZ-treated) group, displaying severe pathological lesions, evidenced by diffuse tubular dilation with marked hydropic degeneration in epithelial lining (thin black arrows) with few pyknotic nuclei (thick black arrows), congested intratubular capillaries (red arrows), swollen congested glomerular tuft with dilated Bowman\u0026apos;s capsule (black arrowheads), interstitial edema (*). On the other hand, the renal section in \u003cstrong\u003eFigure\u003cem\u003e\u0026nbsp;9F\u003c/em\u003e\u003c/strong\u003e, from the \u003cstrong\u003eSTZ+EXs\u003c/strong\u003e group, shows slightly less severe pathological lesions: diffuse tubular dilation with hydropic degeneration in epithelial lining (thin black arrows), some pyknotic nuclei (thick black arrows), dilated Bowman\u0026apos;s capsule (black arrowheads), interstitial edema (*). The renal sections in Figure\u003cstrong\u003e\u003cem\u003e\u0026nbsp;9G\u003c/em\u003e\u003c/strong\u003e, from the \u003cstrong\u003eSTZ+EXs+Se\u003c/strong\u003e group, showed decreased tubular dilation and hydropic degeneration in the epithelial lining (thin black arrows) with dilated Bowman\u0026apos;s capsule (black arrowheads). Likely, the renal sections of the \u003cstrong\u003eSTZ+EXs+NSe\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003e(Figure 9H)\u003c/em\u003e\u003c/strong\u003e revealed the greatest renal histological improvement, nearly resembling the control kidney, except for slightly dilated Bowman\u0026apos;s capsule (black arrowheads), highlighting the renal protective and ameliorative superiority of such treatment protocol on diabetic kidney over the two other protocols.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eIn DM, hyperglycemia activates DN-various renal inflammatory pathways through renal ROS overproduction and repressing the antioxidant enzymes activity, leading to oxidative stress progression, DNA fragmentation, lipid peroxidation, protein damage, promoting the infiltration of inflammatory cells, and increased profibrotic cytokines release, leading collectively to progressive podocyte fibrosis and apoptosis, renal tubular damage, and associated albuminuria (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Accordingly, MSCs-EXs are considered a prominent approach for relieving kidney fibrosis because of their kidney regeneration therapeutic potential in the restoration of normal cell functions, immunoregulation, and homing mechanisms, which could be attributed mainly to the essential roles of their microRNAs (miRNAs) abundance, among other cargos (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAccording to our results, AD-MSCs-EXs injection into STZ-diabetic mice showed an efficient anti-fibrotic effect via the suppression of podocyte apoptosis, autophagy downregulation, reversion, and DN attenuation, evidenced by diminished levels of serum creatinine (Scr), urine protein, blood urea nitrogen (BUN), and TGF-β fibrotic marker (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). AD-MSCs-EXs-dependent renal protection and amelioration against acute and chronic renal inflammation were suggested relying on the capability of their miRNAs, mRNAs, and growth and immunosuppressive factors contents, in (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) regression of destructive immune response in the kidneys, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) increased renal tubular epithelial cells proliferation and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) suppression of oxidative stress progression, necrosis, and apoptosis (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Additionally, MSCs-EXs significantly alleviated renal fibrosis and inflammation in diabetic rats through miR-21 and miR-125a delivery which targeted the inflamed kidneys' TGF-β1 pro-fibrotic gene, resulting in (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) reduced Th1 and Th17 cells activation, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) lowering the inflammatory IL-1β and TNF-α cytokines release, via the inflammatory M1 cells conversion into immunosuppressive M2 macrophages, and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) neo-angiogenesis induction by MSCs-EXs-derived vascular endothelial growth factor (VEGF) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eInterestingly, bone marrow stem cell-derived (BM-MSCs) exosomes can also improve diabetes-induced cognitive nephropathy. Meanwhile, miR-let-7a transported by BM-MSC-EXs inhibited the JAK2/STAT3 pathway, which resulted in decreased BUN, TGs, and TCs in rats with DN, leading to the inhibition of renal cells, oxidative stress, apoptosis, and renal tubular epithelial cells degeneration (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). According to \u003cb\u003eNagaishi et al.\u003c/b\u003e (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), in STZ-diabetic rats with DN, BM-MSCs-EXs delivered to the subcapsular region of the kidney markedly relieved kidney injury by (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) minimizing the infiltration of inflammatory cells, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) the release of TGF-β, and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) degeneration and apoptosis of renal cells.\u003c/p\u003e\u003cp\u003eOn the other hand, \u003cb\u003eZhang et al.\u003c/b\u003e (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) have shown that human umbilical cord-MSCs-EXs (hUC-MSCs-EXs) carried abundant miR-146a-5p, which can (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) promotes the polarization of M2 macrophage, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) dramatically downregulated hyperglycemia-induced pro-inflammatory cytokines, and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) transferred growth factors including EGF, FGF, HGF and VEGF, resulting in marked renal inflammation suppression and the restoration of normal renal function (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Interestingly, a significant anti-fibrotic effect of UC-MSC-EXs injection, following unilateral ureteral obstruction (UUO)-induced renal damage, was highlighted, evidenced by the decreased secretion of TGF-β1, MDA, and ROS, kidney fibrosis marked alleviation, and suppression of renal cells apoptosis, leading to regular renal function restoration (declined Scr, uric acid, and BUN) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMoreover, urine-derived stem cell EXs (USC-EXs) intravenous injections alleviated albuminuria in the STZ-DN rat model through their delivery of miRNA-16-5p to the injured kidney, which attenuated the impairment of renal functions (decreased Ucr, Scr, and BUN). The renoprotection mechanism was likely attributed to (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) the downregulation of podocyte apoptosis-associated proteins (caspase-3, BAX, and P53), TNF-α, and TGF-β1, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) cell survival and vascular regeneration promotion, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) mesangial angiogenesis glomerular endothelial cell proliferation induction, which collectively protected diabetic rats from DN (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). All these results propose a rationale for the role of different miRNAs in inducing the amelioration of renal resident cells in the DN model treated with various EXs from various sources.\u003c/p\u003e\u003cp\u003eRegarding Se, its antidiabetic and renoprotective actions appear to arise from its behavior as a mainly antioxidant as well as an insulin-mimetic with a tremendous free radical scavenging effect, which in turn reflects the insulin signaling and secretion role in the cellular redox modulation (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Indeed, Se promoted renal glucose excretion in rats (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). According to \u003cb\u003eHuang et al.\u003c/b\u003e (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), the Se contents in the plasma were significantly lower in DN patients, with a significant negative correlation with renal function and a positive correlation with HbA1c than in the healthy controls. In this line, the \u003cb\u003eBahmani et al.\u003c/b\u003e (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) study demonstrated that daily Se supplementation (200 \u0026micro;g) for 12 weeks among patients with DN had increased serum insulin levels, plasma GPX, ameliorated lipid profiles, and enhanced kidney functions. Furthermore, it was found that a Se-rich diet supplementation for 6 months activated many selenoprotein antioxidants, which was suggested to delay the onset of DN in diabetic rats (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eNevertheless, the SeNPs insulin-mimetic activity can also mitigate the STZ-diabetic rats' hyperlipidemia and hyperglycemia, probably via improving the, since oral administration of SeNPs (0.1 mg/kg) to STZ-diabetic rats significantly decreased FBG levels while enhanced serum insulin concentration, after 28 days of treatment. Furthermore, the SeNP hypoglycemic effect significantly declines renal function markers (creatinine, urea, and uric acid), TL, TC, TG, and LDL-C levels, while increasing kidney glycogen contents and HDL-C levels, besides ameliorating the renal tissues' histological architecture (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Consistently, oral administration of SeNPs (0.5 mg kg) daily for eight weeks to STZ-induced DN rats significantly reversed the disturbance of the renal redox status, confirmed by the significant decrease in FBG, Scr, urea, MDA, NO, IL-6, NF-κB, TNF-α, BAX, and caspase-3, while marked elevations in renal antioxidants, such as HO-1, GPX, CAT, SOD, and GSH, compared to the untreated-DN group, confirming the SeNPs\u0026rsquo; anti-inflammatory and antiapoptotic potential renoprotective effects against DN (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Interestingly, \u003cb\u003eLotfy et al.\u003c/b\u003e (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) suggested that the anti-fibrotic and ameliorative effects of the SeNPs against kidney injury caused by diabetic complications result from their inhibitory potential on TGF-β1 and its receptor gene expression in renal tissues.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eBoth unloaded and loaded EXs with either elemental or nano Se showed a renoprotective impact and minimized the risk of DN progression in type 1 diabetic rats. However, further studies are needed regarding maximizing the EXs tissue-protective abilities through loading with other therapeutic nano-drugs before MSCs-EXs can be given as a global human therapy for various inflammatory and autoimmune diseases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAD-MSCs:\u0026nbsp;\u003c/strong\u003eAdipose-derived mesenchymal stem cells,\u003cstrong\u003e\u0026nbsp;BUN:\u0026nbsp;\u003c/strong\u003eBlood urea nitrogen,\u003cstrong\u003e\u0026nbsp;CAT:\u003c/strong\u003e Catalase,\u003cstrong\u003e\u0026nbsp;CD:\u0026nbsp;\u003c/strong\u003eCluster of differentiation, \u003cstrong\u003eD:\u0026nbsp;\u003c/strong\u003eDiabetic,\u003cstrong\u003e\u0026nbsp;DM:\u003c/strong\u003e Diabetes mellitus, \u003cstrong\u003eDMEM:\u003c/strong\u003e Dulbecco\u0026apos;s modified Eagle\u0026apos;s medium, \u003cstrong\u003eDN:\u003c/strong\u003e Diabetic nephropathy, \u003cstrong\u003eEXs:\u003c/strong\u003e Exosomes, \u003cstrong\u003eFBG:\u003c/strong\u003e Fasting blood glucose, \u003cstrong\u003eFBS:\u003c/strong\u003e Fetal bovine serum,\u003cstrong\u003e\u0026nbsp;GPX:\u003c/strong\u003e Glutathione peroxidase, \u003cstrong\u003eGSH:\u003c/strong\u003e Glutathione\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003eHbA1c:\u003c/strong\u003e glycosylated hemoglobin, \u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2:\u003c/sub\u003e\u003c/strong\u003e\u003csub\u003e\u0026nbsp;\u003c/sub\u003eHydrogen peroxide, \u003cstrong\u003eMDA:\u003c/strong\u003e Malondialdehyde, \u003cstrong\u003eMSCs:\u003c/strong\u003e Mesenchymal stem cells, \u003cstrong\u003eNSe:\u003c/strong\u003e Nano selenium, \u003cstrong\u003ePBS:\u0026nbsp;\u003c/strong\u003ePhosphate-buffered saline, \u003cstrong\u003eROS:\u003c/strong\u003e Reactive oxygen species,\u003cstrong\u003e\u0026thinsp;Scr:\u0026nbsp;\u003c/strong\u003eSerum creatinine,\u003cstrong\u003e\u0026nbsp;Se:\u0026nbsp;\u003c/strong\u003eSelenium\u003cstrong\u003e, SEM:\u003c/strong\u003e Standard error of the mean\u003cstrong\u003e, SOD:\u003c/strong\u003e Superoxide dismutase, \u003cstrong\u003eSPSS:\u003c/strong\u003e Statistical Package for Social Scientists, \u003cstrong\u003e\u0026nbsp;STZ:\u003c/strong\u003e Streptozotocin, \u003cstrong\u003eT1DM:\u003c/strong\u003e Type 1 diabetes mellitus.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Our design was approved by the Animal Ethics Committee of the Faculty of Science, Arish University, North Sinai, Egypt (ARU/SF. 04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent to participate:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eNot applicable. \u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent to publish:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eNot applicable. \u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; Contributions:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eSGE, FAA, IY, LSA, MAA, DSA, EIE, FGE, AAE, ME, and EF conceived and designed the study. Experiments and lab work were done by SGE, FAA, IY, EIE, LSA, AAE, and ME; data tabulating and acquisition, searching for literature, and preparing the first draft of the manuscript were performed by SGE, FAA, IY, DYK, RYK, EIE, FAA, ME, AAE, and LSA. All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e The authors extend their appreciation to the Deanship of Scientific Research and Graduate Studies at King Khalid University for funding this work through the Large Research Project under grant number RGP2/63/46. The authors extend their appreciation to the Deanship of Scientific Research of Princess Nourah bint Abdulrahman University, Researchers Supporting Project number (PNURSP2025R465), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e The authors extend their appreciation to the Deanship of Scientific Research and Graduate Studies a King Khalid University for funding this work through the Large Research Project under grant number RGP2/63/46. Y. The authors extend their appreciation to the Deanship of Scientific Research of Princess Nourah bint Abdulrahman University, Researchers Supporting Project number (PNURSP2025R465), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors would also like to express sincere gratitude to AlMaarefa University, Riyadh, Saudi Arabia, for supporting this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting Interests:\u003c/em\u003e\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData Availability:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli dir=\"LTR\"\u003eHe, C., Zheng, S., Luo, Y. \u0026amp; Wang, B. Exosome theranostics: Biology and translational medicine. \u003cem\u003eTheranostics\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e(1), 237\u0026ndash;55. doi: 10.7150/thno.21945 (2018).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eHe, Q., Wang, L., Zhao, R. et al. Retraction Note: Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy. \u003cem\u003eStem Cell Res. Ther.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 505. DOI.org/10.1186/s13287-022-03191-6 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eAl-Tamimi, O., Awwad, S. H., Issa, R., Al-Qaisi, T., Abazid, H., Daraosheh, A. \u0026amp; Abu-Samak, M. The effect of roasting degrees on bioactive compounds levels in Coffea arabica and their associations with glycated hemoglobin levels and kidney function in diabetic rats. \u003cem\u003eJournal of Applied Pharmaceutical Science\u003c/em\u003e DOI.org/10.7324/JAPS.2024.181047 (2024). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eNewton, W. C., Kim, J. W., Luo, J. Z. Q. \u0026amp; Luo, L. Stem cell-derived exosomes: a novel vector for tissue repair and diabetic therapy. \u003cem\u003eJournal of Molecular Endocrinology\u003c/em\u003e \u003cstrong\u003e59\u003c/strong\u003e(4), R155\u0026ndash;R165 (2017). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eChen, J., Zhang, Q., Liu, D. \u0026amp; Liu Z. Exosomes: Advances, development and potential therapeutic strategies in diabetic nephropathy. \u003cem\u003eMetabolism Clinical and Experimental\u003c/em\u003e 122, 154834, DOI.org/10.1016/j.metabol.2021.154834 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eAbd El‐lateef, H. M., Qahl, S., Fayad, E., Altalhi, S. A., Jafri, I., Shabana E, Darwish, M. K., et al. The potency of N, N\u0026prime;-diphenyl-1,4-phenylenediamine and adipose-derived stem cell co-administration in alleviating hepatorenal dysfunction complications associated with type 1 diabetes mellitus in rats. \u003cem\u003eBiocell\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e(8), DOI: 10.32604/biocell.2023.030680 (2023). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eAbd El‐lateef, H. M., Ali, L. S., Qahl, S. H., Fayad, E., Binjawhar, D. N., Fayad, E., Alghamdi, M. A. et al. Therapeutic effect of N, N-Diphenyl-1,4-phenylenediamine and adipose‐derived stem cells coadministration on diabetic cardiomyopathy in type 1 diabetes mellitus‐rat model. \u003cem\u003eJournal of Experimental Zoology Part A: Ecological and Integrative Physiology\u003c/em\u003e, 1\u0026ndash;11. DOI.org/10.1002/jez.2810 (2024).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eHarrell, C.R., Jovicic, N., Djonov, V., Volarevic, V. Therapeutic Use of Mesenchymal Stem Cell-Derived Exosomes: From Basic Science to Clinics. \u003cem\u003ePharmaceutics\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 474. DOI.org/10.3390/pharmaceutics12050474 (2020).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eYang, M., Chen, J. \u0026amp; Chen, L. The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications. \u003cem\u003eFrontiers in Endocrinology\u003c/em\u003e. \u003cstrong\u003e13\u003c/strong\u003e, 1027686, DOI.org/10.3389/fendo.2022.1027686 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Sun, Y., Tao, Q., Wu, X., Zhang, L., Liu, Q. \u0026amp; Wang, L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. \u003cem\u003eFrontiers in Endocrinology\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 756581, DOI.org/10.3389/fendo.2021.756581 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Cao, Q., Huang, C., Chen, X., \u0026amp; Pollock, C. A. Mesenchymal Stem Cell-Derived Exosomes: Toward Cell-Free Therapeutic Strategies in Chronic Kidney Disease. \u003cem\u003eFrontiers in Medicine\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 816656. DOI.org/10.3389/fmed.2022.816656 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Alahmari, L. A., Ali, L. S., Fansa, H. A., Alshaya, D. S., Al‐Salmi, F. A., El‐Hallous, E.I. et al. Antioxidant and antiapoptotic effects of selenium and nano selenium-loaded exosomes on hepatic dysfunction of type 1 diabetic rats. \u003cem\u003eJournal of Experimental Zoology Part A: Ecological and Integrative Physiology\u003c/em\u003e 1\u0026ndash;9. DOI.org/10.1002/jez.2881 (2024).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Wei, W., Ao, Q., Wang, X., Cao, Y., Liu, Y. \u0026amp; Tian, X. Mesenchymal Stem Cell-Derived Exosomes: A Promising Biological Tool in Nanomedicine. \u003cem\u003eFrontiers in Pharmacology\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 590470. DOI.org/10.3389/fphar.2020.590470 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Al-Samydai, A., Abu Hajleh, M. N., Al-Sahlawi, F., Nsairat, H., Khatib, A. A., Alqaraleh, M. \u0026amp; Ibrahim, A. K. Advancements of metallic nanoparticles: A promising frontier in cancer treatment. \u003cem\u003eScience Progress\u003c/em\u003e 107(4):00368504241274967. DOI.org/10.1177/00368504241274967 (2024).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Shahidi, S., Asl, S.S., Gholamigeravand, B., Afshar, S., Hashemi-Firouzi, N., Samzadeh-Kermani, A., Majidi, M., Amiri, K. Effect of co-treatment with mesenchymal stem cells and polyvinyl alcohol-coated selenium nanoparticles on rats with streptozotocin-induced Alzheimer\u0026apos;s disease. \u003cem\u003eResearch Square\u003c/em\u003e, DOI.org/10.21203/rs.3.rs-2077811/v1 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Moon, S. \u0026amp; Oh, C.M. Selenium and Risk of Diabetes. Biomarkers in Diabetes. Biomarkers in Disease: Methods, Discoveries, and Applications. \u003cem\u003eCham.\u003c/em\u003e DOI.org/10.1007/978-3-031-08014-255 (2023).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Fontenelle, L. C., Feitosa, M. M., Morais, J. B. S., Severo, J. S., de Freitas, T. E. C., Beserra, J. B., Henriques, G. S. \u0026amp; Marreiro, D. N. The role of selenium in insulin resistance. \u003cem\u003eBrazilian Journal of Pharmaceutical Sciences\u003c/em\u003e, DOI.org/10.1590/s2175-97902018000100139 9 (2018).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Wang, Y., Shan, S. K., Guo, B., Li, F., Zheng, M. H., Lei, L. M., Xu, Q. S., Ullah, M. H. E., Xu, F., Lin, X. et al. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. \u003cem\u003eFront. Endocrinol\u003c/em\u003e., \u003cstrong\u003e12\u003c/strong\u003e, 671566 (2021). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Kumar, A. \u0026amp; Prasad, K. S. Role of nano-selenium in health and environment. \u003cem\u003eJournal of Biotechnology\u003c/em\u003e \u003cstrong\u003e325\u003c/strong\u003e, 152-163. DOI.org/10.1016/j.jbiotec.2020.11.004\u003cu\u003e \u003c/u\u003e(2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Al-Quraishy, S., Dkhil, M. A. \u0026amp; Moneim, A. E. A. Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. \u003cem\u003eInternational Journal of Nanomedicine\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e(1), 6741-6756. DOI.org/10.2147/IJN.S91377 (2015).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Haney, M. J., Klyachko, N. L., Zhao, Y., Gupta, R., Plotnikova, E. G., He, Z., Patel, T., Piroyan, A., Sokolsky, M., Kabanov, A.V. et al.. Exosomes as drug delivery vehicles for Parkinson\u0026rsquo;s disease therapy. \u003cem\u003eJ. Control. Release\u003c/em\u003e. \u003cstrong\u003e207\u003c/strong\u003e, 18-30, DOI.10.1016/j.jconrel.2015.03.033 (2015).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Suvarna, S. K., Layton, C., Bancroft, J. D. Bancroft\u0026apos;s theory and practice of histological techniques. \u003cstrong\u003e7th\u003c/strong\u003e ed. (1) online resource (2013).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Ratliff, B. B., Abdulmahdi, W., Pawar, R., Wolin \u0026amp; M. S. Oxidant mechanisms in renal injury and disease. \u003cem\u003eAntioxid. Redox. Signal\u003c/em\u003e. \u003cstrong\u003e25\u003c/strong\u003e, 119-146. DOI:10.1089/ars.2016.6665 (2016).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e El-Sawah, S. G., Althobaiti, F., Aldahahrani, A., Fayad, E. Shabana E, El-Hallous, E. I., Rashwan, H. M. AD-MSCs and BM-MSCs Ameliorating Effects on The Metabolic and Hepato-renal Abnormalities in Diabetic Rats. \u003cem\u003eSaudi Journal of Biological Sciences\u003c/em\u003e, DOI.org/10.1016/j.sjbs.2021.09.067 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e El-Sawah, S. G., El-Hallous, E. I., Khalil, D. Y., Rashwan, H. M., Ameliorating effects of mesenchymal stem cells derived from adipose and bone marrow tissues on cardiomyopathy of diabetic rats: A comparative study. \u003cem\u003eEgyptian Journal of Zoology\u003c/em\u003e, DOI: 10.21608/ejz.2022.121278.1073 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Shaaban, S., El-Shamy, H., Gouda, M., Darwish, M. K., Khalaf, M. M. et al. N, N- Diphenyl-1,4-phenylenediamine Antioxidant\u0026rsquo;s Potential Role in Enhancing the Pancreatic Antioxidant, Immunomodulatory, and Anti-Apoptotic Therapeutic Capabilities of Adipose-Derived Stem Cells in Type I Diabetic Rats. \u003cem\u003eAntioxidants\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 58. DOI.org/10.3390/antiox12010058 (2023).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Jin, J., Shi, Y., Gong, J., Zhao, L., Li, Y., He, Q. et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocytes. \u003cem\u003eStem Cell Res. Ther\u003c/em\u003e. \u003cstrong\u003e10\u003c/strong\u003e, 95. Doi: 10.1186/s13287-019-1177-1 (2019).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Bruno, S., Tapparo, M., Collino, F., Chiabotto, G., Deregibus, M. C., Lindoso, S. et al. Renal Regenerative Potential of Different Extracellular Vesicle Populations Derived from Bone Marrow Mesenchymal Stromal Cells. \u003cem\u003eTissue Eng. Part A\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 1262\u0026ndash;1273 (2017). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Tsuji, K., Kitamura, S. \u0026amp; Wada, J. Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity. \u003cem\u003eStem Cells Int.\u003c/em\u003e 8693137, 2018. \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Harrell, C. R., Jovicic, N., Djonov, V., Arsenijevic, N. \u0026amp; Volarevic, V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. \u003cem\u003eCells\u003c/em\u003e. \u003cstrong\u003e8\u003c/strong\u003e, 1605. DOI.org/10.3390/cells8121605 (2019).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Hao, Y., Miao, J., Liu, W., Cai, K., Huang, X., Peng, L. et al. Mesenchymal stem cell-derived exosomes carry MicroRNA-125a to protect against diabetic nephropathy by targeting histone deacetylase 1 and downregulating endothelin-1. \u003cem\u003eDiabetes Metab. Syndr. Obes.\u003c/em\u003e\u003cstrong\u003e14\u003c/strong\u003e,140518. DOI: 10.2147/DMSO.S286191 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Mao, R., Shen, J. \u0026amp; Hu, X. BMSCs-derived exosomal microRNA-let-7a plays a protective role in diabetic nephropathy via inhibition of USP22 expression. \u003cem\u003eLife Sci. \u003c/em\u003e\u003cstrong\u003e268\u003c/strong\u003e,118937, Doi: 10.1016/j.lfs.2020.118937 (2021).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M., Konari, N. et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 34842, Doi: 10.1038/srep34842 (2016).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M. T. et al. Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy. \u003cem\u003eSci. Rep\u003c/em\u003e. \u003cstrong\u003e7\u003c/strong\u003e(1), 1-17, DOI: 10.1038/s41598-017-08921-y (2017). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Zhang, Z., Mi, T., Jin, L., Li, M., Hao, C., Huang, Z. et al. Comprehensive proteomic analysis of exosome mimetic vesicles and exosomes derived from human umbilical cord mesenchymal stem cells. \u003cem\u003eStem Cell Res. Ther.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e(1), 312. DOI: 10.1186/s13287-022-03008-6 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Xiang, E., Han, B., Zhang, Q., Rao, W., Wang, Z., Chang, C. et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy by inhibiting inflammation and fibrosis. \u003cem\u003eStem Cell Res. Ther\u003c/em\u003e. \u003cstrong\u003e11\u003c/strong\u003e, 336. DOI: 10.1186/s13287-020-01852-y (2020).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Liu, B., Hu, D., Zhou, Y., Yu, Y., Shen, L., Long, C. et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK/ERK signaling pathway. \u003cem\u003eAm. J. Transl. Res.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 4998\u0026ndash;5014 (2020).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Jiang, Z. Z., Liu, Y. M., Yin, J. Y., Hu, B. \u0026amp; Guo, S. C. Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. \u003cem\u003eStem Cell Res. Ther\u003c/em\u003e. \u003cstrong\u003e7\u003c/strong\u003e, 24, DOI.org/10.1186/s13287-016-0287-2 (2016).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Duan, Y. R., Chen, B. P., Chen, F., Yang, S. X., Zhu, C. Y. \u0026amp; Ma, Y. L et al. Exosomal microRNA-16-5p from human urine-derived stem cells ameliorates diabetic nephropathy by protecting podocytes. \u003cem\u003eJ. Cell Mol. Med\u003c/em\u003e. \u003cstrong\u003e25\u003c/strong\u003e, 10798 813, DOI: 10.1111/jcmm 14558.\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Mueller, A. S. \u0026amp; Pallauf, J. Compendium of the antidiabetic effects of supranutritional selenate doses: in vivo and in vitro investigations with type II diabetic db/db mice. \u003cem\u003eJ. Nutr. Biochem\u003c/em\u003e. \u003cstrong\u003e17\u003c/strong\u003e, 548-560 (2006). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003eHuang, F., Zhao, L., Cheng, L., Chen, Z., Fu, R. \u0026amp; Tian, L. Changes of selenium and selenoprotein expressions in diabetic nephropathy. \u003cem\u003eJournal of Xi\u0026apos;an Jiaotong University (Medical Sciences)\u003c/em\u003e\u003cem\u003e \u003c/em\u003e\u003cstrong\u003e6\u003c/strong\u003e, 562-566\u003cem\u003e \u003c/em\u003e(2018)\u003cem\u003e.\u003c/em\u003e\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Bahmani, F., Kia, M., Soleimani, A., Asemi, Z. \u0026amp; Esmaillzadeh, A. Effect of Selenium Supplementation on Glycemic Control and Lipid Profiles in Patients with Diabetic Nephropathy. \u003cem\u003eBiol Trace Elem Res\u003c/em\u003e. \u003cstrong\u003e172\u003c/strong\u003e(2), 282-289. doi: 10.1007/s12011-015-0600-4 (2016).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Alkhudhayri, A., Al-Shaebi, E. M., Qasem, A. A., Murshed, M., Mares, M. H., Al-Quraishy, S., Dkhil, M. A. Antioxidant and anti-apoptotic effects of selenium nanoparticles against murine eimeriosis. \u003cem\u003eAn Acad. Bras. Cienc\u003c/em\u003e. \u003cstrong\u003e92\u003c/strong\u003e(2), e20191107, https://doi 10.1590/0001-3765202020191107 (2020). \u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Zaghloul, R. A., Abdelghany, A. M. \u0026amp; Samra, Y. A. Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats by downregulating the Jak-2/Stat3 pathway and upregulating the Nrf-2/HO-1 pathway. \u003cem\u003eEur J Pharmacol.\u003c/em\u003e \u003cstrong\u003e933\u003c/strong\u003e, 175289, DOI: 10.1016/j.ejphar.2022.175289 (2022).\u003c/li\u003e\n \u003cli dir=\"LTR\"\u003e Lotfy, M. M., Dowidar, M. F., Ali, H. A. \u0026amp; Ahmed, A. I. Effect of Selenium Nanoparticles and Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy. \u003cem\u003eMetabolites\u003c/em\u003e \u003cstrong\u003e\u003cem\u003e13\u003c/em\u003e\u003c/strong\u003e(3), 400, DOI.org/10.3390/metabo13030400 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Apoptosis, Diabetic nephropathy, Exosomes, Stem cells, Streptozotocin","lastPublishedDoi":"10.21203/rs.3.rs-6940168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6940168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEndocrinologists and nephrologists continually seek new therapeutic approaches for diabetic nephropathy (DN). Lately, mesenchymal stem cells (MSCs)-derived exosomes (MSCs-EXs) have been applied as natural carriers for targeted drug delivery. Thus, we aim to estimate the therapeutic potentialities of MSCs-EXs loaded with ordinary selenium (Se) or its nanoform (NSe) as a promising cell-free therapy in diabetic nephropathy (DN). Eighty rats were randomly split into 8 groups; control, EXs, EXs\u0026thinsp;+\u0026thinsp;Se, EXs\u0026thinsp;+\u0026thinsp;NSe, diabetic (D), D\u0026thinsp;+\u0026thinsp;EXs, D\u0026thinsp;+\u0026thinsp;EXs\u0026thinsp;+\u0026thinsp;Se, and D\u0026thinsp;+\u0026thinsp;EXs\u0026thinsp;+\u0026thinsp;NSe groups. After 4 weeks, our results indicated renal hypolipidemic and renal ameliorating effects of unloaded or loaded EXs with Se or NSe, evidenced by the declined serum levels of urea, uric acid, and creatinine, compared to diabetic-untreated rats. Such observations might be a reflection of the observed antioxidant activity of both EXs alone or in the combined form with either Se or NSe, evidenced by decreased renal MDA, NO, H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e levels coupled with increased GSH, SOD, CAT, and GPX, besides their anti-inflammatory and antiapoptotic effects, indicated by the decreased renal levels of IL-6, TGF-β, TNF-α, BAX, caspase-3, and P53, with Bcl-2 upregulation. Consequently, the kidney architecture in the three diabetic-treated groups was greatly improved. Likely, the EXs-loaded NSe treatment protocol highlighted the DN improvement superiority most significantly compared to the other protocols.\u003c/p\u003e","manuscriptTitle":"Therapeutic potential of mesenchymal stem cells-derived exosomes loaded with elemental or nano selenium on diabetic nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 14:07:57","doi":"10.21203/rs.3.rs-6940168/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d8cae25-50a4-4f74-aa0e-2f8e599ef065","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55104245,"name":"Biological sciences/Cell biology"},{"id":55104246,"name":"Biological sciences/Physiology"},{"id":55104247,"name":"Biological sciences/Zoology"}],"tags":[],"updatedAt":"2025-10-08T09:09:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 14:07:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6940168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6940168","identity":"rs-6940168","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}