Control of diabetic nephropathy in male Wistar rats using ethanolic extract of Monodora myristica seeds and its biosynthesized selenium nanoparticles

Abstract

Aim: This research utilizes the ethanolic extract from seeds of Monodora myristica and its biosynthesized selenium nanoparticles (SeNPs) for the treatment of diabetic nephropathy (DN) in male Wistar rats.

Methods: Biosynthesis of crystalline, quasi-spherical shape 5.0 ± 0.25 nm SeNPs was achieved using M. myristica seed extract as a reducing agent, followed by surface plasmon resonance measurement by ultraviolet-visible (UV-Vis) spectrophotometer, Fourier transformed infrared spectroscopy (FTIR), high-resolution transmission electron microscopy (HR-TEM), and selected area electron diffraction (SAED) for confirmation of nanoparticle biosynthesis. Male Wistar rats were induced with diabetes using a 3-weeks high-fat diet and a single intraperitoneal injection of streptozotocin (STZ). Experimental groups included normal control group, untreated diabetic controls and those treated with either metformin (a standard drug), ethanolic extract or biosynthesized SeNPs ofM. myristica seed extract. Biochemical analyses assessed renal function via serum creatinine and urea levels. Histological evaluations of kidney tissues were performed to assess structural changes.

Results: Treatment with M. myristica seed extract and its biosynthesized SeNPs significantly improved renal function, evidenced by reduced serum creatinine and urea levels. Histopathological studies showed preserved renal architecture and reduced inflammatory damage, particularly in the combination therapy group, indicating a synergistic effect.

Conclusions: This study highlights the potential of M. myristica and its biosynthesized SeNPs in mitigating DN through nephroprotective mechanisms. These findings advocate for the exploration of nanotechnology combined with bioactive plant compounds as effective strategies for managing DN.

Keywords

Monodora myristica / selenium nanoparticles / diabetic nephropathy / nephroprotection / nanomedicine / streptozotocin / oxidative stress

References

[1] Selby NM, Taal MW. An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab. 2020; 22: 3-15.

[2] Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020; 16: 377-90.

[3] Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. ; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9^th edition. Diabetes Res Clin Pract. 2019; 157: 107843.

[4] Spyridopoulou K, Aindelis G, Pappa A, Chlichlia K. Anticancer Activity of Biogenic Selenium Nanoparticles: Apoptotic and Immunogenic Cell Death Markers in Colon Cancer Cells. Cancers (Basel). 2021; 13: 5335.

[5] Bisht N, Phalswal P, Khanna PK. Selenium nanoparticles: a review on synthesis and biomedical applications. Mater Adv. 2022; 3: 1415-31.

[6] Javed B, Ikram M, Farooq F, Sultana T, Mashwani Z, Raja NI. Biogenesis of silver nanoparticles to treat cancer, diabetes, and microbial infections: a mechanistic overview. Appl Microbiol Biotechnol. 2021; 105: 2261—75.

[7] Majeed MI, Bhatti HN, Nawaz H, Kashif M. Nanobiotechnology: Applications of nanomaterials in biological research. In: ul—Islam S, editor. Integrating Green Chemistry and Sustainable Engineering. Scrivener Publishing LLC; 2019. pp. 581-615.

[8] Okonji RE, Akinwunmi KF, Madu JO, Bamidele FS, Funmilola A. In vitro study on α—amylase inhibitory activities of Digitaria exilis, Pentadiplandra brazzeana (Baill) and Monodora myristica. Int J Biol Chem Sci. 2014; 8: 2306—13.

[9] Aghebati—Maleki A, Dolati S, Ahmadi M, Baghbanzhadeh A, Asadi M, Fotouhi A, et al. Nanoparticles and cancer therapy: Perspectives for application of nanoparticles in the treatment of cancers. J Cell Physiol. 2020; 235: 1962-72.

[10] Vázquez—Núñez E, Molina—Guerrero CE, Peña—Castro JM, Fernández—Luqueño F, de la Rosa—Álvarez MG. Use of Nanotechnology for the Bioremediation of Contaminants: A Review. Processes. 2020; 8: 826.

[11] Akinfenwa AO, Abdul NS, Docrat FT, Marnewick JL, Luckay RC, Hussein AA. Cytotoxic Effects of Phytomediated Silver and Gold Nanoparticles Synthesised from Rooibos(Aspalathus linearis), and Aspalathin. Plants (Basel). 2021; 10: 2460.

[12] Cadmus SIB, Daramola OF. Responsible conduct of research: animal care use and research ethics. Afr J Biomed Res. 2020; 23: 35-9.

[13] Hohlbaum K, Bert B, Dietze S, Palme R, Fink H, Thöne—Reineke C. Severity classification of repeated isoflurane anesthesia in C57BL/6JRj mice—Assessing the degree of distress. PLoS One. 2017; 12: e0179588.

[14] Ramadan W, Dewasmes G, Petitjean M, Loos N, Delanaud S, Geloen A, et al. Spontaneous motor activity in fat—fed, streptozotocin—treated rats: a nonobese model of type 2 diabetes. Physiol Behav. 2006; 87: 765—72.

[15] Oloyede HOB, Bello TO, Ajiboye TO, Salawu MO. Antidiabetic and antidyslipidemic activities of aqueous leaf extract of Dioscoreophyllum cumminsii (Stapf) Diels in alloxan—induced diabetic rats. J Ethnopharmacol. 2015; 166: 313—22.

[16] Nzekwe S, Morakinyo A, Ntwasa M, Oguntibeju O, Oyedapo O, Ayeleso A. Influence of Flavonoid—Rich Fraction of Monodora tenuifolia Seed Extract on Blood Biochemical Parameters in Streptozotocin—Induced Diabetes Mellitus in Male Wistar Rats. Metabolites. 2023; 13: 292.

[17] Hassan I, Ebaid H, Al—Tamimi J, Habila MA, Alhazza IM, Rady AM. Selenium nanoparticles mitigate diabetic nephropathy and pancreatopathy in rat offspring via inhibition of oxidative stress. J King Saud Univ — Sci. 2021; 33: 101265.

[18] Veniamin MP, Vakirtzi—Lemonias C. Chemical basis of the carbamidodiacetyl micromethod for estimation of urea, citrulline, and carbamyl derivatives. Clin Chem. 1970; 16: 3-6.

[19] Tietz NW. Clinical Guide to Laboratory Tests. Saunders; 1995. pp. 1096.

[20] Bartels H, Böhmer M, Heierli C. Serum creatinine determination without protein precipitation. Clin Chim Acta. 1972; 37: 193—7. German.

[21] Drury RA, Wallington EA. Carleton’s Histologic Techniques. 5th ed. London: Oxford University Press; 1980. pp. 520.

[22] Pyrzynska K, Sentkowska A. Selenium Species in Diabetes Mellitus Type 2. Biol Trace Elem Res. 2024; 202: 2993-3004.

[23] Cittrarasu V, Kaliannan D, Dharman K, Maluventhen V, Easwaran M, Liu WC, et al. Green synthesis of selenium nanoparticles mediated from Ceropegia bulbosa Roxb extract and its cytotoxicity, antimicrobial, mosquitocidal and photocatalytic activities. Sci Rep. 2021; 11: 1032.

[24] Dougnon G, Ito M. Medicinal uses, thin—layer chromatography and high—performance liquid chromatography profiles of plant species from Abomey—Calavi and Dantokpa Market in the Republic of Benin. J Nat Med. 2020; 74: 311—22.

[25] Nitnavare R, Bhattacharya J, Thongmee S, Ghosh S. Photosynthetic microbes in nanobiotechnology: Applications and perspectives. Sci Total Environ. 2022; 841: 156457.

[26] Sharma G, Sharma AR, Bhavesh R, Park J, Ganbold B, Nam J, et al. Biomolecule—mediated synthesis of selenium nanoparticles using dried Vitis vinifera (raisin) extract. Molecules. 2014; 19: 2761-70.

[27] Moloto N, Moloto MJ, Coville NJ, Sinha Ray S. Synthesis and characterization of nickel selenide nanoparticles: size and shape determining parameters. J Cryst Growth. 2011; 324: 41-52.

[28] Pattanaik L, Acharya M, Yadav MK, Mishra PK, Nayak M. Alterations in serum electrolyte homeostasis in type—2 diabetes mellitus patients — A cross—sectional study in VIMSAR, Burla. J Evid Based Med Healthc. 2020; 7: 3148-52.

[29] Good CB, Kolb NR, Meyer M. World Health Organization Guidelines on Medicines for Diabetes Treatment Intensification. Ann Intern Med. 2019; 170: 583.

[30] Gembillo G, Ingrasciotta Y, Crisafulli S, Luxi N, Siligato R, Santoro D, et al. Kidney Disease in Diabetic Patients: From Pathophysiology to Pharmacological Aspects with a Focus on Therapeutic Inertia. Int J Mol Sci. 2021; 22: 4824.

[31] Pandya D, Nagrajappa AK, Ravi KS. Assessment and Correlation of Urea and Creatinine Levels in Saliva and Serum of Patients with Chronic Kidney Disease, Diabetes and Hypertension— A Research Study. J Clin Diagn Res. 2016; 10: ZC58-62.

[32] Galicia—Garcia U, Benito—Vicente A, Jebari S, Larrea—Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020; 21: 6275.

[33] Park SY, Gautier J, Chon S. Assessment of Insulin Secretion and Insulin Resistance in Human. Diabetes Metab J. 2021; 45: 641—54.

[34] Okaiyeto K, Adeoye RI, Oguntibeju OO. Some common West African spices with antidiabetic potential: A review. J King Saud Univ — Sci. 2021; 33: 101548.

[35] Daisy P, Saipriya K. Biochemical analysis of Cassia fistula aqueous extract and phytochemically synthesized gold nanoparticles as hypoglycemic treatment for diabetes mellitus. Int J Nanomedicine. 2012; 7: 1189-202.

[36] Kalakotla S, Jayarambabu N, Mohan GK, Mydin RBSMN, Gupta VR. A novel pharmacological approach of herbal mediated cerium oxide and silver nanoparticles with improved biomedical activity in comparison with Lawsonia inermis. Colloids Surf B Biointerfaces. 2019; 174: 199-206.

[37] Vafaei—Pour Z, Shokrzadeh M, Jahani M, Shaki F. Embryo—Protective Effects of Cerium Oxide Nanoparticles against Gestational Diabetes in Mice. Iran J Pharm Res. 2018; 17: 964-75.

[38] Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Rienzo LD, et al. The hormetic role of dietary antioxidants in free radical—related diseases. Curr Pharm Des. 2010; 16: 877—83.

[39] Omar SH, Scott CJ, Hamlin AS, Obied HK. Biophenols: Enzymes (β—secretase, Cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.) . Fitoterapia. 2018; 128: 118—29.

[40] Moiseeva EP, Manson MM. Dietary chemopreventive phytochemicals: too little or too much? Cancer Prev Res (Phila). 2009; 2: 611-6.

[41] Yusuf BO, Lukman HY, Okeme U, Ganiyu AI, Salawu MO, Moronfolu IA, et al. Cow Urine Extract of Nicotiana tabacum Leaf Portends Hepatotoxicity in Male Wistar Rats. Int J Biochem Res Rev. 2023; 32: 34-43.

[42] Xie Y, Bowe B, Li T, Xian H, Yan Y, Al—Aly Z. Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus. Kidney Int. 2018; 93: 741-52.

[43] Du J, Zhang W, Niu J, Wang S. Association between blood urea nitrogen levels and the risk of diabetes mellitus in Chinese adults: secondary analysis based on a multicenter, retrospective cohort study. Front Endocrinol (Lausanne). 2024; 15: 1282015.

[44] Anjaneyulu M, Chopra K. Quercetin, an anti—oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 2004; 31: 244-8.

[45] Hao HH, Shao ZM, Tang DQ, Lu Q, Chen X, Yin XX, et al. Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci. 2012; 91: 955-67.

[46] Din UAASE, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res. 2017; 8: 537-48.

[47] Lytvyn Y, Perkins BA, Cherney DZI. Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes. 2015; 39: 239-46.

[48] Aktas G, Kocak MZ, Bilgin S, Atak BM, Duman TT, Kurtkulagi O. Uric acid to HDL cholesterol ratio is a strong predictor of diabetic control in men with type 2 diabetes mellitus. Aging Male. 2020; 23: 1098—102.

[49] Xiong Q, Liu J, Xu Y. Effects of Uric Acid on Diabetes Mellitus and Its Chronic Complications. Int J Endocrinol. 2019; 2019: 9691345.

[50] Abd El—Khalik SR, Nasif E, Arakeep HM, Rabah H. The Prospective Ameliorative Role of Zinc Oxide Nanoparticles in STZ—Induced Diabetic Nephropathy in Rats: Mechanistic Targeting of Autophagy and Regulating Nrf2/TXNIP/NLRP3 Inflammasome Signaling. Biol Trace Elem Res. 2022; 200: 1677-87.

[51] Kashani K, Rosner MH, Ostermann M. Creatinine: From physiology to clinical application. Eur J Intern Med. 2020; 72: 9-14. Erratum in: Eur J Intern Med. 2023;116:168— 9.

[52] Kene K, Wondimnew T, Welde M, Mateos T, Adugna T, Gerema U, et al. Prevalence and determinants of impaired serum creatinine and urea among type 2 diabetic patients of jimma medical center, Jimma, Southwestern Ethiopia, 2019. Endocr Metab Sci. 2021; 3: 100096.

[53] Garcia G, Pacchini VR, Zamoner W, Balbi AL, Ponce D. Drug—induced acute kidney injury: a cohort study on incidence, identification of pathophysiological mechanisms, and prognostic factors. Front Med (Lausanne). 2024; 11: 1459170.

[54] Welch HK, Kellum JA, Kane—Gill SL. Drug—Associated Acute Kidney Injury Identified in the United States Food and Drug Administration Adverse Event Reporting System Database. Pharmacotherapy. 2018; 38: 785-93.

[55] Mears J, Treacy M. Body fluids and electrolytes. Acute Nursing Care. 2020. pp. 97-134.

[56] Dhondup T, Qian Q. Electrolyte and Acid—Base Disorders in Chronic Kidney Disease and End—Stage Kidney Failure. Blood Purif. 2017; 43: 179-88.

[57] Sehgal S, Gupta S, Mishra MK. Electrolytes and acid—base disorders. In: Singh RL, Singh P, Pathak N, editors. Clinical Applications of Biomolecules in Disease Diagnosis. Singapore: Springer; 2024. pp. 155—75.

[58] Venkateswarlu D, Kumar MP. A study of high serum calcium level in diabetes mellitus and its association with left ventricular remodeling. Int Arch Integr Med. 2019; 6: 66-71.

[59] Shrimanker I, Bhattarai S. Electrolytes. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.

[60] Awais M, Aizaz A, Nazneen A, Bhatti Q ul A, Akhtar M, Wadood A, et al. A review on the recent advancements on therapeutic effects of ions in the physiological environments. Prosthesis. 2022; 4: 263-316.

[61] Walker MD, Shane E. Hypercalcemia: A Review. JAMA. 2022; 328: 1624—36.

[62] Stautz J, Hellmich Y, Fuss MF, Silberberg JM, Devlin JR, Stockbridge RB, et al. Molecular Mechanisms for Bacterial Potassium Homeostasis. J Mol Biol. 2021; 433: 166968.

[63] Wagle L, Regmi DR, Regmi R, Poudel S, Pant HN. Metformin Toxicity Leading to Severe Refractory Hyperkalemia and Metabolic Acidosis: A Case Report. Cureus. 2024; 16: e63130.

[64] Fiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency. Nutrients. 2021; 13: 1136.

[65] Akram M, Munir N, Daniyal M, Egbuna C, Găman MA, Onyekere PF, et al. Vitamins and minerals: Types, sources and their functions. In: Egbuna C, Dable Tupas G, editors. Functional Foods and Nutraceuticals. Cham: Springer; 2020. pp. 149-72.

[66] Dubey P, Thakur V, Chattopadhyay M. Role of Minerals and Trace Elements in Diabetes and Insulin Resistance. Nutrients. 2020; 12: 1864.

[67] Kebir NE, Zahzeh T. Magnesium deficiency associated with stress, systemic inflammation, and insulin resistance in diabetes mellitus: A review. Egypt Acad J Biol Sci C, Physiol Mol Biol. 2022; 14: 31-46.

[68] Barbagallo M, Dominguez LJ. Magnesium and type 2 diabetes. World J Diabetes. 2015; 6: 1152-7.

[69] Feng J, Wang H, Jing Z, Wang Y, Cheng Y, Wang W, et al. Role of Magnesium in Type 2 Diabetes Mellitus. Biol Trace Elem Res. 2020; 196: 74-85.

[70] Liu H, Li N, Jin M, Miao X, Zhang X, Zhong W. Magnesium supplementation enhances insulin sensitivity and decreases insulin resistance in diabetic rats. Iran J Basic Med Sci. 2020; 23: 990—8.

[71] Parvizi MR, Parviz M, Tavangar SM, Soltani N, Kadkhodaee M, Seifi B, et al. Protective effect of magnesium on renal function in STZ—induced diabetic rats. J Diabetes Metab Disord. 2014; 13: 84.

[72] Loha M, Mulu A, Abay SM, Ergete W, Geleta B. Acute and Subacute Toxicity of Methanol Extract of Syzygium guineense Leaves on the Histology of the Liver and Kidney and Biochemical Compositions of Blood in Rats. Evid Based Complement Alternat Med. 2019; 2019: 5702159.

[73] Azhar J, John P, Bhatti A. Thymus serpyllum Exhibits Anti—Diabetic Potential in Streptozotocin—Induced Diabetes Mellitus Type 2 Mice: A Combined Biochemical and In Vivo Study. Nutrients. 2022; 14: 3561.

[74] Jwad SM, AL—Fatlawi HY. Diabetic nephropathy and its effect on the physiological factors of the body. Ren Fail. 2022; 4: 24-30.