INTRODUCTION:

Diseases including cancer, diabetes, and bacterial infections have devastating effects on people's health all around the globe. “Cancer and diabetes are the second and seventh leading causes of mortality worldwide, respectively, as reported by the Centers for Disease Control and Prevention (CDC).” According to the World Health Organisation (WHO), there are 14 million new instances of cancer each year, resulting in 9.6 million deaths worldwide. However, chronic metabolic illnesses like diabetes are on the rise due to insufficient physical exercise, unhealthy diets, and other lifestyle factors. Some epidemiological studies have shown a strikingly increased cancer risk in patients with diabetes. “It is crucial to discover and create novel medications and treatments with greater efficacy and cheaper costs against both illnesses^1,2 due to the practically unknown links between cancer and diabetes and the costly, complicated, and poor-impact treatment techniques of the patients.” The majority of chronic illnesses and deaths worldwide are caused by bacteria. Many studies have shown that antibiotic overuse contributes to the rise of germs that are resistant to many classes of antimicrobial drugs. Infrequent use of antibiotics has led to the rise of super-bacteria that are immune to almost all available treatments.³ Nanoparticles (NP) method of action involves making direct contact with the bacterial cell wall without penetrating the cell, rendering most antibiotic resistance mechanisms moot. Materials with sizes between 1 and 100nm are considered nanoparticles. “The fields of medicine, biology, agriculture, chemistry, physics, and materials science may all benefit from NPs”.⁴

The chemical, pharmaceutical, mechanical, and food processing sectors are just a few examples of how nanotechnology is being put to use today. The fields of computers, power production, optics, medication delivery, and environmental sciences all find novel nanotechnology applications. Many nanoscale devices, including those based on physical, chemical, and environmentally friendly processes, have been invented since the emergence of nanotechnology.⁵ “However, green nanoparticle synthesis is a preferred technology since it is simple to create,⁶ Traditional methods for synthesizing nanoparticles have several limitations, including lengthy processing times, high costs, time-consuming processes, and the usage of hazardous substances, Due to these constraints, much of the relevant research has focused on developing quick and environmentally friendly synthesis techniques for the manufacture of nanoparticles”.⁷ In recent years, there has been a lot of attention paid by material scientists to the creation of environmentally benign techniques for synthesizing nanoscale materials. In this regard, there is a rising trend towards easy, affordable, and safe green synthesis of NPs, particularly via the use of various plant extracts⁸ “Nanotechnology's contributions to energy sufficiency, climate change, the beauty, textile, and health sectors, and the treatment for lethal illnesses like cancer and Alzheimer's, are just a few examples of how it has raised the quality of living for the human race.” The last decade has seen a surge in research into metal oxide nanoparticles due to their wide range of potential technological uses.⁹ ZnO-NPs are intriguing inorganic materials because of their many uses and advantages. Applications for ZnO-NPs range from energy efficiency to textiles to electronics to healthcare to catalysis to cosmetics to semiconductors to chemical sensing. The NPs are safe and biodegradable, and they have several promising medicinal uses. Some examples include targeted medication delivery, wound healing, and bioimaging.

The chemical, physical, and biological processes all lead to nanoproducts that are very versatile in their uses. “Despite prior reports of plant-based ZnO-NP production, there is a lack of information on these nanoparticles' wide range of biological capabilities, including their antibacterial, anti-larvicidal, protein kinase, and anticancer effects.” Myristica fragrans (Jaiphal) is widely utilized for its medicinal properties, especially as an anti-inflammatory, anti-diarrheal, painkiller, and aphrodisiac.¹⁰

Metallic oxide nanoparticles, and more specifically ZnO NPs, have attracted a lot of interest for their adaptable properties in many different areas. Nanoparticles of metallic oxides have been the subject of much study for their potential impact on both cancer and diabetes. Furthermore, some research has questioned these nanoparticles' antifungal, antibacterial, and anti-inflammatory activities. Metal oxide nanoparticles may also be used for treating wastewater, mending wounds, and imaging biological processes.¹¹

The synthesis route used for ZnO NPs has a significant impact on the nanoparticles' final physical characteristics. Plants, bacteria, fungi, and algae may be employed in place of chemical and physical processes to accomplish the green synthesis of nanoparticles.¹² Green nanoparticles synthesized with plant help are inexpensive, stable, non-toxic, environmentally benign, and scalable.¹³ Numerous phenolic chemicals, vitamins, and terpenoids are shown to exist in therapeutic plants. These chemicals are likely responsible for the antimicrobial, antifungal, anticancer, anti-glucose, and anti-malarial properties.¹⁴ In the past, ZnO NPs have been synthesized using M. mozaffarianii, C. pictus, and A. ampeloprasum extracts.^15,16

Biological Applications of Nanoparticles for Diabetes:

Over the last several decades, nanotechnology has emerged as a potentially game-changing technology with wide-ranging medicinal uses. Nanoparticles (NPs) are tiny pieces of material that have interesting qualities (at least 100 nm in one dimension). Material reduction to the nanoscale may potentially modify their characteristics, allowing them to interact with cell proteins in a targeted manner. Nanoparticles (NPs) are loaded with therapeutic substances for delivery to target cells.¹⁷ Furthermore, metal nanoparticles have a multifaceted influence on the body and are safer than mineral salts.

Zinc oxide NPs:

Anti-diabetic, anti-cancer, anti-fungal, medication delivery and anti-inflammatory effects are only some of the many medicinal applications for ZnO NPs.¹⁸ Zinc is essential for insulin production, secretion, and storage¹⁹, and it is vital for preserving insulin structure.²⁰ “Zinc transporters like zinc transporter-8 have been found to play an important function in insulin release from pancreatic beta cells, Increased insulin receptor phosphorylation, increased phosphoinositide 3-kinase activity, and suppression of glycogen synthase kinase-3 are only some of the potential mechanisms by which zinc improves insulin signaling.” ZnO NPs may also reverse diabetes-related alterations to pancreatic tissue. “Previous research has used a Type 2 diabetes rat model to test ZnO NPs with a conventional anti-diabetes medicine to preserve cell function and structure and to ascertain the efficacy of dipeptidyl peptidase-IV (DPP-IV) nanoparticles with or without zinc oxide.” The sol-gel approach was used to synthesize ZnO NPs with a total size of 20 nm. “After 10 days of diabetes induction, 90 Wistar rats were randomly split into three groups, Both ZnONPs and Vildagliptin have been shown to have beneficial effects in the treatment of type 2 diabetes ²¹, Using a streptozotocin (STZ) - induced rat model of diabetes, Nashwa et al 2016 investigated the therapeutic benefits of ZnO NPs in reversing histological/functional alterations in the pancreas.” Rats with diabetes were randomly assigned to one of three groups: treated with ZnO NPs, untreated, or in the control group. “ZnO NPs reversed the ultrastructural and structural changes caused by diabetes, and their effects on blood sugar and serum insulin levels were substantiated by their capacity to maintain a relatively constant mean biochemical value. Researchers in this study administered (Ag NPs), (CeO2 NPs), (ZnO NPs), and Momordica charantia (MC) to rats and measured their antidiabetic effects. Nanoparticles of silver (Ag NPs), cerium dioxide (CeO2 NPs), and zinc oxide (ZnO) were all synthesised using eco-friendly methods. Because of their wide range of pharmacological and biological characteristics, ZnO NPs and Ag NPs were shown to be more effective anti-diabetic agents than MC and CeO2 NPs”.²² “Using the Andrographis paniculata leaf extract's reduction and capping capabilities, Govindasamy et al (2017) synthesized ZnO NPs. Biological uses in the cosmetics, food, and biomedical sectors have been established for the synthesized nanoparticles, which have been proven to exhibit high biological activity about antioxidants, anti-inflammatory, and anti-diabetes potentials”.²³ “Abdulrahman et al. (2017) researched the antidiabetic benefits of thiamine and ZnO NPs after experimental DM.” Fifty-six female mice were employed, and the results showed that there were no adverse effects of thiamine on the pancreatic tissue of the mice. ZnO nanoparticles, either alone or in conjunction with thiamine, have proven to be an effective therapy for diabetes. This may be indicative of substantial antidiabetic action ²⁴ in terms of both blood glucose and lipid markers. By comparing ZnO NPs to ZnSO4, the research team at Siamak et al. 2017 determined whether or not ZnO NPs may help prevent diabetes-related cardiac disease. “A total of 120 rats were split into healthy and diabetic groups without any discernible pattern. Mid-dose zinc oxide nanoparticles (ZnO NPs) protect against and reverse cardiac damage.” Damage recovery was also aided by ZnSO4, but the middle dosage of ZnO NPs was superior. ZnO NPs may, in the end, create Zn in diabetes individuals. ²⁵ ZnO NPs were synthesized by Abolfazl et al., 2017 with the use of a microwave oven and a fruit extract called Vaccinium Arctostaphylos L. The diabetic rats that had been exposed to alloxane were separated into two groups: those who were treated and those who weren't. ZnO NPs were shown to be more successful in treating alloxan-diabetic rats than any of the other therapy agents used.²⁶ “Experimental diabetes was used by Jihan et al (2018) to study the impact of silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnO NPs) on insulin signaling pathways and insulin sensitivity.” We used pullulan (a natural polymer) as a reducer to make silver nanoparticles and zinc oxide nanoparticles. Ag NPs and ZnO NPs were shown to be the most effective remedies for reducing diabetes-related problems and insulin resistance. In this study, there was little to no difference in the effects of ZnO NPs and Ag NPs.²⁷ Abolfazl et al. 2019 observed that ZnO nanoparticles may be significantly stimulated by Nasturtium officinale leaf extract, leading to increased antidiabetic and antibacterial activities. Another research looked at the role of ZnO NPs in microRNA dysregulation in streptozotocin-induced hyperglycemia in rats. Treatment with ZnO NPs significantly enhanced blood insulin levels, glucose tolerance, and pancreatic cell activity. ZnO NPs were discovered to have encouraging antidiabetic properties in the investigation. In addition, ZnO NPs were synthesized via a sonochemical technique in a work by Shafayet et al. in 2020. This research suggests that ZnONPs have a strong potential as a therapeutic candidate for the treatment of diabetes. “All prior research has shown that ZnO NPs are effective in treating diabetes and minimizing the disease's consequences.”²⁸

Anti-Diabetic Effects of ZnO-NPs

Anti-Hyperglycemic:

A person is considered to have diabetes if their blood glucose levels are above 140 mg/dL in the fasting state and over 200 mg/dL in the two hours after a meal.²⁹ “Several studies ³⁰ have shown that ZnO-NPs may reduce blood glucose levels in diabetic rats, ZnO-NPs reduced blood glucose levels in diabetic rats in a concentration- and time-dependent manner when given orally (1-10 mg/kg/day) for 56 days straight”.³¹

ZnO-NPs were shown to improve glucose tolerance in experimental DM, as measured by an oral glucose tolerance test. “Clinically, poor glucose tolerance is often diagnosed using the area under the curve (AUC) obtained from an oral glucose tolerance test.” When compared to normal rats, diabetic rats had an AUC that was 3.8 times higher. At a dosage of 10 mg/kg/day, ZnO-NPs relieved the impact in between 40 and 70 percent of the diabetic group. The next sections describe the variables that presumably mediate the anti-hyperglycemic action of ZnO-NPs.

Enhancement of Pancreatic Functions:

Insulin and glucagon are two major pancreatic hormones that work together to keep blood glucose levels stable. ³² Although the processes that lead to pancreatic dysfunction and damage are unknown, they play a crucial role in the development of diabetes mellitus.³³ Histological examinations of diabetic rats indicated damage signs, such as a loss of pancreatic islet cells and a general thinning of the organ. “However, ZnO-NPs at 10 mg/kg/day alone or in conjunction with a dipeptidyl peptidase-IV inhibitor, vildagliptin (10 mg/kg/day, p.o.), for 7 weeks reduced these histological changes in the diabetic rat pancreas. AlloXan-induced diabetic mice treated with ZnO-NPs at doses of 0.1 and 0.5 mg/kg showed a decrease in the loss of mean islet volume, islets per square micrometre, and pancreatic volume density.” After 24 hours of incubation, a concentration-dependent increase in cell proliferation was seen when ZnO-NPs (1-10 g/ml) were added to insulin-secreting RIN-5F cells.³⁴

Pancreatic cells secrete insulin, a hormone essential for maintaining stable blood glucose levels and putting that glucose to good use.³² When blood glucose levels are high, as they often are after consuming carbohydrate-rich meals, the pancreas responds by secreting insulin. All insulin-sensitive tissues include insulin receptors. “Therefore, insulin resistance may result from a decrease in insulin receptors, Hyperglycemia is a symptom of diabetes mellitus and is caused by a lack of insulin or insulin resistance, Serum insulin was shown to be significantly lower in diabetic rats compared to their healthy counterparts. The drop in blood insulin levels in these animals was slowed by the ZnO-NPs, ZnO-NPs were shown to stimulate insulin release in rat insulinoma RIN-5F cells in a concentration-dependent manner in cell culture experiments, Streptozotocin (STZ)-induced diabetic rats had insulin gene expression reduced to 40% of the control value.” ZnO-NPs (10 mg/kg/day) were administered to these animals for a month, and the downregulation of the insulin gene was mitigated. When exposed to the same amount of ZnO-NPs as the untreated control, insulin receptor A gene expression rose by 1.3-fold.³⁵

Both glycogenolysis and gluconeogenesis play crucial roles in the generation of glucose. The liver and skeletal muscles respond to the hormone glucagon, which is released by beta cells in the pancreas. “Blood glucose levels are returned to normal by the enzyme glucose-6-phosphatase, which catalyzes the last phase of glycogenolysis and gluconeogenesis by converting glucose-6-phosphate into free glucose, which is then released into plasma”.³⁵ Diabetic rat liver microsomes were found to have glucose-6-phosphate levels that were four times higher than normal.³⁶ Human hepatocarcinoma HepG2 cells treated with ZnO-NPs (1-10 g/ml, 24 h) showed dose-dependent suppression of glucose-6-phosphatase gene expression. “Phosphoenolpyruvate carboXykinase is an enzyme in the gluconeogenic pathway that ZnO-NPs reduced in gene expression to below 50% of the control value.”

Weight Maintenance:

Glycogen synthesis from glucose is stimulated in the liver and skeletal muscles in response to elevated blood glucose levels by insulin. Many organisms store excess energy as glycogen. In diabetic individuals, a lack of insulin makes this more difficult to do. As a result, the body shifts its energy needs and begins to burn up reserves of fat and muscle. This symptom was also seen in a rat model of diabetes used in experiments. “The weight loss symptom was reduced in these rats when they were given ZnO-NPs (10 mg/kg/day, p.o.) for 4 or 7 weeks.”

Anti-dyslipidemic:

Dyslipidemia is a major risk factor for the onset of type 2 diabetes.³⁷“Higher tri-glyceride and low-density lipoprotein (LDL) levels and lower high-density lipoprotein (HDL) levels have been linked to an increased risk of cardiovascular issues in people with type 2 diabetes”. ³⁸ While improvements in diet and exercise might help, most diabetic individuals still need pharmacological therapy for dyslipidemia.³⁹ ZnO-NPs reduce the increases in bad cholesterol, good cholesterol, lipoprotein(a), triglyceride, and free fatty acid levels seen in diabetic mice. “HDL levels were restored in diabetic rats after oral administration of 3 mg/kg of ZnO-NPs for 8 weeks.”

Cell signaling, glucose homeostasis, and lipid metabolism are all significantly impacted by hormone-sensitive lipase (HSL), an intracellular lipase. “Hydrolytic sphingomyelinase (HSL) is capable of hydrolyzing a wide variety of lipids, including monoglycerides, diglycerides, triglycerides, cholesterol esters, and retinyl esters. Increased lipolysis has been linked to type 2 diabetes”.⁴⁰ The skeletal muscles of HSL mutant mice were also more sensitive to insulin ⁴¹. ZnO-NPs (1-10 g/ml) were incubated with 3T3-L1 adipocytes for a day, and the results showed a dose-dependent tendency towards HSL inactivation. Interestingly, insulin therapy wasn't able to produce the same result.

Anti-inflammatory:

Peripheral insulin resistance and hyperglycemia may be caused by inflammation, however, the specific function of inflammation in DM is mainly unknown. “Diabetic patients were shown to have elevated levels of many pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1, IL-1, IL-6, and IL-8.” TNF-, for example, is a key player in the development of insulin resistance. Diabetic rats had 3.6 times higher serum TNF- levels than controls. Diabetic rat serum TNF- was lowered by 30% after 8 weeks of oral therapy with ZnO-NPs (3 mg/kg/day). STZ (60 mg/kg, s.c.)-induced diabetic rats had IL-1 levels that were 1.8-fold greater than the control group. However, when rats were given 10 mg/kg/day of ZnO-NPs for a month, the rise was reduced. Both glucose homeostasis and -cell function may be thrown off by IL-1.⁴² ZnO-NPs, however, have been shown to increase IL-1 and IL-8 in human eosinophils. ⁴³ As a result, further in vivo studies on this topic utilizing diabetes animals are required. The polypeptide molecule C-reactive protein (CRP), which is a member of the pentraxin family, is crucial to the inflammatory response. Inflammation biomarkers have shown it to be an important indicator of disease. ⁴⁴

The liver is responsible for the majority of this molecule's production after being stimulated by pro-inflammatory cytokines. “On the other hand, oxidative stress and inflammation are linked to asymmetrical dimethylarginine (ADMA), an inhibitor of NO synthase.” Microvascular complications in diabetic individuals and animal models have been linked to increased ADMA levels. ⁴⁵ In diabetic rats, CRP and ADMA levels rose by 6.3 and 3.1 times, respectively, whereas NO levels dropped by 2/3. “These alterations were mitigated after 30 days of oral treatment of ZnO-NPs at a dose of 10 mg/kg.”

Inhibition of α-Amylase and α-Glucosidase:

The digestive enzymes alpha-amylase and beta-glucosidase are responsible for converting complex carbs into easily absorbed simple sugars.^{46, 47} Inhibiting these enzymes is a promising method for controlling type 2 diabetes since it reduces the rise in blood sugar that occurs after a meal. ⁴⁸ Type 2 diabetes may be treated with -glucosidase inhibitors including acarbose, miglitol, voglibose, and emiglitate.⁴⁹ ZnO-NPs have been demonstrated to inhibit -amylase from pig pancreatic tissue and human saliva in enzyme inhibition tests. ^50,
51 ZnO-NPs inhibited the activity of both pancreatic (21% inhibition) and intestinal (98% inhibition) murine-glucosidase. ⁵⁰ ZnO-NPs had a slight edge over acarbose in their ability to inhibit murine intestine glu- oxidase. ⁵⁰

Zno-nps Ameliorates Diabetic Complications:

Cardiovascular Complications:

The heart releases a hormone called B-type natriuretic peptide (BNP). Clinically, BNP is often utilized to diagnose cardiac dysfunction and heart failure. Diabetic rats given ZnO-NPs (3 mg/kg/day) for 8 weeks saw their atherogenic index drop by 80% and their BNP level drop by 50%. ZnO-NP-treated diabetic mice also showed improvements in heart muscle histopathology. “By reducing caspase-3 activity by two-thirds, ZnO-NPs (3 mg/kg/day, 8 weeks) reduced apoptosis in diabetic cardiac tissue.” However, ZnO-NPs at a concentration of 30 mg/kg were hazardous to heart muscle. Plasma albumins are the primary carriers of advanced oxidation protein products (AOPPs), which may develop in people with renal disease and heart disease. “ZnO-NPs suppressed plasma AOPPs in streptozotocin (STZ) (60 mg/kg, S.C.) diabetic rats. An additional powerful atherogenic mechanism is lipid peroxidation.” Protecting LDL from peroxidation is a major function of plasma paraoxonase. The activity of plasma paraoxonase dropped to 40% of normal levels in diabetic rats. “The decrease in plasma paraoxonase activity in these animals may be prevented by a month of therapy with 10 mg/kg/day ZnO-NPs.”

Reproductive Impairments:

Male infertility is exacerbated by diabetes and oxidative stress. “Both the activity and mRNA expression of antioxidant enzymes such SOD, CAT, GSH-Px, glutathione S-transferase and glutathione reductase were decreased by more than half in the testicular tissue of diabetic rats.” At the same time, glutathione (GSH) levels declined to about 30%, and malondialdehyde (MDA) levels rose almost 5-fold. These alterations were suppressed after 30 days of oral administration of 10 mg/kg of ZnO-NPs. The creation and upkeep of sperm depend critically on glucose metabolism. Due to the negative effects of DM on sperm function, motility, and quality, the incidence of subfertility is significant among diabetic guys. Diabetes may also hinder the production of testosterone, an androgen that stimulates spermatogenesis in the testes. ⁵² A single dosage of 60 mg/kg of STZ has been shown to significantly reduce blood testosterone levels in experimental DM compared to control rats (by 60%) ⁵³. ZnO-NPs boosted testosterone sperm count and motility in diabetic rats. Damage to spermatogenesis may be shown on histopathology slides of diabetic rats, which show a disorganized seminiferous epithelium and hyalinized interstitial tissue.⁵³ “The structure of the seminiferous epithelium and interstitium was likewise restored by ZnO-NPs”.⁵³ Immunohistochemical studies also showed that ZnO-NPs might increase the number of nutrient- and support-producing Sertoli cells, primary spermatocytes, and spermatogonia cells. ⁵³ Spermatogenesis and male fertility are controlled by DNA methylation of germ cell-specific genes. DNA-methylated testicular cells were more few in diabetes populations.⁵³ “The number of cells that had DNA methylation altered by ZnO-NPs was higher ⁵³, Evidence suggests that nuclear respiratory factor 1 (NRF1) ^{54, 55} and sirtuin 1 (SIRT1) ⁵⁶may control DNA methylation.” By stimulating NRF1 and SIRT1, ZnO-NPs may control DNA methylation. Women's reproductive abilities may be hampered by diabetes.⁵⁶ Diabetic Wistar rats were shown to have decreased reproductive success in their female offspring. The size of the fetus, the skull, and the placenta were all adversely impacted. Because of this, it is equally important to assess ZnO-NPs' potential for reversing reproductive abnormalities in women.

Future Perspectives:

Green synthesis, in which nanoparticles are produced from plant sources rather than chemical or physical ones, has been suggested as a more ecologically friendly and cost-effective alternative. “Significant in vitro antioxidant and free radical scavenging capabilities were also shown for ZnO-NPs synthesized by the green technique employing plant extracts.” ZnO-NPs synthesized by a chemical route exhibited no free radical scavenging activity, which was a big surprise. Cholesterol levels were significantly lowered in diabetic rats induced with alloxan (170 mg/kg, intraperitoneally) when ZnO-NPs were used. However, animals given chemically synthesized ZnO-NPs or insulin did not show this decrease. “ZnONPs, both chemically and biologically produced, are superior to insulin in lowering fasting blood sugar.” ZnO-NPs derived from various medicinal plants should also be the subject of more comparative research. Recent research has compared the toxicity and absorption of ZnO-NPs to that of their bulk-size counterparts. “In addition, ZnO-NPs and ZnO bulk may induce a variety of zinc-transport-related gene transcription in the mouse small intestine after oral treatment. Pancreatic cells include zinc transporters as well, including the insulin-important zinc transporter 8.” Zinc supplementation in diabetic rats has been used to infer zinc's positive function in the disease. In STZ (50 mg/kg, i.p.)-induced diabetic rats, ZnO-NPs increased blood zinc and insulin levels and improved glucose clearance compared to zinc sulfate. “Similar to zinc nitrate, ZnO-NPs synthesized from Andrographis paniculata leaf extract displayed -amylase inhibition and anti-inflammatory potential, but to a lesser extent.” However, there is a dearth of research comparing ZnO-NPs to bulk or salt treatments for easing additional diabetes symptoms and consequences. Since there are anti-diabetic medications with a variety of modes of action, researchers have long been interested in the potential synergistic benefits of combining diverse chemicals. “Combination treatment targeting sodium-glucose cotransporter 2 and metformin has been shown to improve glycemic control in patients when compared to the use of either medication alone.” ZnO-NPs have been observed to interact synergistically with drugs like vildagliptin and thiamine in the experimental DM. Consequently, ZnO-NPs' synergistic capabilities with other diabetic medications or dietary supplements need further investigation.

CONCLUSION:

As the number of people affected with DM across the world continues to rise, effective treatments must be developed. “Thanks to the development of nanotechnology, many other substances, including ZnO-NPs, may now be evaluated for use in biomedicine and as disease-modifying therapeutics.” According to our analysis, ZnO-NPs may attack many DM symptoms simultaneously. Therefore, ZnO-NPs are an intriguing candidate for future study and clinical trials as an anti-diabetic drug.

ACKNOWLEDGMENT:

We would like to express our sincere gratitude to Rani Chennamma College of Pharmacy, Belagavi, for providing the necessary facilities and support.

REFERENCES:

1. Ruddaraju LK, Pammi SVN, Pallela PNVK, Padavala VS, Kolapalli VRM. Antibiotic potentiation and anti-cancer competence through bio-mediated ZnO nanoparticles. Mater Sci Eng C. 2019; 103:109756.

2. Nguyen NH, Pham QT, Luong TN, Le HK, Vo VG. Potential antidiabetic activity of extracts and isolated compound from Adenosma bracteosum (Bonati). Biomolecules. 2020 29; 10(2): 201.

3. Van Giau V, an SSA, Hulme JP. Mitochondrial therapeutic interventions in Alzheimer’s disease. J Neurol Sci. 2018; 395:62–70.

4. Gupta M, Tomar RS, Kaushik S, Mishra RK, Sharma D. Effective antimicrobial activity of green ZnO nanoparticles of Catharanthus roseus. Front Microbiol. 2018; 9:1–13.

5. Ramsden J. Nanotechnology: an introduction. William Andrew; 2016 May 11.

6. Albrecht MA, Evans CW, Raston CL. Green chemistry and the health implications of nanoparticles. Green Chem. 2006;8(5):417–32.

7. Herlekar M, Barve S, Kumar R. Plant-mediated green synthesis of iron nanoparticles. J Nanopart. 2014; 2014:140614.

8. Simonis F, Schilthuizen S. Nanotechnology: Innovation Opportunities for Tomorrow’s defence. TNO Science & Industry Future Technology Center: The Netherlands; 2006.

9. Iravani S. Green synthesis of metal nanoparticles using plants. Green Chem. 2011; 13(10):2638–50.

10. Periasamy G, Karim A, Gibrelibanos M, Gebremedhin G. Nutmeg (Myristica Fragrans Houtt.) oils. In: Essential Oils in Food Preservation, Flavor and Safety. Elsevier; 2016. 607–16.

11. Suresh J, Pradheesh G, Alexramani V, Sundrarajan M, Hong SI. Green synthesis and characterization of zinc oxide nanoparticle using insulin plant (Costus pictus D. Don) and investigation of its antimicrobial as well as anticancer activities. Advances in Natural Sciences: Nanoscience and Nanotechnology. 2018; 9(1): 015008.

12. El-Borady OM, Ayat MS, Shabrawy MA, Millet P. Green synthesis of gold nanoparticles using Parsley leaves extract and their applications as an alternative catalytic, antioxidant, anticancer, and antibacterial agents. Adv Powder Technol. 2020;31(10):4390-400.

13. Rabiee N, Bagherzadeh M, Kiani M, Ghadiri AM. Rosmarinus Officinalis directed palladium nanoparticle synthesis: Investigation of potential antibacterial, anti-fungal, and Mizoroki-Heck catalytic activities. Adv Powder Technol.2020;1402–11

14. Zaman SU, Ali A, Asif M, Mashrai A, Khanam H. Green synthesis of ZnO NPs using Bacillus Subtilis and their catalytic performance in the one-pot synthesis of steroidal thiophenes. Eur Chem Bull. 2014; 9:939–45.

15. Moghaddam AB, Moniri M, Azizi S, Abdul Rahim R, Ariff AB, Saad WZ, et al. Biosynthesis of ZnO NPs by a new Pichia kudriavzevii yeast strain and evaluation of their antimicrobial and antioxidant activities. Molecules. 2017; 22:872.

16. Sanaeimehr Z, Javadi I, Namvar F. Antiangiogenic and antiapoptotic effects of green-synthesized zinc oxide nanoparticles using Sargassum muticum algae extraction. Cancer nano. 2018; 9:1-6.

17. Wahba NS, Shaban SF, Kattaia AA, Kandeel SA. Efficacy of zinc oxide nanoparticles in attenuating pancreatic damage in a rat model of streptozotocin-induced diabetes. Ultrastruct Pathol. 2016; 40:358–73.

18. Mishra PK, Mishra H, Ekielski A, Talegaonkar S, Vaidya B. Zinc oxide nanoparticles: A promising nanomaterial for biomedical applications. Drug Discov Today. 2017; 22:1825–34.

19. Nazarizadeh A, Asri-Rezaie S. Comparative study of antidiabetic activity and oxidative stress induced by zinc oxide nanoparticles and zinc sulfate in diabetic rats. Pharmscitech. 2016; 17:834–43.

20. Umrani RD, Paknikar KM. Zinc oxide nanoparticles show antidiabetic activity in streptozotocin-induced Type 1 and 2 diabetic rats. Nanomedicine. 2014; 9:89–104.

21. El-Gharbawy RM, Emara AM, Abu-Risha SES. Zinc oxide nanoparticles and a standard antidiabetic drug restore the function and structure of beta cells in Type-2 diabetes. Biomed Pharmacother. 2016; 84:810–20

22. Shanker K, Naradala J, Mohan GK, Kumar GS, Pravallika PL. A sub-acute oral toxicity analysis and comparative in vivo anti-diabetic activity of zinc oxide, cerium oxide, silver nanoparticles, and Momordica charantia in Streptozotocin-induced diabetic Wistar rats. RSC Adv. 2017; 7:37158–67.

23. Rajakumar G, Thiruvengadam M, Mydhili G, Gomathi T, Chung IM. Green approach for synthesis of zinc oxide nanoparticles from Andrographis paniculata leaf extract and evaluation of their antioxidant, anti-diabetic, and anti-inflammatory activities. Bioprocess Biosyst Eng. 2018; 41:21–30.

24. Amiri A, Dehkordi RAF, Heidarnejad MS, Dehkordi MJ. Effect of zinc oxide nanoparticles and thiamine for the management of diabetes in alloxan-induced mice: A stereological and biochemical study. Biol Trace Elem Res. 2018; 181:258–64.

25. Asri-Rezaei S, Dalir-Naghadeh B, Nazarizadeh A, Noori-Sabzikar Z. Comparative study of cardio-protective effects of zinc oxide nanoparticles and zinc sulfate in streptozotocin-induced diabetic rats. J Trace Elem Med Biol. 2017; 42:129–41.

26. Bayrami A, Parvinroo S, Habibi-Yangjeh A, Rahim Pouran S. Bio-extract-mediated ZnO nanoparticles: Microwave-assisted synthesis, characterization, and antidiabetic activity evaluation. Artif Cells Nanomed Biotechnol. 2018; 46:730–9.

27. Hussein J, El Naggar ME, Latif YA, Medhat D, El Bana M, Refaat E, et al. Solvent-free and one-pot synthesis of silver and zinc nanoparticles: Activity toward cell membrane components and insulin signaling pathways in experimental diabetes. Colloids Surf B Biointerfaces. 2018; 170:76–84.

28. Bayrami A, Ghorbani E, Pouran SR, Habibi-Yangjeh A, Khataee A, Bayrami M. Enriched zinc oxide nanoparticles by Nasturtium officinale leaf extract: Joint ultrasound-microwave-facilitated synthesis, characterization, and implementation for diabetes control and bacterial inhibition. Ultrason Sonochem. 2019; 58:104613.

29. Umrani RD, Paknikar KM. Jasada Bhasma, a zinc-based Ayurvedic preparation: Contemporary evidence of antidiabetic activity inspires the development of nanomedicine. Evid Based Complement Alternat Med. 2015; 2015:193156.

30. Alkaladi A, Abdelazim AM, Afifi M. Antidiabetic activity of zinc oxide and silver nanoparticles on streptozotocin-induced diabetic rats. Int J Mol Sci. 2014; 15:2015–23.

31. Umrani RD, Paknikar KM. Zinc oxide nanoparticles show antidiabetic activity in streptozotocin-induced Type 1 and 2 diabetic rats. Nanomedicine. 2014; 9:89–104.

32. Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48:e219.

33. Gerber PA, Rutter GA. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal. 2017; 26:501–18.

34. Asani SC, Umrani RD, Paknikar KM. In vitro studies on the pleiotropic antidiabetic effects of zinc oxide nanoparticles. Nanomedicine. 2016; 11:1671–87.

35. Bernsmeier C, Dill MT, Provenzano A, Makowska Z, Krol I, Muscogiuri G, Duong FH. Hepatic Notch1 deletion predisposes to diabetes and steatosis via glucose-6-phosphatase and perilipin-5 upregulation. Lab Investig. 2016; 96:972–80.

36. Burchell A, Cain DI. Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes. Diabetologia. 1985; 28:852–6.

37. Huynh K, Martins RN, Meikle PJ. Lipidomic profiles in diabetes and dementia. J Alzheimer's Dis. 2017; 59:433–44.

38. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004; 27:1496–504.

39. Asri-Rezaei S, Dalir-Naghadeh B, Nazarizadeh A, Noori-Sabzikar Z. Comparative study of cardio-protective effects of zinc oxide nanoparticles and zinc sulfate in streptozotocin-induced diabetic rats. J Trace Elem Med Biol. 2017; 42:129–41.

40. Dahlman I, Ryden M, Arner P. Family history of diabetes is associated with enhanced adipose lipolysis: evidence for the implication of epigenetic factors. diabetes Metab. 2018; 44:155–9.

41. Serup AK, Alsted TJ, Jordy AB, Schjerling P, Holm C, Kiens B. Partial disruption of lipolysis increases postexercise insulin sensitivity in skeletal muscle despite accumulation of Dag. Diabetes. 2016; 65:2932–42.

42. Herder C, Dalmas E, Boni-Schnetzler M, Donath MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab. 2015; 26:551–63.

43. Silva LR, Girard D. Human eosinophils are direct targets to nanoparticles: Zinc oxide nanoparticles (ZnO) delay apoptosis and increase the production of the proinflammatory cytokines IL-1β and IL-8. Toxicol Lett. 2016; 259:11–20.

44. Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: Conformational changes affect function. Biol Chem. 2015; 396:1181–97.

45. Moutachakkir M, Lamrani Hanchi A, Baraou A, Boukhira A, Chellak S. Immunoanalytical characteristics of C-reactive protein and high sensitivity C-reactive protein. Ann Biol Clin. 2017; 75:225–9.

46. Du MR, Ju GX, Li NS, Jiang JL. Role of asymmetrical dimethylarginine in diabetic microvascular complications. J Cardiovasc Pharmacol. 2016; 68:322–6.

47. Bashary R, Vyas M, Nayak SK, Suttee A, Verma S, Narang R, Khatik GL. An insight of alpha-amylase inhibitors as a valuable tool in the management of type 2 diabetes mellitus. Current diabetes reviews. 2020;16(2):117-36.

48. Jhong CH, Riyaphan J, Lin SH, Chia YC, Weng CF. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico. Biofactors. 2015; 41:242–51.

49. Lee MY, Choi DS, Lee MK, Lee HW, Park TS, Kim DM, et al. Comparison of acarbose and voglibose in diabetes patients who are inadequately controlled with basal insulin treatment: Randomized, parallel, open-label, active-controlled study. J Korean Med Sci. 2014; 29:90–7.

50. Kitture R, Chordiya K, Gaware S, Ghosh S, More PA, Kulkarni P, Kale SN. ZnO nanoparticles-red sandalwood conjugate: A promising anti-diabetic agent. J Nanosci Nanotechnol. 2015; 15:4046–51.

51. Shaik F, Kumar A. ZnO nanoparticles and their acarbose-capped nanohybrids as inhibitors for human salivary amylase. IET Nanobiotechnol. 2017; 11:329–35.

52. Walker WH. Testosterone signaling and the regulation of spermatogenesis. Spermatogenesis. 2011;1(2):116-20.

53. El-Behery EI, El-Naseery NI, El-Ghazali HM, Elewa YH, Mahdy EA, El-Hady E, Konsowa MM. The efficacy of chronic zinc oxide nanoparticles using on testicular damage in the streptozotocin-induced diabetic rat model. Acta Histochemica. 2019;121(1):84-93.

54. Wang J, Tang C, Wang Q, Su J, Ni T, Yang W, et al. NRF1 coordinates with DNA methylation to regulate spermatogenesis. Faseb J. 2017; 31:4959–70.

55. Heo J, Lim J, Lee S, Jeong J, Kang H, Kim Y, et al. Sirt1 regulates DNA methylation and differentiation potential of embryonic stem cells by antagonizing Dnmt3l. Cell Rep. 2017;18:1930–45.

56. Jangir RN, Jain GC. Diabetes mellitus induced impairment of male reproductive functions: A review. Curr Diabetes Rev. 2014; 10:147–57.

Received on 10.07.2025 Revised on 16.08.2025

Accepted on 20.09.2025 Published on 15.10.2025

Available online from October 30, 2025

Research J. Science and Tech. 2025; 17(4):297-304.

DOI: 10.52711/2349-2988.2025.00041

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.