Rutin health effects

Posted on January 1, 2024  •  25 minutes  • 5118 words  • Other languages:  Русский

Abstract

The present-day scientific community now acknowledges flavonoids as a distinct category of therapeutic molecules owing to their varied therapeutic properties. Among these, rutin, alternatively known as vitamin P or rutoside, has been investigated for numerous pharmacological effects. Rutin is found in tea leaves, apples, and various other sources as one of its active constituents. Currently, rutin is recognized for its nutraceutical impact. This post emphasizes the latest information on rutin and its health-promoting effects.

Introduction

Medicinal plants have played a crucial role in traditional medicine throughout history. The process of drug discovery has incorporated phytochemicals as a means to identify new leads. Among these, flavonoids, a significant class of plant-derived chemicals containing a benzopyrone moiety, have gained attention. Approximately 4000 types of flavonoids have been documented in various plants.

Rutin (3,30,40,5,7-pentahydroxyflavone-3-rhamnoglucoside), a flavonol abundantly present in plants like passion flower, buckwheat, tea, and apples, serves as a crucial nutritional component in food. Also known as rutoside, quercetin-3-rutinoside, and sophorin, rutin is a citrus flavonoid glycoside found in buckwheat. The name ‘rutin’ is derived from the plant Ruta graveolens, which also contains this compound.

Ruta Graveolens

Chemically, it is a glycoside consisting of the flavonolic aglycone quercetin and the disaccharide rutinose. Rutin has demonstrated various pharmacological activities, including antioxidant, cytoprotective, vasoprotective, anticarcinogenic, neuroprotective, and cardioprotective effects.

Rutin’s actions

Neuroinflammation protector

Rutin has exhibited a neuroprotective impact in cases of brain ischemia. The administration of rutin has been linked to a reduction in ‘ischemic neural apoptosis’ by inhibiting p53 expression and lipid peroxidation, while simultaneously enhancing ‘endogenous antioxidant defense enzymes’ . Rutin has shown efficacy in addressing hypoxic, glutamate, and oxidative stress conditions. Furthermore, the administration of rutin has demonstrated a decrease in ‘neuroinflammation’ in a rat model of ‘sporadic dementia of Alzheimer type’ and exhibited neuroprotective effects in ‘dexamethasone-treated mice’.

Enhancement of Survival in Neural Crest Cells

The neural crest serves as a progenitor with both neural and mesenchymal potentials. When trunk neural crest cells were treated with rutin, their viability increased without affecting cell differentiation and proliferation. This effect could be attributed to the modulation of ERK2 and PI3K pathways.

Sedative Effects

The impact of rutin on the central nervous system (CNS) and behavior was evaluated using the hole board, thiopental-induced sleeping time, and locomotor activity tests in mice. Administration of rutin via the intraperitoneal route exhibited a depressant effect on the CNS. Studies indicated that the CNS depressant activity of rutin was unlikely to be associated with the GABAA receptor.

Anticonvulsant Properties

Rutin exhibits anticonvulsant activity and appears to be well-tolerated by individuals with epilepsy, as it neither modifies the effectiveness of administered antiepileptic drugs nor manifests any adverse effects.

Anti-Alzheimer’s Activity and Treatment of Hyperkinetic Movement Disorder

Rutin effectively suppressed the activity of proinflammatory cytokines by reducing TNF-a and IL-1b production in microglia. This beneficial effect suggests potential utility in Alzheimer’s disease treatment, demonstrated by the prevention of b-amyloid oligomeric cytotoxicity. Rutin also mitigated streptozotocin-induced inflammation by reducing glial fibrillary acidic protein, interleukin-8, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-kB activity. This intervention prevented substantial anatomical changes in the rat hippocampus, showcasing promise in averting cognitive deficits and benefiting the treatment of ‘sporadic dementia of Alzheimer type’.

In addressing ‘tardive dyskinesia,’ a motor disorder in the orofacial region associated with prolonged neuroleptic drug treatment and a significant concern in schizophrenia therapy, rutin exhibited promise. In a study involving haloperidol-induced orofacial dyskinesia, rutin treatment reversed behavioral changes, including orofacial dyskinetic movements, stereotypic rearing, locomotor activity, and percent retention, while also restoring biochemical and neurochemical parameters. Consequently, rutin emerges as a promising candidate in the treatment of hyperkinetic movement disorders.

Anti-arthritic Effects

Administration of rutin to animals resulted in a notable reduction in rheumatoid arthritis and Fanconi anemia by inhibiting the ‘oxygen radical overproduction’. In a rat model of adjuvant arthritis, rutin demonstrated inhibition of both acute and chronic phases of inflammation, with its highest activity observed during the chronic stage. Rutin’s therapeutic impact on septic arthritis caused by Candida albicans is attributed to its antifungal and anti-arthritic effects. Additionally, an independent study revealed that rutin slowed down inflammatory and catabolic cartilage markers in osteoarthritic lesions in Hartley guinea pigs.

Analgesic and antinociceptive effects

The analgesic effect of rutin was investigated using the hot plate test on Swiss albino mice, confirming its analgesic properties. Moreover, it was verified that rutin demonstrated both peripheral and central antinociceptive activities.

Antidiabetic Effects

Streptozotocin, a toxic chemical, is known to deplete insulin levels by destroying pancreatic islets. This compound selectively attacks pancreatic β-cells, generating free radicals of oxygen and nitrogen monoxide while reducing NAD and NADP levels. The fundamental bases of hyperglycemia involve excessive glucose production and decreased tissue utilization. In a study, the chronic administration of rutin in streptozotocin-induced diabetic rats resulted in a decrease in plasma glucose, an increase in insulin levels, and restoration of glycogen content and glycolytic enzymes. Rutin-treated diabetic rats showed significant rejuvenation of pancreatic islets and reduced fatty infiltrate. Rutin also led to a reduction in fasting plasma glucose, glycosylated hemoglobin, C-peptide, and malondialdehyde levels in streptozotocin-induced diabetic rats.

Rutin prevented the elevation of enzymes such as ALT, AST, and LDH in the serum, liver, and heart, demonstrating a protective effect against hepatic and cardiac toxicity associated with streptozotocin. Rutin also altered the activity of matrix metalloproteinase and provided protection to the kidneys against streptozotocin-induced damage. The stimulation of glucose uptake in the soleus muscle by rutin was thought to be mediated through extracellular calcium and calcium-calmodulin-dependent protein kinase II activation. Rutin, through its mediation of increased intracellular calcium concentration, played a role in DNA activation. Rutin contributed to glycemic control by enhancing insulin receptor kinase activity, thereby promoting the ‘insulin signaling pathway,’ resulting in increased GLUT4 translocation and augmented glucose uptake.

Anti-hypercholesterolemic Effects

Rutin serves as a ‘selective and non-toxic modulator’ of hypercholesterolemia. In a study conducted on a diet-induced hypercholesterolemic Golden Syrian hamster model, rutin significantly decreased plasma triglyceride levels in the experimental animals. Additionally, rutin led to a reduction in total cholesterol and HDL cholesterol levels.

In male Wistar rats fed a high-cholesterol diet, rutin administration demonstrated a protective effect against hepatotoxicity, as evidenced by a decrease in plasma levels of alanine transaminase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL). Another study established that the chronic consumption of flavonoids, including rutin, could be beneficial for cardiovascular health.

Stimulation of Thyroid Uptake

The process of ‘thyroid iodide uptake,’ facilitated by the sodium-iodide symporter, plays a crucial role in thyroid hormone biosynthesis and is instrumental in the diagnosis and treatment of various thyroid disorders. However, some patients with thyroid cancer exhibit resistance to radioiodine therapy, leading to reduced iodine uptake ability and significantly decreasing the likelihood of survival. Consequently, there is a need to explore natural agents that can enhance thyroid iodide uptake.

In a study, rutin was found to induce a slight reduction in serum T4 and T3 levels without affecting serum thyrotropin. Notably, there was a significant increase in the activities of hypothalamic, pituitary, and brown adipose tissue type 2 deiodinase, accompanied by a decrease in liver type 1 deiodinase activities. Administration of rutin was associated with an increase in thyroid iodide uptake, likely attributed to the elevated activity of the sodium-iodide symporter. This study highlights the efficacy of rutin as an adjunct in radioiodine therapy.

Hypertension

Buckwheat, known for its rich rutin content, has been identified as a potential preventive agent against oxidative damage in ‘aortic endothelial cells’ by reducing nitrotyrosine immunoreactivity. The germinated extract of buckwheat has demonstrated an antihypertensive effect, potentially shielding ‘arterial endothelial cells’ from the harmful effects of oxidative stress (Kim et al., 2009). Rutin, when administered orally, plays a pivotal role in reducing oxidative stress, leading to the restoration of ‘impaired baroreflex sensitivity’ and ‘vascular reactivity’ in hypertensive rats. Additionally, rutin has been shown to enhance nitric oxide (NO) production in human endothelial cells, thereby improving endothelial functions.

Blood Coagulation

In a study, the effects of rutin on the anticoagulant activity of oral warfarin and the protein binding, along with the pharmacokinetics of its enantiomers in rats, were investigated. Rutin was found to enhance the in vitro serum protein binding of both S- and R-warfarin. Furthermore, rutin treatment significantly reduced the elimination half-life of S-warfarin by 37%, resulting from a 69% increase in the unbound clearance of the S-enantiomer. In summary, the concurrent administration of rutin potentially diminishes the anticoagulant effect of racemic warfarin.

Antiplatelet Aggregatory Effect

In vitro, rutin demonstrated a concentration-dependent inhibition of platelet-activating factor-induced washed rabbit platelet aggregation. Rutin also inhibited the dose-dependent elevation of intra-platelet free calcium concentration induced by platelet-activating factor.

Antiulcer Effects

Peptic ulcers are a prevalent ailment affecting a substantial portion of the global population. Ulcers occur when there is an imbalance between ‘aggressive’ and ‘protective’ factors at the luminal surface of the gastric epithelium. Dynamic factors contributing to ulcers include HCl, pepsins, nonsteroidal anti-inflammatory drugs, Helicobacter pylori, bile acids, ischemia, hypoxia, smoking, and alcohol. Defensive factors comprise bicarbonate, a mucus layer, mucosal blood flow, prostaglandins (PGs), and growth factors.

Ethanol is a notorious agent known to cause damage to the gastric mucosa in both animal and clinical studies. Ethanol concentrations exceeding 400 ml/l result in significant alterations in the gross morphology of the stomach, characterized by mucosal hyperemia, necrosis, edema, and mucosal or submucosal hemorrhage. The formation of lesions is attributed to oxygen-derived free radicals. Rutin pretreatment before ethanol administration provided significant protection against necrosis, accompanied by the restoration of glutathione peroxidase levels and an ‘anti-lipoperoxidant effect’. Similarly, in an indomethacin-induced model of ulcers, rats pretreated with rutin demonstrated the restoration of altered oxidative stress and biochemical parameters, potentially due to the suppression of neutrophil infiltration, oxidative stress generation, and replenishment of nitrite/nitrate levels. The protective effects were also evident in histopathological investigations.

Another investigation shed light on the molecular mechanism of rutin’s action on gastric proton pumps. Rutin exhibited a concentration-dependent inhibition of goat gastric ATPase, with an IC50 of 36 μg/ml, suggesting that rutin exerts an antiulcer effect by inhibiting the gastric proton pump.

Antiasthmatic Activity and Other Associated Effects

The efficacy of rutin in addressing asthma was investigated in ovalbumin-sensitized conscious guinea pigs exposed to aerosolized ovalbumin. The study assessed airway resistance during both the immediate and late-phase responses. Rutin demonstrated significant inhibition of specific airway resistance and the immediate-phase response. Additionally, it showed a suppressive effect on histamine, phospholipase A2, and eosinophil peroxidase, contributing to reduced recruitment of neutrophils and eosinophils into the lungs.

Furthermore, the use of rutin was suggested in managing whooping cough, in combination with vitamins C and K. Rutin has also proven effective in the management of idiopathic chylothorax in cats and whippets.

Antiosteoporotic and Antiosteopenic Effect

Osteoporosis, characterized by a decrease in bone strength and an elevated risk of fractures, particularly among the elderly, is emerging as a significant global health concern. The condition arises when bone resorption by osteoclasts surpasses bone formation by osteoblasts. Current therapeutic strategies for osteoporosis predominantly focus on inhibiting ‘osteoclast-mediated bone resorption,’ with parathyroid hormones being the only class of agents that stimulate bone formation.

In osteogenic-related assays, rutin demonstrated the promotion of proliferation and differentiation of human osteoblast-like MG-63 cells. This effect was accompanied by an increase in alkaline phosphatase activity, expression of collagen type I, and the degree of mineralization. Similar positive effects were observed in rat calvarial osteoblast cells. Rutin also exhibited inhibition of osteoclast formation by reducing oxygen reactive species and TNF-alpha, achieved through the inhibition of NF-kappaB activation. In rats subjected to ovariectomy-induced osteopenia, rutin demonstrated a protective effect by slowing down resorption and increasing osteoblastic activity. Therefore, rutin can be considered as an ‘osteoblast stimulant.’

Anticataract and Ophthalmic Effect

The formation of advanced glycation end products (AGE) is linked to cataracts, a complication associated with diabetes. Thus, inhibiting such glycation processes could be a valuable strategy to prevent this complication. In a study, rutin demonstrated the inhibition of protein glycation, chelation of metal complexes, and partial inhibition of post-Amadori formation. Another investigation, using selenium to induce cataracts in Wistar rat pups, explored the protective effect of rutin in retarding cataractogenesis. Rats treated with rutin exhibited the restoration of lenticular antioxidant enzymes and a decrease in malondialdehyde formation in the eye lens. The experimental findings suggest that rutin may prevent cataractogenesis through its antioxidant mechanisms.

Additionally, oral administration of rutin has been associated with a significant reduction in intraocular pressure. The combined involvement of vitamins B1, B2, forskolin, and rutin demonstrates a ‘defensive effect’ on the ocular surface, helping to restore the ‘normal equilibrium’ of the tear film disrupted by toxins.

Diuretic Effect

Quercetin, a metabolite derived from rutin and abundantly present in Hibiscus sabdariffa Linn, acted on the vascular endothelium, leading to the release of nitric oxide. This action resulted in increased renal vasorelaxation, thereby enhancing kidney filtration.

Effect on Sperm Quality and Male Reproductive Organs

In a study, rutin demonstrated a protective effect against damage to human sperm induced by lipid peroxidation. Additionally, rutin exhibited potential protective effects on testicular tissue and reproduction from oxidative stress observed in type 1 diabetes mellitus (Butchi Akondi et al., 2011). Moreover, rutin showed ameliorative effects on cyclophosphamide-induced reproductive toxicity (Abarikwu et al., 2012) and oxidative stress induced by testicular ischemia–reperfusion in rats.

Anticancer Effects

Cancer encompasses a group of diseases characterized by the abnormal growth of cells that can potentially invade or spread to other parts of the body. Flavonoids are known for exhibiting a wide range of biological effects, including antioxidant and radical-scavenging activities. Reactive oxygen species have been linked to the pathogenesis of various diseases, such as atherosclerosis and certain cancers.

Rutin has been extensively investigated for its anticancer/antineoplastic effects. In a study using a murine model with implanted human leukemia HL-60 cells, rutin (at a dose of 120 mg/kg) significantly reduced tumor size, demonstrating anti-leukemic potential. In another independent study, rutin administered to SW480 tumor cell lines (human colon cancer cell lines) showed less detrimental effects on the body and relative organ weight in mice, along with a 50-day increment in mean survival time. It was demonstrated the antineuroblastoma effect of rutin, inhibiting the growth and chemotactic ability of LAN-5 cells. The study indicated that rutin could decrease BCL2 expression and BCL2/BAX ratio, along with a reduction in MYCN mRNA levels and TNF-a secretion. Rutin is also known to inhibit cancer cell growth through cell cycle arrest and/or apoptosis, as well as the inhibition of proliferation, angiogenesis, and/or metastasis in colorectal cell lines. A rutin analog, quercetin, was studied against the proliferation of the ovarian cancer cell line OVCA 433, showing dose-related inhibition. In another study, quercetin enhanced apoptosis and prevented metastasis in a model of pancreatic cancer. Rutin also appears to be useful as an adjuvant in radioiodine therapy.

Antibacterial Activity

Extensive research has been conducted on the antimicrobial properties of rutin against various bacterial strains. It has displayed significant inhibition of Escherichia coli growth. Rutin, quantified in honey, has exhibited inhibitory effects against Proteus vulgaris, Shigella sonnei, and Klebsiella sp. Documented antimicrobial activity includes effects on Pseudomonas auruginosssa and Bacillus subtilis. Rutin and other polyphenols have been studied for their in situ antimicrobial activity in the food system, revealing promising contributions of flavonoids to food preservation. It is demonstrated rutin’s antibacterial activity against E. coli by inhibiting DNA isomerase IV. Rutin also synergistically enhanced the antibacterial activity of other flavonoids against Bacillus cereus and Salmonella enteritidis in a study, with a remarkable decrease in the minimum inhibitory concentration value for kaempferol upon the addition of rutin.

Antifungal Activities

Rutin exhibited antifungal activity against Candida gattii, with a minimum inhibitory concentration of 60 µg/ml. It was suggested that chemical modification of rutin by introducing substitute groups might alter physicochemical properties, such as electron density, hydrophobicity, and steric strain, potentially enhancing antifungal activity. Rutin’s use in the treatment of septic arthritis caused by C. albicans has also been proposed.

Antimycobacterial Activity

In a study, a flavonoid-rich extract containing rutin demonstrated antimycobacterial activity against Mycobacterium smegmatis.

Larvicidal Activity

Rutin significantly inhibited the growth and propagation of larvae of S. aegypti in a study, with maximum larval mortality observed at 72 hours.

Antiretroviral Activity

In a study, the anti-HIV activity of sodium rutin sulfate, a sulfated rutin analog, was investigated against HIV-1 X4 viruses IIIB, HIV-1 R5 isolates Ada-M, and Ba-L strains. Sodium rutin sulfate demonstrated its antiretroviral effect by blocking viral entry and virus-cell fusion, mediated through interaction with the HIV-1 envelope glycoprotein.

Antiviral Activity

The availability of antiviral agents for treating infections caused by various viruses underscores the importance of developing novel antiviral drugs, especially with the emergence of new resistant viral strains.

Rutin has been tested against vesicular stomatitis virus on mouse fibroblasts, providing protection for about 24 hours (Wacker and Eilmes, 1978). In the case of canine distemper virus infection, rutin significantly inhibits viral replication when added during the adsorption and penetration phases of the viral replicative cycle (Carvalho et al., 2013). Rutin, a major constituent of Capparis sinaica Veill, has demonstrated profound antiviral effects against avian influenza strain H5N1 using a plaque inhibition assay in Madin-Darby canine kidney cells (Ibrahim et al., 2013).

Hair

Apoptosis of hair follicular cells is a leading cause of hair follicle degeneration. In a study, apoptosis of human follicular dermal papilla cells induced by staurosporine was observed. This event was completely reversed by exposure to rutin, spermidine, and zeaxanthin. The study demonstrated the preservation of the expression of anti-apoptotic molecules such as Bcl-2, MAP-kinases, and their phosphorylated forms, suggesting the potential use of rutin in preventing apoptosis of hair follicular cells, a significant contributor to baldness.

Sunscreen Effects

The pursuit of having healthy, beautiful, and disease-free skin has been a timeless goal, with the history of cosmetics and skincare products dating back to ancient Greek, Roman, and Egyptian civilizations. Advances in science, technology, and modern chemistry have facilitated the realization of this aspiration.

Exposure to ultraviolet B (UVB) radiations leads to oxidative and inflammatory skin damage, increasing the risk of skin carcinogenesis. Rutin’s effects on UVB-induced inflammation in mouse skin have been studied in vivo. Topical application of rutin on mice skin, 30 minutes before UVB irradiation, resulted in reduced epidermal hyperplasia and protein levels. There was also a significant inhibition of UVB-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), possibly due to the inhibition of p38 MAP kinase and JNK, leading to a reduction in UVB-induced COX-2 expression in mouse skin.

In a study, the incorporation of rutin into oil-in-water emulsions (at a concentration of 10% w/w) demonstrated sun protection factor (SPF) values comparable to homosalate. When combined with TiO2, SPF values approached 30.

In Atopic Dermatitis

In a model of atopic dermatitis using BALB/c mice, achieved by repeated local exposure to house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) on the ears, rutin treatment suppressed interleukin (IL)-4, IL-5, IL-13, IL-31, IL-32, and interferon (INF)-c in the tissue. In a local lymph node assay for allergic contact dermatitis sensitized with 2,4-dinitroflourobenzene, rutin demonstrated suppression of allergic contact dermatitis based on parameters such as ear thickness, lymphocyte proliferation, serum IgG2a levels, and the expression of INF-c, IL-4, IL-5, IL-10, IL-17, and tumor necrosis factor-a in allergic contact dermatitis ears. This study highlights the anti-atopic dermatitis and allergic contact dermatitis activity of rutin. Additionally, rutin has shown anti-aging effects on the skin. Therefore, rutin can be considered an effective topically applied compound due to its antioxidant activity and skin penetration profile.

Immune Effects

The impact of rutin on the immune and physiological response to Vibrio alginolyticus challenge was studied in white shrimp. The investigation analyzed physiological and innate non-specific immune responses, respiratory bursts, and superoxide dismutase activity against the pathogen. Rutin from Toona sinensis was administered to the shrimp. In summary, shrimps treated with rutin exhibited lower glucose, lactate, and lipid levels in response to the pathogen. Survival rates of shrimps treated with rutin were higher (Hsieh et al., 2008). Another study demonstrated the promotion of macrophage phagocytosis activity in cells.

Anti-Fatigue Activity

Fatigue serves as an indicator closely tied to an individual’s health and is often associated with a decline in physical performance. Intense physical activity can lead to the accumulation of excess reactive free radicals, causing oxidative stress injuries to the body. Fatigue results from energy depletion and the buildup of surplus metabolites.

In mice, the administration of rutin prevented the depletion of superoxide dismutase and reduced glutathione. Following seven days of rutin treatment, mice were sacrificed, and their soleus muscle and brain were analyzed for peroxisome proliferator-activated receptor-alpha coactivator and sirtuin one mRNA expression. The up-regulation of CB1 cannabinoid receptor-interacting protein 1, myelin basic protein, Rho GDP dissociation inhibitor (GDI) alpha, and TPI suggested that rutin treatment inhibited condition anxiety by enhancing the expression of anxiety-associated proteins. In summary, treatment with rutin appears to ameliorate various impairments associated with physical fatigue.

Neuroprotective Activity

In a mouse model, rutin exhibited inhibitory effects on oxaliplatin-induced chronic painful peripheral neuropathy. Oxaliplatin, a crucial platinum compound in colorectal cancer chemotherapy, is associated with the challenging issue of peripheral neuropathy. Rutin notably reduced peroxidative changes and lipid peroxidation induced by oxaliplatin in the spinal cord, along with a decrease in inducible nitric oxide.

Retinoprotective Activity

The impact of rutin on ocular blood flow was assessed using the “colored microsphere technique.” Electroretinography was employed to evaluate b-wave recovery, providing an estimation of retinal function recovery. Rutin increased ocular blood flow and demonstrated a significant effect on retinal function recovery.

Protective Effect on Lung Tissue

Acute lung injury represents a severe condition associated with high mortality and morbidity, lacking an established therapeutic strategy to date. Rutin displayed protective effects on histopathological changes in lung tissue, preventing the infiltration of polymorphonuclear granulocytes in bronchoalveolar lavage fluid. Moreover, rutin reduced the secretion of lipid peroxidation and proinflammatory cytokines. Rutin reversed the lipopolysaccharide-induced suppression of antioxidant enzymes, including catalase, glutathione peroxidase, superoxide dismutase, and heme oxygenase-1 (Yeh et al., 2014). Pretreatment with rutin inhibited lipopolysaccharide-induced arterial blood gas exchange impairment and neutrophil infiltration in the lungs, suppressing macrophage inflammatory protein-2 and matrix metalloproteinase-9. Additionally, rutin effectively inhibited vascular cell adhesion molecule-1 and inducible nitric oxide synthase, providing evidence of its preventive role in early adult respiratory distress syndrome.

Cardioprotective Effects

Ischemic heart disease stands as a predominant cause of morbidity and mortality worldwide. The intricate pathophysiology underlying cellular damage resulting from ischemia involves multifaceted mechanisms. Reactive oxygen species play a crucial role in the pathogenesis of various diseases (Li and Jackson, 2002). Ischemic tissues are known to generate oxygen-derived free radicals, causing oxidative damage to membrane lipids, proteins, and carbohydrates, leading to qualitative and quantitative alterations in the myocardium.

The cardioprotective effects of rutin were investigated in normal and streptozotocin diabetic rats subjected to ischemia-reperfusion-induced myocardial infarction. Rutin administration significantly provided cardioprotection and limited infarct size in both normal and diabetic rats. The underlying mechanism of this protection may involve the attenuation of lipid peroxidation in myocardial tissues.

Isoproterenol, a β-adrenergic agonist used to treat bradycardia and heart block, can lead to cardiac toxicity with frequent administration, as evidenced by an increase in the activity of serum cardiac marker enzymes, including lactate dehydrogenase, aspartate transaminase, creatine kinase, and alanine transaminase, along with a significant decrease in their activity in the heart. Rutin restored the levels of cardiac marker enzymes and reduced lipid peroxidation, indicating its cardioprotective effect attributed to its antioxidant properties.

The administration of rutin repressed the isoproterenol-induced increase in angiotensin II and aldosterone in plasma. Additionally, rutin-treated animals showed reduced overexpression of transforming growth factor β1, connective tissue growth factor, and decreased excessive deposition of extracellular matrix in isoproterenol-treated myocardial tissues.

Nephroprotective Activity

Nephropathy stands as a prevalent pathogenic condition affecting people worldwide, transcending age, caste, creed, race, and environment. The origins of this condition lie in anomalies arising from various metabolic and physiological disturbances, making nephropathy one of the top ten leading causes of death globally. Compounds such as gentamicin, ecstasy, cisplatin, and carbon tetrachloride are known to exhibit nephrotoxicity.

In a study, rutin exhibited protective activity against oxonate-induced hyperuricemia and renal dysfunction in mice. Rutin administration led to a decrease in levels of serum urate, creatinine, and blood urea nitrogen, as well as serum and kidney uromodulin levels. There was an increase in urine uromodulin, urate, and creatinine excretion in hyperuricemic mice. Additionally, rutin significantly downregulated mRNA and protein levels of mouse glucose transporter 9 and urate transporter 1. Simultaneously, it upregulated mRNA and protein levels of organic anion transporter 1 and organic cation/carnitine transporters in the kidneys of hyperuricemic mice. In a fructose-fed rat model for hyperuricemia, rutin blocked NOD-like receptor three inflammasome activation, improved signaling, and reduced lipid accumulation in the kidneys of rats. This was accompanied by the reversal of dysregulation of renal transporters. Inhibition of inducible nitric oxide synthase activity and reduction in 3-nitrotyrosine formation, along with the inhibition of reactive oxygen species, appear to be crucial approaches to prevent renal ischemia/reperfusion injury.

In cisplatin-treated Wistar rats, rutin pretreatment restored kidney function and oxidative stress biomarkers. Rutin partially inhibited the NFκB and TNF-α pathway-mediated inflammation, caspase-3-mediated tubular cell apoptosis, and helped in the restoration of histopathological changes caused by cisplatin administration. Rutin also exhibited protective effects against potassium bromate-induced nephrotoxicity in rats. It resulted in a reduction in DNA fragmentation, upregulation in the activity of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and reduced glutathione. Additionally, there was a decrease in lipid peroxidation.

Wound Healing Activity

When formulated as a hydrogel and applied to skin lesions in rats, rutin exhibited notable wound healing activity by reducing the wound area compared to control hydrogels. This effect was accompanied by a decrease in oxidative stress in the wound area, evident through reduced lipid peroxidation and protein carbonyl content, along with increased catalase activity. Rutin-releasing chitosan hydrogels, designed as injectable dressings for dermal wound healing, demonstrated their efficacy by promoting the formation of well-defined neo-epithelium and thicker granulation, closely resembling the original epithelial tissue.

Radio Modulatory Effects

Radiation therapy stands as a primary strategy in anticancer therapy for various cancers. However, its use is limited due to adverse effects on normal tissues. Ionizing radiations induce the generation of free radicals, leading to DNA damage and subsequent cell death. This damage extends beyond cancerous cells to affect normal cells. While some radioprotectors have been explored, their clinical effectiveness is constrained by frequent administration-related toxicity.

In a study, rutin was investigated for its potential radioprotective effects. Administered to Swiss albino mice, rutin exhibited optimal radioprotective effects at a dose of 10 mg/kg. This intervention increased radiation tolerance, restored antioxidant enzyme levels, and decreased lipid peroxidation in the liver, thereby mitigating radiation-induced sickness and improving survival rates. Similar protective effects of rutin against gamma radiations were also observed.

Prevention of Splenocyte Apoptosis

Rutin has been observed to influence the viability and function of mitogen-stimulated splenocytes and thymocytes compared to non-stimulated cells. In a study involving the culture of splenocytes with mitogens, a decrease in interferon-gamma production was noted, accompanied by a reduction in splenocyte apoptosis.

Hepatoprotective Activity

Cirrhosis, characterized by hepatocyte destruction and the subsequent replacement with scar tissue, alters blood flow through the liver, resulting in hepatocyte death and impaired liver function. Hepatic fibrosis, a consequence of repeated injury, involves the regeneration of apoptotic cells, and when the death of regenerating cells occurs, it leads to the deposition of extracellular matrix, including fibrillar collagen. Such pathological conditions are challenging to treat, and the effectiveness of treatments with colchicines, interferons, penicillamine, and corticosteroids is inconsistent and questionable.

Given that oxidative stress is one of the factors contributing to cirrhosis, the use of antioxidants emerges as a unique strategy for treatment. Rutin has undergone extensive study for its hepatoprotective activity in experimental animals. In a study, it was assessed the protective effect of rutin in carbon tetrachloride (CCl₄)-induced liver injuries in rats. Rutin administration resulted in a reduction in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase caused by carbon tetrachloride. Blood cholesterol levels were regulated, and the levels of endogenous liver antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and glutathione were increased, while lipid peroxidation decreased in a dose-dependent manner. Additionally, rutin treatment restored the activity of p53 and CYP2E1. In a separate study involving BALB/c mice, rutin treatment alleviated oxaliplatin-induced hepatotoxicity and neurotoxicity. The prevention of mechanical allodynia, coupled with histopathological observations, suggested the protective role of rutin in preventing hepatotoxicity.

Reasons for the diverse positive effects of rutin on various biological systems

The diverse positive effects of rutin on various biological systems can be attributed to its multifaceted pharmacological properties and interactions with different molecular pathways. Rutin, a flavonoid glycoside, possesses several biological activities due to its chemical structure and ability to interact with various cellular components. Here are some factors that contribute to the broad spectrum of positive effects associated with rutin:

1. Antioxidant Activity: Rutin is a potent antioxidant, meaning it can neutralize reactive oxygen species (ROS) and free radicals. This antioxidant property helps protect cells and tissues from oxidative stress, a common factor in various diseases and aging processes.

2. Anti-Inflammatory Effects: Rutin has anti-inflammatory properties, which can modulate immune responses and reduce inflammation. This is crucial in conditions where inflammation plays a role, such as arthritis or inflammatory skin disorders.

3. Enzyme Inhibition: Rutin can inhibit certain enzymes involved in pathological processes. For example, it can inhibit the activity of enzymes related to bone resorption, contributing to its anti-osteoporotic effects.

4. Cellular Signaling Modulation: Rutin can influence various cellular signaling pathways, affecting processes like cell proliferation, differentiation, and apoptosis. This modulation can contribute to its effects on cancer cells, immune cells, and other cell types.

5. Metal Chelation: Rutin has metal-chelating properties, which can be beneficial in conditions where metal ions play a role in disease progression.

6. Interaction with Cellular Receptors: Rutin may interact with specific receptors on cell membranes, influencing cellular responses. For example, it may affect receptors involved in neurotransmission, contributing to its neuroprotective effects.

7. Regulation of Gene Expression: Rutin can influence the expression of genes involved in various cellular functions. This ability to modulate gene expression contributes to its effects on cell differentiation, inflammation, and other processes.

8. Bioavailability and Distribution: Rutin’s bioavailability and distribution in the body may allow it to exert effects on different organs and systems. Its ability to reach and accumulate in specific tissues contributes to its efficacy in diverse conditions.

It’s important to note that while rutin exhibits these positive effects in experimental studies, individual responses can vary, and the translation of these findings to clinical applications may require further research. Additionally, the complexity of biological systems means that the effects of rutin are likely interconnected and influenced by multiple factors.

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