What Are the Benefits of Rutin and Its Derivatives?

With の のdvのcement の science と technology, people hのve gradually recognized that compounds derived from natural products are more 効果ive で preventでg と treating diseases.の use の plant-derived chemicals to promote health is currently a hot topic の research. Dietary polyphenols are widely distributed in plants, と it is well known that increasing の intake の fru◆ と vegetables can reduce の incidence の diseases, which is attributed to の 効果 の dietary polyphenols. Flavにoids are cにsidered to be dietary polyphenols in の daily diet [1].

ルチン (ルチン, Figure 1) belongs to the flavonoid family と is a glycoside の quercetin. It is found in fruits such as oranges, grapefruits, lemons, と sour oranges; vegetables such as asparagus, tomatoes, と cucumbers; と traditional Chinese herbs such as Sophora japonica, のstragalus membranaceus, Pueraria lobata, と Citrus reticulata.ルチン possesses antioxidant, anti-inflammatory, anti-allergic, antibacterial, antiviral, antiがん, cardiovascular protective, and antidiabetic effects [2]. Increasing evidence suggests that flavonoids derived from vegetables, fruits, and medicinal plants exert important roles in human health and disease prevention を通じて their free radical scavenging 活動, influencing cellular growth, differentiation, and function [3].

Rutin is a promising natural dietary compound with preventive and control effects 反対 diseases [4]. Rutin is widely used as a 麻薬 to maintain and restore the normal elasticity の capillaries. Due to its low bioavailability, structural optimization and modification have been conducted, resulting in the 合成 の many 派生商品 with high bioavailability and significant activity [5].The authors reviewed the research progress の ルチン and its derivatives over the past decade from various databases, such as Elsevier Journal, Springer, PubMed, Google Scholar, SciFinder, and China National Knowledge Infrastructure (CNKI), focusing on the antiがん and hypoglycemic effects of ルチン, as well as the antibacterial, anticancer, and hypoglycemic effects of rutin derivatives, providing references ため the development and utilization of natural compounds.

1 Rutin

1.1 Common drugs containing rutin

Rutin belongs to the vitamin category and has the effect of reducing capillary permeability and fragility, thereby maintaining and restoring the normal elasticity of capillaries. It is used for the prevention and treatment of hypertension-induced cerebral hemorrhage, diabetic retinopathy hemorrhage, and hemorrhagic purpura.Currently, the Pharmacopoeia of the People's Republic of China (2018 edition) lists four drugs containing rutin:

Rutin tablets: Used for capillary hemorrhagic disorders with increased fragility, as well as for the adjunctive treatment of hypertensive encephalopathy, cerebral hemorrhage, retinal hemorrhage, hemorrhagic purpura, acute hemorrhagic nephritis, recurrent epistaxis, traumatic pulmonary hemorrhage, and postpartum hemorrhage.

Rutin compound tablets: A compound preparation made from rutin and vitamin C primarily used for the treatment of hypertension and increased capillary fragility, as well as an adjunctive therapy for various bleeding symptoms. Rutin has the effects of maintaining vascular resistance, reducing fragility, lowering permeability, and exhibiting antiviral and anti-inflammatory 文化財; vitamin C is an essential nutrient that the human body must consume daily, clinically used for the prevention and treatment of scurvy, and can enhance resistance.Rutin acts as a hydrogen carrier, participating in the activity of oxidoreductase enzymes in the body. It influences thyroid function and prevents the oxidation of adrenaline. In the body, it enhances the effects of vitamin C and promotes its accumulation.The primary 薬理作用 effects of compound rutin are to maintain vascular elasticity, enhance capillary resistance, reduce fragility and permeability, and promote cell proliferation while preventing blood cell aggregation [6].

Linoleic acid vitamin E capsules / Biluodine tablets (trade name: Yishouning): A compound preparation, linoleic acid vitamin E capsules are made from linoleic acid and vitamin E, while Biluodine tablets are made from rutin, vitamin B6, and vitamin C. They are used for the treatment of hypercholesterolemia and atherosclerosis.The two components work synergistically [7].

Compound Triazine Rutin Tablets: Containing 10 main ingredients including hydrochlorothiazide, dihydrochlorothiazide, isopropyl hydrochloride, rutin, and excipients, this medication is primarily used for the treatment of hypertension [8].

Zhenju Hypotensive Tablets are a commonly used compound formulation of traditional Chinese and Western medicines for lowering blood pressure, composed of wild chrysanthemum, clonidine hydrochloride, hydrochlorothiazide, rutin, pearl layer powder, and other ingredients [9]. Zhenju Hypotensive Tablets are not included in the Pharmacopoeia but are listed in the Ministry of Health standards and are commonly used antihypertensive drugs.

Currently, over 130 registered medications worldwide contain rutin [10].

Rutin is also used as a food coloring (similar to lemon yellow), an antioxidant, and a nutritional supplement. It is primarily used in cold beverages, drinks, pastries, meat products, and seafood products.

1.2Antioxidant Properties

During human metabolism, a large number of free radicals are produced. When free radicals interact with molecules such as タンパク質, pathological changes occur. Rutin is a natural antioxidant that can scavenge free radicals. Kamalakkannan et アル [11] investigated the antioxidant potential of rutin in streptozotocin (STZ)-induced diabetic rats. Intraperitoneal injection of streptozotocin (50 mg/kg) induces diabetes. Fasting plasma glucose and insulin levels, as well as lipid peroxidation products and antioxidant activity in the liver, kidneys, and brain, were assessed. Oral administration of rutin (100 mg/kg) for 45 days (p < 0.05) reduced lipid peroxidation products, significantly lowered fasting blood glucose levels, increased insulin levels, and improved the antioxidant status of diabetic rats. Histopathological studies of liver, kidney, and brain tissues demonstrated that rutin has protective effects.

1.3 Antibacterial activity

The antibacterial activity of flavonoids, along with their synergistic and inhibitory effects with antibiotics, is attributed to three mechanisms: damage to the cell membrane, inhibition of nucleic acid synthesis, and suppression of energy metabolism.The antibacterial activity of rutin primarily involves regulating the expression levels of proteins during the general stress response, particularly the activation control system of inducible proteins, and influencing carbohydrate and amino acid metabolism, protein synthesis, and cell wall integrity [12].The inhibitory zone of rutin in a hydrogel system was assessed using a hydrogel method. An experiment targeting Staphylococcus aureus and Escherichia coli showed that the rutin hydrogel formulation exhibited significant antibacterial activity [13]. In another study, a methanol-water solution of rutin was used to perform disk diffusion growth of eight intestinal microorganisms and a microdilution method.The results showed effective activity against Pseudomonas aeruginosa, Pseudomonas aeruginosa, and Klebsiella pneumoniae [14]. Stojkovi et アル [15] used a more practical chicken broth method instead of microbial culture medium to test the antioxidant and antibacterial 文化財 of rutin. They observed that rutin inhibited the growth of Staphylococcus aureus in chicken broth, a food contaminant.

1.4 Anticancer Effects

Numerous studies have demonstrated that rutin possesses anticancer activity. These effects have been evaluated in both in vitro and in vivo studies. The multifaceted mechanisms of flavonoids as anticancer agents have been identified, including carcinogen inactivation, anti-proliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidant activity, and reversal of multidrug resistance or combinations of these mechanisms [16].

Lung cancer is the most common cancer worldwide, characterized by the highest mortality rate, high metastatic potential, resistance to chemotherapy drugs, and drug-induced cytotoxicity, which are common causes of death in lung cancer patients.

Rutin can regulate the expression of glycogen synthase kinase 3 (GSK-3) in human lung adenocarcinoma A549 cells. GSK-3 is involved in numerous cellular networks, including proliferation, cell cycle, and apoptosis processes.Fibronectin, type I, and type IV play crucial roles in the formation of the extracellular matrix, which regulates cell adhesion and migration. Rutin 抑制 the adhesion of A549 cells to fibronectin and collagen types I and IV,thereby inhibiting the migration of lung cancer cells. Sghaier et al. [17] demonstrated that rutin, as a multifunctional drug, can inhibit proliferation by reducing the production of reactive oxygen species (ROS) and decreasing the adhesion and migration of human lung cancer cells and colon cancer cells.Rutin blocked the effect of carotene on 4-(methylnitrosyl)-1-(3-pyridyl)-1-butanone-induced single-strand DNA breaks in A549 cells, which can be attributed to its antioxidant properties, as it eliminated ROS levels.Rutin inhibits lung metastasis and lung tumor nodules induced by mouse B16F10 melanoma cells and extends mouse lifespan [18].

Rutin can inhibit platelet aggregation, exhibit anti-inflammatory and antioxidant effects, and reduce blood lipids and cholesterol. Chen H et al. [19] investigated the effects of rutin on neuroblastoma.The results showed that rutin induced G2/M arrest in the cell cycle process and induced apoptosis. Reverse transcription-polymer chain reaction (RT-PCR) revealed that rutin reduced BCL2 expression and the BCL2/BAX ratio. Additionally, it inhibited MYCN mRNA levels and TNF-α secretion.These results indicate that rutin, by inducing G2/M arrest in the cell cycle process and inducing apoptosis, and inhibiting the expression of apoptosis-related genes in neuroblastoma, can serve as a new therapeutic agent for neuroblastoma.

Rutin can regulate multiple molecular targets involved in carcinogenesis, such as cell cycle mediators, cell kinases, inflammatory cytokines, transcription factors, drug transporters, and reactive oxygen species. Rutin is a promising natural dietary compound with excellent anticancer potential and can be widely used in functional foods, dietary supplements, and drugs for the prevention and control of cancer.

Numerous studies have shown that rutin can serve as a chemotherapeutic and chemopreventive agent, with its anticancer effects mediated by inhibiting cell proliferation, inducing apoptosis or autophagy, and blocking angiogenesis and metastasis [20]. Triple-negative breast cancer (TNBC) has a high rate of metastasis and mortality and lacks effective treatment methods.

Abnormal dysregulation of the receptor tyrosine kinase c-Met promotes the progression, motility, and survival of TNBC, making it a promising therapeutic target. Among various identified anticancer drugs, plant polyphenols, including flavonoids, have been demonstrated to be safe and have exhibited antitumor activity by regulating multiple macromolecular targets.Studies have shown: For the first time, c-Met kinase was identified as a potential target for the anticancer effects of rutin on TNBC cell lines. Similarly, intraperitoneal injection of rutin at a dose of 30 mg/kg, three times weekly, significantly reduced the growth of TNBC MDA-MB-231/GFP orthotopic xenografts in a nude mouse model.These results clearly indicate that functional dietary flavonoids, such as rutin, are potential lead compounds for the prevention and control of c-Met-dependent breast malignant tumors [21].

Another approach using rutin is combination therapy with anticancer drugs. Nasiri et al. 。[22] demonstrated that rutin, when used in combination with 5-FU and/or oxaliplatin, was more effective than monotherapy in colon cancer cells. They also found that rutin, when used with lower doses of 5-FU and oxaliplatin, may help reduce the adverse effects of anticancer drugs.

1.5 Antidiabetic effects

 Flavonoids derived from vegetables and medicinal plants can exert beneficial effects on diabetes by improving blood glucose control, lipid distribution, and antioxidant status. The hypoglycemic mechanism of rutin includes reducing carbohydrate absorption in the small intestine, inhibiting tissue gluconeogenesis, increasing tissue glucose uptake, and stimulating β-cell insulin secretion.Rutin also reduces the formation of sorbitol, reactive oxygen species, advanced glycation end product precursors, and inflammatory cytokines. These effects are believed to underlie rutin's protective role against kidney disease, neuropathy, liver damage, and cardiovascular diseases caused by hyperglycemia and dyslipidemia.Given the negative correlation between the risk of diabetes complications and the control of blood glucose and lipids, rutin is recommended as a dietary supplement for the prevention of diabetes complications [23].

Diabetes and its major risk factors, obesity, have become a global epidemic and a cause of suffering for millions of people. Chronic hyperglycemia and dyslipidemia are associated with changes in intracellular metabolic pathways that damage tissues.Intracellular changes include excessive production of reactive oxygen species, sorbitol accumulation, increased levels of diacylglycerol, reduced activity of glycogen phosphorylase (GAPDH), and increased activity of the hexosurine pathway. Studies have shown that dietary rutin inhibits aldose reductase and reduces sorbitol concentration in red blood cells.In diabetic animals, administration of rutin improved antioxidant status in various tissues and reduced blood glucose levels [24].

2  Rutin derivatives

2.1 Troxerutin

Troxerutin is the most successful example of a rutin derivative used as a drug.

Troxerutin (also known as Vitamin P4, Trihydroxyethyl Rutin, or 7,3′,4′-Trihydroxyethyl Rutin) is a semi-synthetic flavonoid compound.Troxerutin is a semi-synthetic flavonoid compound derived from rutin through hydroxyethylation. Zyma S. A first reported the synthesis method of troxerutin in a patent [25,26].Rutin is dissolved in a sodium hydroxide solution, and ethylene oxide is slowly added while heating to 80–85°C. The mixture is maintained at this temperature for 6 hours, then acidified, crystallized, and recrystallized with ethanol to obtain the product [27].

Quercetin is widely used in the treatment of ischemic cerebrovascular diseases, such as chronic venous insufficiency-induced cardiovascular and cerebrovascular diseases, hemorrhoids, microvascular lesions, diabetes, and retinal lesions.Recent studies have found that quercetin also exhibits neuroprotective effects on cognitive deficits, demonstrating certain protective effects in diseases such as Alzheimer' s病、Parkinson's disease, colon cancer, and hepatocellular carcinoma.

人民の薬局方's Republic of China (2018 edition) lists 14 drugs containing quercetin:

Curcumin tablets, indicated for occlusive syndrome, thrombophlebitis, and capillary hemorrhage. This product inhibits platelet aggregation and prevents thrombus formation. It also counteracts vascular damage caused by 5-hydroxytryptamine and bradykinin, enhances capillary resistance, reduces capillary permeability, and prevents edema caused by increased vascular permeability.

Quercetin coumarin tablets, composed of quercetin and coumarin. Coumarin is derived from salicylic aldehyde via the Perkin reaction and possesses anticoagulant and antiplatelet aggregation effects. Quercetin coumarin tablets are commonly used for the treatment of trauma, fever reduction, and swelling in arthritis [28].

2.2 Rutin derivatives with antibacterial activity

Many studies have demonstrated that rutin possesses antibacterial properties and can enhance the antibacterial activity of other compounds. Classic penicillin has some drawbacks, such as low water solubility.Typically, penicillin is poorly soluble in water, with only potassium or sodium salts being water-soluble; however, the use of these salts may lead to adverse side effects. Lupa§cu et al. [29] synthesized derivatives of rutin 6-amino penicillin acid and characterized them chemically and microbiologically, determining the structures of these compounds.These derivatives are water-soluble and exhibit good antibacterial activity against both Gram-positive and Gram-negative bacteria, similar to ampicillin and amoxicillin. The results show that compared to standard antibiotics, especially for compounds 3a and 3b, they exhibit good antibacterial activity against both Gram-positive and Gram-negative bacteria.

Antibiotic resistance is a hot topic and one of the major threats to public health. Statistics show that multidrug-resistant microorganisms, such as bacteria, fungi, and protozoa, have increased in recent decades and continue to spread. Therefore, developing new 抗菌の drugs to combat drug-resistant infections is of great importance.The quinoline ring is a highly interesting structure due to its diverse biological properties (抗菌の, anticancer, anticonvulsant, anti-inflammatory, and cardiovascular disease-related 活動). On the other hand, some studies have shown that rutin exhibits good antimicrobial activity. Based on the above considerations, Lupascu et al. [30] designed and synthesized eight rutin derivatives containing aminoquinoline. The results indicated that the tested compounds exhibited good activity against Gram-positive and Gram-negative bacterial strains (including Pseudomonas aeruginosa), similar to ciprofloxacin, and were inactive against Candida albicans.

2.3 Rutin derivatives with antidiabetic activity

 Diabetes is a metabolic disorder involving the levels of glucose, lipids, and minerals in the body, as well as oxidative-reductive reactions. One of the primary risk factors for diabetes is cardiovascular disease and its complications, including hypercholesterolemia and hyperhomocysteinemia.The primary treatment for diabetes is to lower blood glucose levels. Albu et al. [31] synthesized a new rutin barbital acid derivative. Data obtained after one month of animal experiments indicated that the rutin barbital acid derivative can lower cholesterol and blood glucose levels, making it significant for the treatment of diabetes.

Xanthine oxidase is an important enzyme in the purine catabolic pathway, which can directly cause gout and is also associated with cancer, diabetes, and metabolic syndrome.Inhibiting xanthine oxidase is an important method for treating gout, diabetes, and other metabolic syndromes. Malik et al. [32] designed and synthesized five rutin Schiff base derivatives and evaluated their antioxidant activity and xanthine oxidase inhibitory potential.

Enzyme kinetic studies on rutin Schiff base derivatives revealed their potential inhibitory effects on XO through competitive inhibition, with IC₅₀ values ranging from 4.708 to 19.377 μM and compound 6b (4.708 μM) exhibiting the highest activity.Molecular simulations showed that the new rutin Schiff base derivatives interact with the amino acid residue PHE798, located within the XO binding site. Antioxidant experiments indicated that all derivatives exhibited excellent antioxidant activity. 6b may be a candidate drug for the treatment of gout, diabetes, and other metabolic syndromes.

2.4 Rutin derivatives with anticancer activity

The interactions between natural flavonoids and natural polysaccharides are attracting researchers' attention, particularly in the field of medicinal chemistry. The synergistic relationship between the two can be utilized as independent entities in formulations [33]. By integrating the structural and functional characteristics of rutin (a low molecular weight plant chemical compound) and fucoidan (a high molecular weight sulfated polysaccharide), an interacting complex is formed.Rutin and fucoidan form therapeutic polymeric complexes through non-covalent complexes, thereby overcoming the limitations of rutin's bioavailability. Stable, functionally effective, biocompatible, and safe anticancer complexes can be developed. Deepika et al. [34] synthesized rutin-fucoidan complexes.Rutin was dissolved in methanol, mixed with fucoidan, sonicated, and then vacuum distilled to obtain the product. The chemopreventive potential of the rutin-fucoidan complex against HeLa cells was analyzed via apoptosis assays and flow cytometry.The results indicated that the rutin-fucoidan complex disrupts cell cycle regulation and possesses the ability to induce apoptosis through nuclear fragmentation, ROS generation, and mitochondrial membrane potential loss. In vitro cell viability assays demonstrated that the rutin-fucoidan complex exhibits biocompatibility in normal cells.

Experiments confirmed that, compared to individual components, the rutin-fucoidan complex exhibits 拡張 cytotoxic and apoptotic effects on HeLa cells. Therefore, this study opens prospects for the development of agents against cervical cancer and other cancers.

Goitia et al. [35] synthesized rutin-vanadium complexes. The coordination of vanadium enhances the antioxidant activity of the ligand against superoxide and hydroxyl radicals. Results showed that 100 mM rutin and V(IV)O did not exhibit cytotoxic activity against A549 cells, but the rutin-vanadium complex demonstrated anticancer activity (IC50 = 95 mM), promoting the production of reactive oxygen species (ROS), oxidized glutathione (GSSG), and the depletion of the non-enzymatic antioxidant glutathione (GSH), while not affecting the viability of normal embryonic lung cell lines (MRC-5) at concentrations up to 100 mM. After treatment with the antioxidant N-acetyl-L-cysteine (NAC), the cytotoxic effects of rutin vanadium complexes were reversed, indicating that their therapeutic effects involve an oxidative stress mechanism.Rutin vanadium complexes can spontaneously bind to bovine serum albumin (BSA) and can be stored and transported by proteins. Further evidence indicates that rutin vanadium complexes enhance the anticancer activity of ligands in lung cancer A549 cell lines. Compared to rutin, rutin vanadium complexes exhibit stronger anticancer activity and increased reactive oxygen species (ROS) production.It inhibits cell growth, leads to a significant increase in ROS formation, and reduces the GSH/GSSG ratio. These results demonstrate that rutin vanadium complexes induce cell death through an oxidative stress mechanism, thereby exerting anticancer effects [36].

3結論

The use of bioactive plant chemicals for the prevention and treatment of chronic diseases, including cancer and cardiovascular diseases, is superior to chemically synthesized drugs. As potential therapeutic agents, polyphenolic compounds are one of the bioactive plant chemicals currently under investigation. Rutin is a bioactive flavonoid found in various foods, capable of regulating intracellular and extracellular signaling pathways associated with the progression of numerous diseases.Structural modifications of rutin have led to the synthesis of numerous rutin derivatives with improved solubility and bioavailability, making them promising drugs with broad therapeutic applications, such as anticancer/antiproliferative, antioxidant/anti-aging, antiviral, anti-inflammatory, and cardioprotective effects.Optimized and modified rutin derivatives are expected to enter clinical trials in the near future as drugs, leveraging their natural medicinal properties to alleviate suffering and serve the global population.

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