Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.

BACKGROUND: Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis. METHODS: Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination. RESULTS: In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1ß and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1ß, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB. CONCLUSIONS: In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage.

Assessment of Anti-Inflammatory and Antioxidant Activities of a Proprietary Preparation of Quercetin-Rutin Blend (SophorOx™) in Exercised Rats.

Objectives: Flavonoids comprise a huge class of phenolic compounds widely distributed throughout the plant kingdom. Although quercetin and rutin have been studied individually for their therapeutic value, the synergistic effect of combining the two has previously not been measured. The objective of this trial was to evaluate the anti-inflammatory and antioxidant properties of both quercetin and rutin when combined in the form of SophorOx™ (a proprietary preparation of quercetin-rutin) in exercised rats. Methods: Sprague-Dawley rats were orally administered SophorOx™ at 500 mg·kg-1·b.w. and subjected to daily exercise on a fabricated treadmill for 4 weeks. A total of 24 animals were randomly divided into four groups. All the animals were examined for body weight, feed consumption, signs of clinical abnormalities, and morbidity. In addition, serum collected on days 8, 15, 22, and 29 were measured for the liver function test (LFT), random blood sugar (RBS), inflammatory markers C-reactive protein (CRP), oxidative stress markers (8-isoprostane (8-iso-PGF2α), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and cytokine levels interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α)) by the ELISA method. Results: Rats that received SophorOx™ showed no signs of adverse effects, and no significant changes were observed in body weight, feed consumption, liver enzymes, and blood glucose levels. The exercise-treated rats administered with SophorOx™ exhibited a significant reduction in oxidative and inflammatory marker levels, viz., CRP (113.32 ng·mL-1) and oxidative stress markers 8-OHdG (19.32 pg·mL-1), MDA (1.06 nmol·mL-1), 8-iso-PGF2α (1.29 ng·mL-1), IL-1ß (0.77 pg·mL-1), and IL-6 (317.14 pg·mL-1) in comparison to those rodents that were exercised without SophorOx™. Conclusion: Oral administration of SophorOx™ significantly reduced oxidative stress and inflammatory marker levels when measured in the rodents subjected to high-intensity exercise.

Effect of the Flavonoid Rutin on the Modulation of the Myenteric Plexuses in an Experimental Model of Parkinson's Disease.

Recent discoveries have shown that enteric glial cells play an important role in different neurodegenerative disorders, such as Parkinson's disease (PD), which is characterized by motor dysfunctions caused by the progressive loss of dopaminergic neurons in the substance nigra pars compacta and non-motor symptoms including gastrointestinal dysfunction. In this study, we investigated the modulatory effects of the flavonoid rutin on the behavior and myenteric plexuses in a PD animal model and the response of enteric glia. Adult male Wistar rats were submitted to stereotaxic injection with 6-hydroxydopamine or saline, and they were untreated or treated with rutin (10 mg/kg) for 14 days. The ileum was collected to analyze tissue reactivity and immunohistochemistry for neurons (HuC/HuD) and enteric glial cells (S100ß) in the myenteric plexuses. Behavioral tests demonstrated that treatment with rutin improved the motor capacity of parkinsonian animals and improved intestinal transit without interfering with the cell population; rutin treatment modulated the reactivity of the ileal musculature through muscarinic activation, reducing relaxation through the signaling pathway of nitric oxide donors, and increased the longitudinal contractility of the colon musculature in parkinsonian animals. Rutin revealed modulatory activities on the myenteric plexus, bringing relevant answers regarding the effect of the flavonoid in this system and the potential application of PD adjuvant treatment.

Rutin prevents pyroptosis and M1 microglia via Nrf2/Mac-1/caspase-1-mediated inflammasome axis to improve POCD.

BACKGROUND: Neuroinflammation following peripheral surgery plays a key role in postoperative cognitive dysfunction (POCD) development and there is no effective therapy to inflammation-mediated cognitive impairment. Recent studies showed that rutin, a natural flavonoid compound, conferred neuroprotection. However, the effects and mechanisms of rutin on cognition of surgical and aged mice and LPS-induced BV2 need deeper exploration. METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells. RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1. CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.

Rutin attenuates inflammation by downregulating AGE-RAGE signaling pathway in psoriasis: Network pharmacology analysis and experimental evidence.

BACKGROUND: Jueyin granules (JYG) is effective against psoriasis, but its utility components are not clear. Rutin is the main monomer of JYG, its therapeutic effect and mechanism on psoriasis need to be further clarified. PURPOSE: To explore the potential mechanisms of rutin on psoriasis through network pharmacology and experiments. METHODS: In vitro, cell viability was determined using the CCK8 assay, and inflammatory factors were identified using RT-qPCR. The hub genes and kernel pathways of action were identified by modular pharmacology analysis. In vivo, a BALB/c mice model of psoriasis was induced by Imiquimod (IMQ). The therapeutic effect and action pathway were detected through Western Blotting, RT-qPCR, histopathologic and immunohistochemical analysis. RESULTS: Rutin inhibited cell proliferation and expression of TNF-α and IL-6 in HaCaT cells. The hub genes include APP, INS, and TNF, while the kernel pathways contain the AGE-RAGE signaling pathway. In IMQ-induced psoriasis-like mice, rutin ameliorated skin lesions and inhibited cell proliferation. Rutin could attenuate inflammation by downregulating the AGE-RAGE signaling pathway. CONCLUSION: This study suggests that rutin can reduce IMQ-induced psoriasis like skin inflammation in mice, and regulation of AGE-RAGE signaling pathway may be one of its potential anti-inflammatory mechanisms. Rutin has a promising therapeutic use for the treatment of psoriasis.

Antilipogenesis Effect of Rutin-Loaded Liposomes Using a Microneedle Delivery System.

Rutin, a flavonoid glycoside phytochemical compound, has a remarkable antiobesity effect. However, its therapeutic potential is hindered by its poor water solubility and low oral bioavailability. In this study, rutin was loaded into liposomes (LR) through the self-assembly of lecithin and cholesterol. It was discovered that liposomes improved the water solubility and cellular uptake of rutin in adipocytes. These rutin-loaded liposomes were then incorporated into a microneedle patch (MP) system formed by polyvinylpyrrolidone and poly(vinyl alcohol), and the MP-LR showed an increased release percentage in the adipose tissue microenvironment of pH 6.5 and achieved local delivery of rutin into adipocytes. Next, the therapeutic potentials of rutin, LR, and MP-LR were investigated in a high-fat diet (HFD)-induced obese mouse model. The MP-LR formulation decreased the weight of the HFD mice the most significantly. The antilipogenesis mechanisms of MP-LR are downregulating the lipid synthesis-related proteins (PPAR γ and C/EBP α) in adipocytes and promoting the expression of the beige adipogenesis-related proteins (UCP 1 and Cyt C). The MP systems further promote the local penetration of LR into the adipose tissue specifically, which again elevates their antiobesity effect. Overall, this study suggests that MP-delivered liposome-based formulation is a promising approach to enhance the antiobesity efficacy of antilipogenesis bioactive compounds.

Rutin from Begonia roxburghii modulates iNOS and Sep A activity in treatment of Shigella flexneri induced diarrhoea in rats: An in vitro, in vivo and computational analysis.

In developing countries, diarrhoea is a major issue of concern, where consistent use of antibiotics has resulted in several side effects along with development of resistance among pathogens against these antibiotics. Since natural products are becoming the treatment of choice, therefore present investigation involves mechanistic evaluation of antidiarrhoeal potential of Begonia roxburghii and its marker rutin against Shigella flexneri (SF) induced diarrhoea in rats following in vitro, in vivo and in silico protocols. The roots of the plant are used as vegetable in the North East India and are also used traditionally in treating diarrhoea. Phytochemically standardized ethanolic extract of B. roxburghii (EBR) roots and its marker rutin were first subjected to in vitro antibacterial evaluation against SF. Diarrhoea was induced in rats using suspension of SF and various diarrhoeagenic parameters were examined after first, third and fifth day of treatment at 100, 200 and 300 mg/kg, p.o. with EBR and 50 mg/kg, p.o. with rutin respectively. Additionally, density of SF in stools, stool water content, haematological and biochemical parameters, cytokine profiling, ion concentration, histopathology and Na+/K+-ATPase activity were also performed. Molecular docking and dynamics simulation studies of ligand rutin was studied against secreted extracellular protein A (Sep A, PDB: 5J44) from SF and Inducible nitric oxide synthase (iNOS, PDB: 1DD7) followed by network pharmacology. EBR and rutin demonstrated a potent antibacterial activity against SF and also showed significant recovery from diarrhoea (EBR: 81.29 ± 0.91% and rutin: 75.27 ± 0.89%) in rats after five days of treatment. EBR and rutin also showed significant decline in SF density in stools, decreased cytokine expression, potential antioxidant activity, cellular proliferative nature and recovered ion loss due to enhanced Na+/K+-ATPase activity, which was also supported by histopathology. Rutin showed a very high docking score of -11.61 and -9.98 kcal/mol against iNOS and Sep A respectively and their stable complex was also confirmed through dynamics, while network pharmacology suggested that, rutin is quite capable of modulating the pathways of iNOS and Sep A. Thus, we may presume that rutin played a key role in the observed antidiarrhoeal activity of B. roxburghii against SF induced diarrhoea.

Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-κB pathway as a central network.

Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO4) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO4 and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-κB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfα), interleukin 6 (il6), interleukin 1ß (il1ß), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.

Rutin ameliorates nitrergic and endothelial dysfunction on vessels and corpora cavernosa of diabetic animals.

Endothelial dysfunction is an early complication of diabetes and it is related to both micro- and macroangiopathies. In addition, >70% of diabetic patients develop autonomic neuropathies. Increased oxidative stress has a major role in the development of both nitrergic and endothelial dysfunction. The aim of this work is to evaluate whether rutin, a potent antioxidant, could ameliorate nitrergic and/or endothelial dysfunction in diabetic animals. Primary and secondary treatment protocols with rutin were investigated on rat aortic rings and the mesenteric arteriolar bed, and on rabbit aortic rings and corpora cavernosa (RbCC) from both euglycemic and alloxan-diabetic animals. Acetylcholine endothelium-dependent and sodium nitroprusside endothelium-independent relaxations were compared in tissues from euglycemic or diabetic animals. Electrical field stimulation (EFS)-induced relaxation was performed only in the RbCC. Endothelial-dependent relaxations were blunted by 40% in vessels and neuronal relaxation was blunted by 50% in RbCC taken from diabetic animals when compared to euglycemic animals. Pre-treatment with rutin restored both neuronal and endothelial dependent relaxations in diabetic animals towards the values achieved in control euglycemic tissues. Rutin was able to ameliorate both endothelial dysfunction and nitrergic neuropathy in animal experimental models. Rutin could be a lead compound in the primary or secondary preventive ancillary treatment of endothelial and nitrergic dysfunction in the course of diabetes.

Lithium co-administration with rutin improves post-stroke neurological outcomes via suppressing Gsk-3ß activity in a rat model.

Cerebral ischemic stroke is one of the leading causes of adult disability worldwide. Reperfusion is the only therapeutic option with a lot of side effects. In the current study, we investigated the efficacy of rutin and lithium co-treatment in improving post-stroke neurological outcomes in a transient global cerebral ischemia-reperfusion injury rat model. Middle-aged male rats were subjected to transient global cerebral ischemia-reperfusion. NORT and Y-maze were used to assess the cognitive processes. Lipid peroxidation, protein carbonylation, and nitric oxide assays were performed to study oxidative stress. The excitotoxicity index was calculated by HPLC. Real time-PCR and western blotting were performed to study gene and protein expressions. The co-administration of rutin and lithium improved the overall survival, recognition memory, spatial working memory, and neurological score following cerebral ischemia-reperfusion in rats. Further, a marked decrease in malonaldehyde, protein carbonyls, and nitric oxide levels was observed following combined treatment. The mRNA expression of antioxidant (Hmox1 and Nqo1) and pro-inflammatory (Il2, Il6, and Il1ß) markers were significantly attenuated in the rutin and lithium co-administrated group. The treatment inhibited the Gsk-3ß and maintained a normal pool of the downstream ß-catenin and Nrf2 proteins. The results revealed that co-administration of rutin and lithium had a neuroprotective potential, suggesting it to be a viable treatment to overcome post-stroke deaths and neurological complications.

Carrier-Free Nanodrug Based on Co-Assembly of Methylprednisolone Dimer and Rutin for Combined Treatment of Spinal Cord Injury.

Spinal cord injury (SCI), which is characterized by excessive inflammatory cell infiltration and accumulation of oxidative substance, would severely impede neurological functional recovery and lead to permanent and profound neurologic deficits and even disability. Methylprednisolone (MP) is the most commonly used clinical anti-inflammatory drug for SCI treatment, but high doses are typically required that can cause severe side effects. Here, we developed a carrier-free thioketal linked MP dimer@rutin nanoparticles (MP2-TK@RU NPs) which can achieve combined SCI treatment by coassembling reactive oxygen species (ROS) cleavable MP dimers and rutin. This proposed nanodrug possesses the following favorable advantages: (1) the carrier-free system is easily accessible and has a high drug-loading capacity, which is preferred by the pharmaceutical industry; (2) The ROS-cleavable linker increases the efficiency of targeted drug delivery to the injury site; (3) Rutin, a type of plant-derived natural flavonoid with good biocompatibility, anti-inflammatory, and antioxidant properties, is codelivered to enhance the therapy outcomes. The obtained MP2-TK@RU NPs exhibited potent anti-inflammatory and antioxidative properties both in vitro and in vivo, demonstrating superior locomotor function recovery and neuroprotective efficacy in rats with SCI. This carrier-free nanodrug is anticipated to provide a promising therapeutic strategy for clinical SCI treatment.

Rutin ameliorates inflammatory pain by inhibiting P2X7 receptor in mast cells

Rutin is a natural anti-inflammatory ingredient widely found in medicinal plants. Studies have shown that rutin inhibits mast cell degranulation and the release of inflammatory mediators. Mast cell P2X7 receptor mediates mast cell degranulation and serves as a therapeutic target for inflammatory pain. Herein, the aim of this study was to investigate whether the anti-inflammatory mechanism of rutin is related to the mast cell P2X7 receptor. Our results showed that rutin could inhibit [Ca2+]i elevation induced by 5 mM ATP or 30 μM BZATP in a concentration-dependent manner in mouse peritoneal mast cells. Rutin also suppressed the inward current mediated by P2X7 receptor. In vivo, rutin could significantly inhibit the mechanical hypersensitivity induced by 100 mM ATP that is associated with P2X7 receptor in mast cells. Moreover, molecular docking revealed the high affinity between rutin and the P2X7 receptor crystal structure. Collectively, this study demonstrated that rutin attenuated inflammatory pain by inhibiting the activity of P2X7 receptor in mast cells. (AU)

Rutin, a Flavonoid Compound Derived from Garlic, as a Potential Immunomodulatory and Anti-Inflammatory Agent against Murine Schistosomiasis mansoni.

Schistosomiasis is a tropical disease caused by trematode worms. The inflammatory response of the host to schistosome eggs leads to formation of granuloma in the liver and intestine. Praziquantel (PZQ) is still an effective treatment for schistosomiasis, however resistance development may reduce its efficacy. The current study investigated the possible immunomodulatory and anti-inflammatory action of rutin, a natural flavonoid compound isolated from garlic, on liver fibrotic markers in mice infected with S. mansoni in comparison to PZQ. Male albino CD1 mice were infected with 100 ± 2 S. mansoni cercariae/mouse and treated with garlic, rutin, or PZQ. At the end of the experiment, the liver and intestines were harvested for parasitological and histological assessment and to analyze the proinflammatory cytokine. Rutin significantly affects the pathological alterations caused by Schistosoma in the liver. This may be partially explained by a decrease in the number of eggs trapped in the tissues of the liver and a modification in the serum levels of certain cytokines, which are implicated in the formation of Schistosoma granuloma. In conclusion, rutin has strong anti-schistosome properties in vivo, raising the possibility that rutin might be further investigated as a therapy for S. mansoni.

Rutin improves diabetes-induced muscle atrophy in mice.

Muscle atrophy is a common complication in diabetes mellitus. Rutin has multiple biologic and therapeutic effects both in diabetic complications and muscle functions. However, no researches have implied prevention and treatment of rutin on muscle atrophy in diabetes mellitus. Our data demonstrated that rutin increased myocyte area and weight of gastrocnemius to promote muscular strength (p<0.01). Moreover, rutin attenuated Atrogin-1 and MuRF1 expressions to improve atrophy (p<0.01). The mechanism of rutin against diabetes-associated muscle atrophy is closely linked to its regulations on decreasing Bax expression (p<0.01) and increasing Pgc-1α, Nrf-1 and Bcl-2 expression (p<0.01). In conclusion, rutin protected against diabetic myopathy through its modulation of mitochondria bioactivity and apoptosis. These data suggested rutin could be a therapeutic agent on the improvement of diabetic muscle atrophy.

Rutin alleviates colon lesions and regulates gut microbiota in diabetic mice.

Diabetes is a common metabolic disorder that has become a major health problem worldwide. In this study, we investigated the role of rutin in attenuating diabetes and preventing diabetes-related colon lesions in mice potentially through regulation of gut microbiota. The rutin from tartary buckwheat as analyzed by HPLC was administered intragastrically to diabetic mice, and then the biochemical parameters, overall community structure and composition of gut microbiota in diabetic mice were assayed. The results showed that rutin lowered serum glucose and improved serum total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride concentrations, tumor necrosis factor-α, interleukin-6, and serum insulin in diabetic mice. Notably, rutin obviously alleviated colon lesions in diabetic mice. Moreover, rutin also significantly regulated gut microbiota dysbiosis and enriched beneficial microbiota, such as Akkermansia (p < 0.05). Rutin selectively increased short-chain fatty acid producing bacteria, such as Alistipes (p < 0.05) and Roseburia (p < 0.05), and decreased the abundance of diabetes-related gut microbiota, such as Escherichia (p < 0.05) and Mucispirillum (p < 0.05). Our data suggested that rutin exerted an antidiabetic effect and alleviated colon lesions in diabetic mice possibly by regulating gut microbiota dysbiosis, which might be a potential mechanism through which rutin alleviates diabetes-related symptoms.

Therapeutic potential of rutin in male infertility: A mini review.

Male infertility has become a problem worldwide, and recent research has emphasized the development of more effective therapy options. Among natural compounds, rutin has been widely studied for its potential to treat dysfunction related to male infertility, including a reduction in sperm quality, spermatogenesis disruption and structural disruption in the testis. A thorough review of scientific literature published in several databases, including Google Scholar, PubMed/MEDLINE and Scopus, was used to synthesize the present state of research on the role of rutin in male reproductive health. Rutin has been shown to possess antiapoptotic, antioxidant and anti-inflammatory activities, among others, which are crucial in the management of male infertility. Numerous investigations have shown that rutin protects against male infertility and have explored the underlying mechanisms involved. The present review, therefore, assesses the therapeutic mechanisms involved in male infertility treatment using rutin. Rutin was able to mitigate the induced oxidative stress, apoptosis, inflammation, and related physiological processes that can cause testicular dysfunction. Please cite this article as: Rotimi DE, Elebiyo TC, Ojo OA. Therapeutic potential of rutin in male infertility: A mini review. J Integr Med. 2023; 21(2): 130-135.

The effects of rutin flavonoid supplement on glycemic status, lipid profile, atherogenic index of plasma, brain-derived neurotrophic factor (BDNF), some serum inflammatory, and oxidative stress factors in patients with type 2 diabetes mellitus: A double-blind, placebo-controlled trial.

This study aimed to investigate the effects of rutin flavonoid in type 2 diabetes mellitus (T2DM) patients. In this trial (double-blind, placebo-controlled), 50 T2DM patients (supplement, n = 25 and placebo, n = 25) were randomized and supplemented with 500 mg rutin or placebo per day for 3-months. At the beginning and at the end of the study, metabolic parameters including fasting blood glucose (FBG), insulin, glycosylated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMO-IR), quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment of ß-cell function (HOMA-ß), triglyceride (TG), total cholesterol (CHOL), high-density and low-density lipoprotein cholesterol (HDL-c and LDL-c), and atherogenic index of plasma (AIP), inflammatory and oxidative stress markers such as interleukin 6 (IL-6), total antioxidant capacity (TAC), and malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) were assessed. The results showed a significant decrease in FBG, insulin, HbA1c, HOMO-IR, LDL-c, TG, VLDL, CHOL, LDL-c.HDL-c ratio, AIP, IL-6, and MDA and a significant increase in HDL-c, QUICKI index, BDNF, and TAC compared with the initial value (p for all <.05). In the adjusted model, the mean changes of FBG, insulin, HbA1c, HOMO-IR, LDL-c, CHOL, LDL.HDL ratio, AIP, MDA, and IL-6 were significantly lower and mean changes of QUICKI index, HDL-c, and TAC were significantly higher in the rutin group compared with the placebo group (adjusted p for all <.05). It seems that rutin may have beneficial effects on improving metabolic parameters, BDNF, and inflammatory and oxidative stress factors in T2DM patients.

Ameliorating effect of rutin against diclofenac-induced cardiac injury in rats with underlying function of FABP3, MYL3, and ANP.

Diclofenac is a widely prescribed anti-inflammatory drug having cardiovascular complications as one of the main liabilities that restrict its therapeutic use. We aimed to investigate for any role of rutin against diclofenac-induced cardiac injury with underlying mechanisms as there is no such precedent to date. The effect of rutin (10 and 20 mg/kg) was evaluated upon concomitant oral administration for fifteen days with diclofenac (10 mg/kg). Rutin significantly attenuated diclofenac-induced alterations in the serum cardiac markers (LDH, CK-MB, and SGOT), serum cytokine levels (TNF-α and IL-6), and oxidative stress markers (MDA and GSH) in the cardiac tissue. Histopathological examination and Scanning Electron Microscopy (SEM) findings displayed a marked effect of rutin to prevent diclofenac-mediated cardiac injury. Altered protein expression of myocardial injury markers (cTnT, FABP3, and ANP) and apoptotic markers (Bcl-2 and Caspase-3) in the cardiac tissue upon diclofenac treatment was considerably shielded by rutin treatment. MYL3 was unaffected due to diclofenac or rutin treatment. Rutin also significantly improved diclofenac-induced gastrointestinal and hepatic alterations based on the observed ameliorative effects in key mediators, oxidative stress markers, histopathology examination, and SEM findings. Overall results suggest that rutin can protect the diclofenac-induced cardiac injury by lowering oxidative stress, inhibiting inflammation, and reducing apoptosis. Further research work directs toward the development of phytotherapeutics for cardioprotection.

Normalization of HPA Axis, Cholinergic Neurotransmission, and Inhibiting Brain Oxidative and Inflammatory Dynamics Are Associated with The Adaptogenic-like Effect of Rutin Against Psychosocial Defeat Stress.

Social defeat stress (SDS) due to changes in biochemical functions has been implicated in the pathogenesis of affective and cognitive disorders. Employing pharmacological approach with adaptogens in the management and treatment of psychosocial stress is increasingly receiving scientific attention. In this study, we investigated the neuroprotective effect of rutin, a bioflavonoid with neuroprotective and anti-inflammatory functions on neurobehavioral and neuro-biochemical changes in mice exposed to SDS. Groups of mice named the intruder mice received normal saline (10 mL/kg), rutin (5, 10, and 20 mg/kg, i.p.), and ginseng (50 mg/kg, i.p.) daily for 14 days, and then followed by 10 min daily SDS (physical/psychological) exposures to aggressor mice from days 7-14. Investigations consisting of neurobehavioral (locomotion, memory, anxiety, and depression) phenotypes, neuro-biochemical (oxidative, nitrergic, cholinergic, and pro-inflammatory cytokines) levels in discrete brain regions, and hypothalamic-pituitary-adrenal (HPA) axis consisting adrenal weight, corticosterone, and glucose concentrations were assessed. Rutin restored the neurobehavioral deficits and reduced the activity of acetylcholinesterase in the brains. Adrenal hypertrophy, increased serum glucose and corticosterone levels were significantly attenuated by rutin. SDS-induced release of tumor necrosis factor-alpha and interleukin-6 in the striatum, prefrontal cortex, and hippocampus were also suppressed by rutin in a brain-region-dependent manner. Moreover, SDS-induced oxidative stress characterized by low antioxidants (glutathione, superoxide-dismutase, catalase) and lipid peroxidation and nitrergic stress were reversed by rutin in discrete brain regions. Collectively, our data suggest that rutin possesses an adoptogenic potential in mice exposed to SDS via normalization of HPA, oxidative/nitrergic, and neuroinflammatory inhibitions. Thus, may be adopted in the management of neuropsychiatric syndrome due to psychosocial stress.

Rutin ameliorates inflammatory pain by inhibiting P2X7 receptor in mast cells.

Rutin is a natural anti-inflammatory ingredient widely found in medicinal plants. Studies have shown that rutin inhibits mast cell degranulation and the release of inflammatory mediators. Mast cell P2X7 receptor mediates mast cell degranulation and serves as a therapeutic target for inflammatory pain. Herein, the aim of this study was to investigate whether the anti-inflammatory mechanism of rutin is related to the mast cell P2X7 receptor. Our results showed that rutin could inhibit [Ca2+]i elevation induced by 5 mM ATP or 30 µM BZATP in a concentration-dependent manner in mouse peritoneal mast cells. Rutin also suppressed the inward current mediated by P2X7 receptor. In vivo, rutin could significantly inhibit the mechanical hypersensitivity induced by 100 mM ATP that is associated with P2X7 receptor in mast cells. Moreover, molecular docking revealed the high affinity between rutin and the P2X7 receptor crystal structure. Collectively, this study demonstrated that rutin attenuated inflammatory pain by inhibiting the activity of P2X7 receptor in mast cells.