Authors: Xiao-Ying Sun, Ling-Jie Li, Quan-Xiu Dong...

BACKGROUND

Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment.

METHODS

The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA.

RESULTS

We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition.

CONCLUSION

In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ.

Topics: Alzheimer Disease; Animals; Brain; Cell Culture Techniques; Disease Models, Animal; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Microglia; Microscopy, Electron, Transmission; Neuroinflammatory Diseases; Rutin; Signal Transduction; Synapses; tau Proteins

PubMed: 34116706
DOI: 10.1186/s12974-021-02182-3

Authors: Hanxin Liu, Qixia Xu, Halidan Wufuer...

Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as senomorphics. Rutin, a phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP. Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while rutin remarkably downregulated these gain-of-functions. Although classic chemotherapy reduced tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with rutin. Our study provides a proof of concept for rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including cancer.

Topics: Humans; Senotherapeutics; Rutin; Cellular Senescence; Aging; Neoplasms

PubMed: 37475161
DOI: 10.1111/acel.13921

Authors: Rui-Yuan Pan, Jun Ma, Xiang-Xi Kong...

The accumulation of aggregated amyloid-β (Aβ) in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD), which also includes synaptic impairment, neuroinflammation, neuronal loss, and eventual cognitive defects. Emerging evidence suggests that impairment of Aβ phagocytosis and clearance is a common phenotype in late-onset AD. Rutin (quercetin-3-rutinoside) has long been investigated as a natural flavonoid with different biological functions in some pathological circumstances. Sodium rutin (NaR), could promote Aβ clearance by increasing microglial by increasing the expression levels of phagocytosis-related receptors in microglia. Moreover, NaR promotes a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS (oxidative phosphorylation), which could provide microglia with sufficient energy (ATP) for Aβ clearance. Thus, NaR administration could attenuate neuroinflammation and enhance mitochondrial OXPHOS and microglia-mediated Aβ clearance, ameliorating synaptic plasticity impairment and eventually reversing spatial learning and memory deficits. Our findings suggest that NaR is a potential therapeutic agent for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Immunohistochemistry; Mice; Mice, Transgenic; Microglia; Mitochondria; Molecular Structure; Phagocytosis; Protein Aggregation, Pathological; Rutin; Sodium; Solubility

PubMed: 30820451
DOI: 10.1126/sciadv.aau6328

Review

Authors: Rebecca M D Smyth, Nasreen Aflaifel, Anthony A Bamigboye...

BACKGROUND

Pregnancy is presumed to be a major contributory factor in the increased incidence of varicose veins in women, which can in turn lead to venous insufficiency and leg oedema. The most common symptom of varicose veins and oedema is the substantial pain experienced, as well as night cramps, numbness, tingling, the legs may feel heavy, achy, and possibly be unsightly. Treatments for varicose veins are usually divided into three main groups: surgery, pharmacological and non-pharmacological treatments. Treatments of leg oedema comprise mostly symptom reduction rather than cure and use of pharmacological and non-pharmacological approaches.

OBJECTIVES

To assess any form of intervention used to relieve the symptoms associated with varicose veins and leg oedema in pregnancy.

SEARCH METHODS

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies.

SELECTION CRITERIA

Randomised trials of treatments for varicose veins or leg oedema, or both, in pregnancy.

DATA COLLECTION AND ANALYSIS

Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.

MAIN RESULTS

We included seven trials (involving 326 women). The trials were largely unclear for selection bias and high risk for performance and detection bias.Two studies were placebo-controlled trials. The first one compared a phlebotonic (rutoside) with placebo for the reduction in symptoms of varicose veins; the second study evaluated the efficacy of troxerutin in comparison to placebo among 30 pregnant women in their second trimester with symptomatic vulvar varicosities and venous insufficiency in their lower extremities. Data from this study were not in useable format, so were not included in the analysis. Two trials compared either compression stockings with resting in left lateral position or reflexology with rest for 15 minutes for the reduction of leg oedema. One trial compared standing water immersion for 20 minutes with sitting upright in a chair with legs elevated for 20 minutes. Women standing in water were allowed to stand or walk in place. One trial compared 20 minutes of daily foot massage for five consecutive days and usual prenatal care versus usual prenatal care. The final trial compared three treatment groups for treating leg oedema in pregnancy. The first group was assigned to lateral supine bed rest at room temperature, women in the second group were asked to sit in a bathtub of waist-deep water at 32 ± 0.5 C with their legs horizontal and the third group included the women who were randomised to sitting immersed in shoulder-deep water at 32 ± 0.5 C with legs extended downward. We did not include this study in the analysis as outcomes reported in the paper were not pre-specified outcomes of this review.We planned to use GRADE methods to assess outcomes for two different comparisons and assign a quality rating. However, only two out of three outcomes for one comparison were reported and could be assessed. Evidence from one trial (rutoside versus placebo) for the outcomes of reduction in symptoms and incidence of complications associated with varicose veins and oedema was assessed as of moderate quality. Rutoside versus placeboOne trial involving 69 women, reported that rutoside significantly reduced the symptoms associated with varicose veins (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.11 to 3.22; moderate quality evidence). The incidence of complications (deep vein thrombosis) did not differ significantly between the two groups (risk ratio (RR) 0.17, 95% CI 0.01 to 3.49; moderate quality evidence). There were no significant differences in side-effects (RR 1.30, 95% CI 0.23 to 7.28). Women's perception of pain was not reported in this trial. External pneumatic intermittent compression versus restOne trial, involving 35 women, reported no significant difference in lower leg volume when compression stockings were compared against rest (mean difference (MD) -258.80, 95% CI -566.91 to 49.31). Reflexology versus restingAnother trial, involving 55 women, compared reflexology with rest. Reflexology significantly reduced the symptoms associated with oedema (reduction in symptoms: RR 9.09, 95% CI 1.41 to 58.54). The same study showed a trend towards satisfaction and acceptability with the intervention (RR 6.00, 95% CI 0.92 to 39.11). Water immersion versus leg elevationThere was evidence from one trial, involving 32 women, to suggest that water immersion for 20 minutes in a swimming pool reduces leg volume (RR 0.43, 95% CI 0.22 to 0.83). Foot massage versus routine careOne trial, involving 80 women reported no significant difference in lower leg circumference when foot massage was compared against routine care (MD -0.11, 95% CI -1.02 to 0.80).No other primary or secondary outcomes were reported in the trials.

AUTHORS' CONCLUSIONS

There is moderate quality evidence to suggest that rutosides appear to help relieve the symptoms of varicose veins in late pregnancy. However, this finding is based on one study (69 women) and there are not enough data presented in the study to assess its safety in pregnancy. Reflexology or water immersion appears to help improve symptoms for women with leg oedema, but again this is based on two small studies (43 and 32 women, respectively).

Topics: Edema; Female; Humans; Immersion; Leg; Massage; Pregnancy; Pregnancy Complications, Cardiovascular; Pressure; Randomized Controlled Trials as Topic; Rutin; Stockings, Compression; Varicose Veins; Vasodilator Agents

PubMed: 26477632
DOI: 10.1002/14651858.CD001066.pub3

Authors: Sergio A de S Farias, Kelvyn M L Rocha, Érica C M Nascimento...

Understanding the role of 3CLpro protease for SARS-CoV-2 replication and knowing the potential of flavonoid molecules like rutin, myricetin, and baicalein against 3CLpro justify an investigation into their inhibition. This study investigates possible bonds and reactivity descriptors of rutin, myricetin, and baicalein through conformational and electronic properties. Density functional theory was used to determine possible interactions. Analyses were carried out through the molecular electrostatic potential, electron localization function, Fukui function descriptors based on frontier orbitals, and non-covalent interactions. A docking study was performed using a resolution of 1.55 Å for 3CLpro to analyze the interactions of rutin, myricetin, and baicalein. Scores of structures showed that rutin is the best ligand, followed by myricetin and baicalein. Docking studies showed that baicalein and rutin can establish effective interactions with residues of the catalytic dyad (Cys145 and His41), but just rutin forms a hydrogen bond. Myricetin, in turn, could not establish an effective interaction with Cys145. Baicalein interaction arose with active residues such as Arg188, Val186, Gln189, and Gln192. Interactions of rutin and myricetin with Arg188 and Gln189 were also found. A critical interaction was observed only for rutin with the hydroxyls of ring A with His41, and also for Cys145 with rings B and C, which is probably related to the highest score of rutin.

Topics: Rutin; Flavonoids; Flavanones; Molecular Docking Simulation; Protease Inhibitors; Molecular Dynamics Simulation; Antiviral Agents

PubMed: 37894797
DOI: 10.3390/ijms242015113

Review

Authors: Ivan Kreft, Mateja Germ, Aleksandra Golob...

Tartary buckwheat ( Gaertn.) is grown in eastern and central Asia (the Himalayan regions of China, Nepal, Bhutan and India) and in central and eastern Europe (Luxemburg, Germany, Slovenia and Bosnia and Herzegovina). It is known for its high concentration of rutin and other phenolic metabolites. Besides the grain, the other aboveground parts of Tartary buckwheat contain rutin as well. After the mixing of the milled buckwheat products with water, the flavonoid quercetin is obtained in the flour-water mixture, a result of rutin degradation by rutinosidase. Heating by hot water or steam inactivates the rutin-degrading enzymes in buckwheat flour and dough. The low buckwheat protein digestibility is due to the high content of phenolic substances. Phenolic compounds have low absorption after food intake, so, after ingestion, they remain for some time in the gastrointestinal tract. They can act in an inhibitory manner on enzymes, degrading proteins and other food constituents. In common and Tartary buckwheat, the rutin and quercetin complexation with protein and starch molecules has an impact on the in vitro digestibility and the appearance of resistant starch and slowly digestible proteins. Slowly digestible starch and proteins are important for the functional and health-promoting properties of buckwheat products.

Topics: Edible Grain; Fagopyrum; Phenols; Quercetin; Rutin; Seeds; Starch; Water

PubMed: 35409281
DOI: 10.3390/ijms23073923

Authors: Ebru Başaran, A Alper Öztürk, Behiye Şenel...

Quercetin (Q) and rutin (R) are well known and most studied flavonoids due to their activities in reduction of inflammation, oxidative damage, platelet aggregation and inhibition of cancer proliferation. Despite their remarkable potentials they have limited oral bioavailability due to the low water solubility. Therefore in this study inclusion complexes of Q and R with hydroxypropyl-β-cyclodextrin (HP-β-CD) were formulated to improve the aqueous solubility, antiproliferative efficacy and also antioxidant activity of the flavonoids. According to the analyses results, aqueous solubilities of Q and R were increased up to ∼630 fold and ∼55 fold, respectively. ZP values were ranged between -21.7±0.3 mV and -6.1±0.8 mV showing the anionic structure of the complexes. H-NMR analyses revealed the complex formation considering the shifts of the protons of the APIs as well as HP-β-CD. The in vitro release analyses revealed that the cumulative release of Q was decreased from 22.9 % to 18.1 and 15.2 for T9 and T 24 formulations respectively while the cumulative release of R increased from 26.8 % up to 64.5 % and 75.8 % with T14 and T24 formulations respectively. According MTT analyses results, Q showed higher antiproliferative effect in MDA-MB-231 and A549 cell lines compared to NIH-3T3 cell lines while R showed remarkable effect only on MDA-MB-231 cell lines at the end of 48 h of incubation period. A synergistic effect was observed in the formulation of combined flavonoid (Q/R) inclusion complexes and an antiproliferative effect was ordered as MDA-MB-231 > A549 > NIH-3T3. The selected complexes T9 (Q), T14 (R) and T24 (Q/R) have shown the highest antioxidant activity with 93.8 %, 65.3 % and 93.1 % respectively with DPPH analyses. In conclusion incoporation of Q, R and Q/R to HP-β-CD based inclusion complexes have great potentials with enhanced in vitro dissolution characteristics and antiproliferative effects on different types of cancer cell lines for efficient treatment of severe disorders.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Biological Availability; Quercetin; Rutin; Solubility

PubMed: 35227839
DOI: 10.1016/j.ejps.2022.106153

Authors: Ahmed I Foudah, Mohammed H Alqarni, Aftab Alam...

Mental disorders have a poor clinical prognosis and account for approximately 8% of the global burden of disease. Some examples of mental disorders are anxiety and depression. Conventional antidepressants have limited efficacy in patients because their pharmacological effects wear off, and side effects increase with prolonged use. It is claimed that herbal medicine's antioxidant capacity helps regulate people's mood and provide a more substantial pharmacological effect. With this background, the purpose of this study is to investigate the effect of rutin on reserpine-induced anxiety and depression in rats. The animals were divided into groups of six rats each: normal control (water), a depression model, a rutin-treated rat model, and an amitriptyline-treated rat model. According to the results, 14 days of treatment with rutin, once daily, showed a modest antidepressant effect. This effect was mediated by increased serotonin, norepinephrine, and dopamine levels in cortical and hippocampal regions. The antioxidant and vasodilator properties of rutin may contribute to its antidepressant properties. According to this study, rutin has shown antidepressant effects by reducing antioxidant activity and acetylcholinesterase.

Topics: Animals; Rats; Reserpine; Depression; Rutin; Serotonin; Acetylcholinesterase; Antioxidants; Antidepressive Agents; Anxiety

PubMed: 36364141
DOI: 10.3390/molecules27217313

Authors: Yeon Jae Jo, Dan Hee Yoo, In Chul Lee...

We focused on the functional components, antioxidant activity, skin-whitening, and anti-wrinkle properties of subcritical and supercritical water (SCW)-treated rutin. Rutin treatments were performed at the following temperature and pressure conditions: 200 °C/15 bar, 300 °C/100 bar, and 400 °C/250 bar. ABTS and DPPH radical scavenging activities and reducing power presented their highest values (1193.72 mg AAE/g, 728.73 mg AAE/g, and 0.65, respectively) at 300 °C/100 bar. The tyrosinase inhibitory activity of SCW-treated rutin was 21.72-60.05% at 1 mg/mL. The ethyl acetate fraction showed 14.91% melanin inhibitory activity at a concentration of 10 µg/mL compared to the α-MSH treatment group. The protein expression inhibition rates of MITF, tyrosinase, TRP-1, and TRP-2 in the ethyl acetate fractions were 14.05%, 72%, 93.05%, and 53.44%, respectively, at a concentration of 10 µg/mL, compared to the control. These results indicate that SCW treatment could be used to develop cosmetic materials and functional food with physiological activity, and that SCW-treated rutin can be used as a skin-whitening cosmetic material.

Topics: Antioxidants; Melanins; Monophenol Monooxygenase; Plant Extracts; Rutin; Water

PubMed: 36080207
DOI: 10.3390/molecules27175441

Authors: Natalia Rosiak, Judyta Cielecka-Piontek, Robert Skibiński...

The influence of ionizing radiation on the physicochemical properties of quercetin and rutin in the solid state was studied. Quercetin and rutin were irradiated with the standard recommended radiation dose (25 kGy) according to EN 522 standard. The samples were irradiated by electron beam radiation. EPR studies indicate the formation of a small number of free radicals due to irradiation. Moreover, some radicals recombined with the mean lifetime of 1200 and 93 h, and a stable radical concentration reached only 0.29 and 0.90 ppm for quercetin and rutin, respectively. The performed spectroscopic study (FT-IR) confirmed the radiostability of the flavonoids tested. Chromatographic tests (HPLC, HPLC-MS) showed that irradiation of quercetin and rutin with a 25 kGy dose did not change the physicochemical properties of the tested compounds. Degradation products were not observed. The antioxidant activities were determined by the 2,2-diphenyl-1-pycrylhydrazyl (DPPH) free radical scavenging activity assay, ABTS Radical Scavenging Assay (ABTS), Ferric Reducing Antioxidant Power Assay (FRAP), Cupric Ion Reducing Antioxidant Capacity Assay (CUPRAC). The conducted research confirmed that exposure to ionizing radiation does not change the chemical structure of tested flavonoids and their antioxidant properties.

Topics: Quercetin; Rutin; Antioxidants; Spectroscopy, Fourier Transform Infrared; Flavonoids

PubMed: 36985686
DOI: 10.3390/molecules28062713