ULK1 Mediated Autophagy-Promoting Effects of Rutin-Loaded Chitosan Nanoparticles Contribute to the Activation of NF-κB Signaling Besides Inhibiting EMT in Hep3B Hepatoma Cells.

Background: Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine. Methods: CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined. Results: Initially, UV-vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 µg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 µg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial-mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis). Conclusion: The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy.

Rutin-loaded chitosan nanoparticles alleviated Freund's adjuvant induced rheumatoid arthritis via modulating oxidative stress and inflammatory parameters in Wistar rats.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, primarily affecting the joints and with stromal tissue dysregulation causing chronic inflammation and joint destruction. Rutin is a natural flavonoid with potential therapeutic properties in chronic destructive conditions including rheumatoid diseases. In this study, the protective effects of rutin nanoformulation in an animal model of rheumatoid arthritis caused by Freund's complete adjuvant (FCA) were investigated. Sixty male rats were randomly divided into ten groups including normal, negative control, prednisolone 10 mg/kg (positive control), 3 doses of rutin (15, 30, 45mg/kg), rutin nanoparticles (15, 30, 45 mg/kg), and nanoparticle without rutin, for 28 days. Different behavioral parameters including the open field test, acetone drop test, hot plate test, Von Frey test, and inclined plane test were evaluated. Serum levels of glutathione (GSH), catalase, and nitric oxide as well as histopathological analyses were measured in different groups. Also, matrix metalloproteinase (MMP)-2 and MMP-9 activity were appraised by gelatin zymography. The injection of FCA prolonged the rats' immobility duration in comparison to the control group. Rheumatoid arthritis induction also increased nitric oxide and decreased GSH and catalase levels, while these effects were reversed in the groups that received nanoparticles containing rutin and prednisolone. Rutin nanoparticles suppressed MMP-9 and activated MMP-2. Also, this rutin drug delivery system plays a significant role in the improvement of histopathological symptoms. Considering the improvement of behavioral and tissue symptoms and the modulation of the level of inflammatory cytokines, nanoparticles containing rutin can be proposed as a suitable approach in the management of patients with rheumatoid arthritis.

Development, Characterization, and In Vitro Evaluation of Cytotoxic Activity of Rutin Loaded PCL-PEG Nanoparticles Against Skov3 Ovarian Cancer Cell.

BACKGROUND AND PURPOSE: Rutin (RUT) is one of the phenolic compounds found in the invasive plant species, Carpobrotus edulis. Several studies have confirmed numerous pharmacological properties of RUT, including antioxidant, antidiabetic, anti-inflammatory, antimicrobial and anticancer activities. As a result, the goal of this work was to make RUT-loaded PCL-PEG and test its anti-cancer effects against the Skov3 human ovarian cancer cell line. MATERIALS AND METHODS: The NPs were made using the W1/O/W2 process, and their physicochemical properties were assessed by FE-SEM, FTIR, and DLS. MTT assay were used to investigate the anti-proliferative characteristics of drug-loaded NPs. Real-time PCR was also utilized to  examine the expression levels of apoptotic genes including caspase-8, -9, -3, and Bax, as well as anti-apoptotic genes like Bcl-2. RESULTS: Cytotoxicity testing revealed that RUT-loaded PCL-PEG improved cytotoxicity in a dose- and time-dependent manner. In treated MDA-MB-231 cells with RUT-loaded PCL-PEG, there was a significant up-regulation of caspase-8, -9, -3, and Bax genes compared to treated cells with free RUT. CONCLUSION: Finally, RUT-loaded PCL-PEG NPs are recommended as ideal delivery nanocarriers for enhancing RUT's anticancer characteristics for ovarian cancer treatment.

Rutin inhibited the advanced glycation end products-stimulated inflammatory response and extra-cellular matrix degeneration via targeting TRAF-6 and BCL-2 proteins in mouse model of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is degenerative joint disorder mainly characterized by long-term pain with limited activity of joints, the disease has no effective preventative therapy. Rutin (RUT) is a flavonoid compound, present naturally. The flavonoid shows range of biological activities such as anti-inflammatory and anti-cancer effect. We screened RUT for its activity against osteoarthritis with in vivo and in vitro models of osteoarthritis. METHODS: Animal model of OA was developed using C57BL/6 mice by surgical destabilization of medial meniscus. For in vitro studies the human articular cartilage tissues were used which were collected from osteoarthritis patients and were processed to isolate chondrocytes. The chondrocytes were submitted to advanced glycation end products (AGEs) for inducing osteoarthritis in vitro. Cell viability was done by CCK-8 assay, ELISA analysis for MMP13, collage II, PGE2, IL-6, TNF-α, ADAMTS-5 and MMP-13. Western blot analysis was done for expression of proteins and in silico analysis was done by docking studies. RESULTS: Pretreatment of RT showed no cytotoxic effect and also ameliorated the AGE mediated inflammatory reaction on human chondrocytes in vitro. Treatment of RT inhibited the levels of COX-2 and iNOS in AGE exposed chondrocytes. RT decreased the AGE mediated up-regulation of IL-6, NO, TNF-α and PGE-2 in a dose dependent manner. Pretreatment of RT decreased the extracellular matrix degradation, inhibited expression of TRAF-6 and BCL-2 the NF-κB/MAPK pathway proteins. The treatment of RT in mice prevented the calcification of cartilage tissues, loss of proteoglycans and also halted the narrowing of joint space is mice subjected to osteoarthritis. The in-silico analysis suggested potential binding affinity of RT with TRAF-6 and BCL-2. CONCLUSION: In brief RT inhibited AGE-induced inflammatory reaction and also degradation of ECM via targeting the NF-κB/MAPK pathway proteins BCL-2 and TRAF-6. RT can be a potential molecule in treating OA.

Rutin loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro.

Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related mortality globally. Despite the availability of therapeutic options, the improvement in patient survival is yet to be achieved. Recent advances in natural product (e.g., Rutin) research, therapeutic nanotechnology and especially the combination of both could aid in achieving significant improvements in the treatment or management of NSCLC. In this study, we explore the anti-cancer activity of Rutin-loaded liquid crystalline nanoparticles (LCNs) in an in vitro model where we have employed the A549 human lung epithelial carcinoma cell line. The anti-proliferative activity was determined by MTT and Trypan blue assays, whereas, the anti-migratory activity was evaluated by the scratch wound healing assay and a modified Boyden chamber assay. We also evaluated the anti-apoptotic activity by Annexin V-FITC staining, and the colony formation activity was studied using crystal violet staining. Here, we report that Rutin-LCNs showed promising anti-proliferative and anti-migratory activities. Furthermore, Rutin-LCNs also induced apoptosis in the A549 cells and inhibited colony formation. The findings warrant further detailed and in-depth anti-cancer mechanistic studies of Rutin-LCNs with a focus towards a potential therapeutic option for NSCLC. LCNs may help to enhance the solubility of Rutin used in the treatment of lung cancer and hence enhance the anticancer effect of Rutin.

Prophylactic administration of podophyllotoxin and rutin combination assists the revival of radiation-induced hematopoietic suppression in lethally irradiated mice.

Hematopoietic syndrome contributes to mortality after exposure to high doses of low LET radiation. In this context, we have earlier demonstrated the potential of G-003 M (a combination of podophyllotoxin and rutin) in alleviating radiation-induced bone marrow suppression. Similarly, we here demonstrate that G-003 M protected mice from death (>83% protection) and increased the populations of CD 34 (Cluster of differentiation 34) as well as CD 117 (Cluster of differentiation 117) positive cell population and their colony forming capacity. This was accompanied with increase in the serum titre of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF). Interestingly, G-003 M lowered down the titre of fms-like tyrosine kinase (Flt-3) ligands. Our results furthermore demonstrates that G-003 M facilitated the nuclear translocation of ß-catenin and upregulated the expression of Wnt 10b. Conditioning of animal with G-003 M activated the expression of survivin, inhibited the activation of Caspase-3 in CD 34/117+ progenitor stem cells and protected the bone marrow vascularity and splenic colonies in lethally irradiated animals, which collectively promoted hemopoietic recovery in lethally irradiated mice.

Formulation and evaluation of rutin-loaded solid lipid nanoparticles for the treatment of brain tumor.

The primary requirement for curing cancer is the delivery of essential drug load at the cancer microenvironment with therapeutic efficacy. Considering this, the present study aims to formulate "Rutin"-encapsulated solid lipid nanoparticles (SLNs) for effective brain delivery across the blood-brain barrier (BBB). Rutin-loaded SLNs were fabricated by oil-in-water microemulsion technique and were characterized for their physicochemical properties. The in vivo biodistribution study of rutin-loaded SLNs was studied using Rattus norvegicus rats. Subsequently, in silico molecular docking and dynamic calculations were performed to examine the binding affinity as well as stability of rutin at the active site of target protein "epidermal growth factor receptor (EGFR)." Formulated rutin-loaded SLNs were predominantly spherical in shape with an average particle diameter of 100 nm. Additionally, the biocompatibility and stability have been proved in vitro. The presence and biodistribution of rutin in vivo after 54 h of injection were observed as 15.23 ± 0.32% in the brain, 8.68 ± 0.63% in the heart, 4.78 ± 0.28% in the kidney, 5.04 ± 0.37% in the liver, 0.92 ± 0.04% in the lung, and 11.52 ± 0.65% in the spleen, respectively. Molecular docking results revealed the higher binding energy of - 150.973 kJ/mol of rutin with EGFR. Molecular dynamic simulation studies demonstrated that rutin with EGFR receptor complex was highly stable at 30 ns. The observed results exemplified that the formulated rutin-loaded SLNs were stable in circulation for a period up to 5 days. Thus, rutin-encapsulated SLN formulations can be used as a promising vector to target tumors across BBB. Graphical abstract.

The reduction impact of monoglucosyl rutin on abdominal visceral fat: A randomized, placebo-controlled, double-blind, parallel-group.

Water soluble α-glycosylated rutin (4G-α-D-glucopyranosyl rutin, monoglucosyl rutin, MR) was used in this study to evaluate its ability to reduce abdominal visceral fat (AVF). We conducted a study examining 66 healthy Japanese men and women with a body mass index of ≥23 and <30 kg/m2  for 8 weeks. The subjects were randomly assigned to groups via computer random numbers as follows: MR200 group (MR 200 mg/day), MR400 group (MR 400mg/day), or placebo group. The primary outcome was change in the AVF area after 8 weeks of intervention. The secondary outcomes were effects of MR on total fat and subcutaneous fat of umbilical area, lipid-related markers, and subjective symptoms. The per-protocol set analysis involved 18 subjects in the placebo group (7 males and 11 females), 20 subjects in the MR200 group (8 males and 12 females), and 20 subjects in the MR400 group (8 males and 12 females). AVF area in both the MR200 and MR400 groups was reduced at week 8, with changes from the baseline (week 0) significantly higher than the placebo group. Additionally, the MR400 group reported improved subjective symptoms concerning being "worried about abdominal fat" at week 4 compared with the placebo group. These results indicate that the consumption of MR (200 and 400 mg/day) for 8 weeks reduced AVF. PRACTICAL APPLICATION: Monoglucosyl rutin, an enzymatically modified form of rutin, is a highly stable and water-soluble flavonoid widely used in food and beverages to prevent oxidation. The present clinical study demonstrated that it may improve overall health by reducing abdominal visceral fat.

Rutin loaded liquid crystalline nanoparticles inhibit lipopolysaccharide induced oxidative stress and apoptosis in bronchial epithelial cells in vitro.

Airway inflammation and infections are the primary causes of damage in the airway epithelium, that lead to hypersecretion of mucus and airway hyper-responsiveness. The role of reactive oxygen species (ROS) and their components in the pathophysiological mechanisms of airway inflammation have been well-studied and emphasized for the past several decades. Rutin, a potent bioflavonoid, is well-known for its antioxidant, anti-inflammatory, especially in bronchial inflammation. However, poor solubility and rapid metabolism have led to its low bioavailability in biological systems, and hence limit its application. The present study aims to investigate the beneficial effects of rutin-loaded liquid crystalline nanoparticles (LCNs) against lipopolysaccharide (LPS) induced oxidative damage in human bronchial epithelial cell line (BEAS-2-B) cells in vitro. LPS was used to stimulate BEAS-2-B cells, causing the generation of nitric oxide (NO) and other reactive oxygen species (ROS) that had led to cellular apoptosis. The levels of NO and ROS were detected by, Griess reagent kit and dichlorodihydrofluorescein diacetate (DCFH-DA) respectively, whereas, cell apoptosis was studied by Annexin V-FITC and PI staining. The findings revealed that rutin-loaded LCNs significantly reduced NO, ROS levels and prevented apoptosis in BEAS-2B cells. The observations and findings provide a mechanistic understanding of the effectiveness of rutin-loaded LCNs in protecting the bronchial cells against airway inflammation, thus possessing a promising therapeutic option for the management of airway diseases.

Supplementation with Whey Protein, Omega-3 Fatty Acids and Polyphenols Combined with Electrical Muscle Stimulation Increases Muscle Strength in Elderly Adults with Limited Mobility: A Randomized Controlled Trial.

Age-related sarcopenia is a progressive and generalized skeletal muscle disorder associated with adverse outcomes. Herein, we evaluate the effects of a combination of electrical muscle stimulation (EMS) and a whey-based nutritional supplement (with or without polyphenols and fish oil-derived omega-3 fatty acids) on muscle function and size. Free-living elderly participants with mobility limitations were included in this study. They received 2 sessions of EMS per week and were randomly assigned to ingest an isocaloric beverage and capsules for 12 weeks: (1) carbohydrate + placebo capsules (CHO, n = 12), (2) whey protein isolate + placebo capsules (WPI, n = 15) and (3) whey protein isolate + bioactives (BIO) capsules containing omega-3 fatty acids, rutin, and curcumin (WPI + BIO, n = 10). The change in knee extension strength was significantly improved by 13% in the WPI + BIO group versus CHO on top of EMS, while WPI alone did not provide a significant benefit over CHO. On top of this, there was the largest improvement in gait speed (8%). The combination of EMS and this specific nutritional intervention could be considered as a new approach for the prevention of sarcopenia but more work is needed before this approach should be recommended. This trial was registered at the Japanese University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN000008382).

Protective effect of rutin on mercuric chloride-induced reproductive damage in male rats.

This study investigated the effects of rutin against reproductive damage caused by toxic mercury in male rats. Thirty-five Sprague Dawley rats were used. Control group was injected with saline for 7 days. The rutin-100 group received 100 mg/kg/b.w. rutin for 7 days. Mercuric chloride (HgCl2 ) group received 1.23 mg/kg/b.w. of HgCl2 for 7 days. Mercury chloride + rutin-50 group received 50 mg/kg/b.w. rutin and HgCl2 1.23 mg/kg/b.w. for 7 days. HgCl2  + rutin-100 group received 100 mg/kg/b.w. rutin and HgCl2 1.23 mg/kg/b.w. for 7 days. It was detected that HgCl2 treatment increased malondialdehyde (MDA) levels, tumour necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) expressions, necrosis and degeneration of spermatogonium, dead and abnormal sperm percentages; tubular walls thinning; and decreased antioxidant enzyme activities and sperm motility. It was determined that rutin application reduced testicular damage caused by HgCl2 . In conclusion, rutin administration may treat HgCl2 toxicity in testes.

Role of Rutin Nanoemulsion in Ameliorating Oxidative Stress: Pharmacokinetic and Pharmacodynamics Studies.

Parkinson's disease is caused due to free radical generation in dopamine neurons leading to oxidative stress induced damage. The aim of this work was to ameliorate the free radical induced oxidative stress in rats by using TPGS (Tocopheryl polyethylene glycol 1000 succinate) loaded rutin nanoemulsion after oral administration. For this purpose, pharmacokinetic and pharmacodynamics studies were performed in albino wistar rats. Various behavioural tests (photoactometer test, rota rod, akinesia and catalepsy) and biochemical estimations for determination of GSH, TBARS and SOD were carried out. The results showed an increase in relative bioavailability of rutin after oral administration of nanoemulsion as compared to pure drug suspension. The AUC and Cmax of rutin nanoemulsion after oral administration were 1.8-fold and 1.9-fold higher than those of drug suspension respectively. Pharmacodynamic studies have shown good results with the rutin nanoemulsion than pure drug suspension. The rats treated with the rutin nanoemulsion exhibited significantly greater locomotor activity, better muscle coordination and improvement in cataleptic behaviour than the normal and haloperidol-induced rats (p < 0.001).Treatment with rutin suspension and rutin nanoemulsion helped in improving the stressed condition by increasing the levels of GSH, SOD and decrease in MDA levels in the brain. Anticancer activity was observed in a dose-dependent manner from 1 to 100 µg/ml. IC50 values for rutin suspension and rutin NE were found to be 36.7 and 25.4 µg/ml respectively. The rutin nanoemulsion has proven to be beneficial in ameliorating oxidative stress.

Anticancer Activity of Rutin and Its Combination with Ionic Liquids on Renal Cells.

The renal cell carcinoma (RCC) is the most common type of kidney cancer. Identifying novel and more effective therapies, while minimizing toxicity, continues to be fundamental in curtailing RCC. Rutin, a bioflavonoid widely found in nature, has shown promising anticancer properties, but with limited applicability due to its poor water solubility and pharmacokinetics. Thus, the potential anticancer effects of rutin toward a human renal cancer cell line (786-O), while considering its safety in Vero kidney cells, was assessed, as well as the applicability of ionic liquids (ILs) to improve drug delivery. Rutin (up to 50 µM) did not show relevant cytotoxic effects in Vero cells. However, in 786-O cells, a significant decrease in cell viability was already observed at 50 µM. Moreover, exposure to rutin caused a significant increase in the sub-G1 population of 786-O cells, reinforcing the possible anticancer activity of this biomolecule. Two choline-amino acid ILs, at non-toxic concentrations, enhanced rutin's solubility/loading while allowing the maintenance of rutin's anticancer effects. Globally, our findings suggest that rutin may have a beneficial impact against RCC and that its combination with ILs ensures that this poorly soluble drug is successfully incorporated into ILs-nanoparticles hybrid systems, allowing controlled drug delivery.

Rutin restores neurobehavioral deficits via alterations in cadmium bioavailability in the brain of rats exposed to cadmium.

Many plant foods are rich sources of rutin, a flavonoid with many biological activities and health benefits. Exposure to cadmium has been implicated in neurotoxicity and cognitive dysfunction in animal models. However, there is a dearth of information on the effect of rutin on the cadmium bioavailability in the brain of rats exposed to cadmium. Thus, the present study investigated the therapeutic efficacy of rutin in an animal model of cognitive impairment via alterations of cadmium bioavailability in cadmium-exposed rats. Animals were divided into six groups (n = 6): group 1 served as control, groups 2 and 3 are normal rats received 25 and 50 mg/kg of rutin respectively, group 4 received cadmium (5 mg/kg), while groups 5 and 6 are cadmium-exposed rats treated with 25 and 50 mg/kg rutin respectively via oral administration for 21 days. Rutin was administered 30 min after cadmium administration each day. The spatial working memory of the exposed and treated rats was assessed using Morris water maze and Y-Maze tasks. Furthermore, the residual level of cadmium ion in the brain of the rats was estimated. The cholinesterase (AChE and BChE) activities and nitric oxide level were determined. Besides, the level of oxidative stress markers (ROS and MDA) was assessed. Results revealed that rutin significantly reduced cadmium bioavailability in the brain of cadmium-exposed rats. Moreso, cadmium increased cholinesterase (AChE and BChE) activities and level of oxidative stress markers in the brain, with a concomitant decrease in nitric oxide level. However, treatment with rutin decreased cholinesterase activities and the level of oxidative stress markers in cadmium-exposed rats. Also, rutin improved spatial working memory and learning processes as revealed by Morris water maze and Y-Maze tasks. Conclusively, rutin could be considered to possess cognitive-enhancing properties possibly through alterations of cadmium bioavailability in the brain of cadmium-exposed rats.

Remarkable rutin-rich Hypericum capitatum extract exhibits anti-inflammatory effects on turpentine oil-induced inflammation in rats.

BACKGROUND: Natural extracts with beneficial biological activities are nowadays of high interest, in various treatment or prophylaxis. Hypericum capitatum has been known for its curative effects for centuries and its extracts have become of interest due to their distinct activity among other Hypericaceae members. In this study, further light is aimed to be shed on the secondary-metabolites composition of H. capitatum extracts, using chromatographic techniques and Electron paramagnetic resonance profiles in alkaline medium. Considering that no previous works explored the anti-inflammatory activity of H. capitatum, here, an in vivo study is also designed in order to evaluate this property by assessing the impact of one of H. capitatum extracts in ameliorating turpentine oil-induced inflammation on rats and to quantify their blood antioxidants level. METHODS: Chromatographic techniques and Electron paramagnetic resonance spectroscopy were used in order to describe the chemical profile in different parts of the plant. The in vivo study on turpentine-oil induced inflammation in rats included three doses of H. capitatum extract expressed in rutin concentration. Oxidative stress was measured using total oxidative status, total antioxidant capacity, oxidative stress index, 3-nitrotyrosine, nitric oxide, malondialdehyde, superoxide dismutase, catalase and the inflammatory response was evaluated by performing a complete blood cells count and C reactive protein. RESULTS: The extract was remarkably rich in rutin; however, other polyphenolic-like minor components appeared important in explaining the observed biological properties. The tested extract prevents the increase of inflammation-induced white blood cell count, number of neutrophils, and serum nitric oxide, and did so in a dose-dependent manner, similarly to the positive control-diclofenac. In addition, the same extract appeared to be a good alternative to diclofenac to restore total oxidative status, thiobarbituric active reactive species, total proteins and C reactive proteins. Moreover, antioxidant enzymes such as catalase, superoxide dismutase and total serum thiol concentration were significantly increased by the tested extract. CONCLUSIONS: Due to its powerful reservoir rich in rutin, H. capitatum extract depicted its in vivo antioxidant and anti-inflammatory effects indicating it to be a good alternative to conventional drugs for oxidative stress protection.

Design, In Silico Modelling, and Functionality Theory of Novel Folate Receptor Targeted Rutin Encapsulated Folic Acid Conjugated Keratin Nanoparticles for Effective Cancer Treatment.

OBJECTIVE: Site-specific and toxic-free drug delivery, is an interesting area of research. Nanoengineered drug delivery systems possess a remarkable potential for effective treatment of various types of cancers. METHODS: In this study, novel Folic Acid (FA) conjugated keratin nanoparticles (NPs) were assembled with encapsulation and delivery of Rutin (Rt) into breast cancer cells through the overexpressed folate receptor. The biocompatible, Rt encapsulated FA conjugated keratin NPs (FA@Ker NPs) were successfully formulated by a modified precipitation technique. Their morphological shape and size, size distribution, stability, and physical nature were characterized and confirmed. The drug (Rt) encapsulation efficiency, loading capacity and release kinetics were also studied. RESULTS: The observed results of molecular docking and density functionality theory of active drug (Rt) showed a strong interaction and non-covalent binding of the folate receptor and facilitation of endocytosis in breast cancer cells. Further, in vitro cytotoxic effect of FA@Ker NPs was screened against MCF-7 cancer cells, at 55.2 µg/mL of NPs and found to display 50% of cell death at 24h. Moreover, the NPs enhanced the uptake of Rt in MCF-7 cells, and the apoptotic effect of condensed nuclei and distorted membrane bodies was observed. Also, NPs entered into the mitochondria of MCF-7 cells and significantly increased the level of ROS which led to cell death. CONCLUSION: The developed FA@Ker NPs might be a promising way to enhance anti-cancer activity without disturbing normal healthy cells.

Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin.

Parkinson's disease (PD) is a common neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years. While treatment options for PD are limited, reports show that plant-derived bioactive compounds such as rutin possess numerous pharmacological benefits, including antioxidant and antiapoptotic activities. This study aimed to investigate the potential role of rutin in MPP+-treated SH-SY5Y neuroblastoma cells, an established cell model of PD. Our findings reveal increased concentrations of Ca2+ and endoplasmic reticulum (ER) stress as well as impaired mitochondrial membrane potential and bioenergetic status in SH-SY5Y cells treated with MPP+ only. This is demonstrated by a significant reduction in the expression levels of BiP, significantly reduced basal respiration, maximal respiration, and spare respiratory capacity as well as a significant increase in the expression levels of CHOP; however, these effects were significantly attenuated following pretreatment with rutin. Also, rutin significantly improved basal and compensatory glycolysis as a response to an impaired oxidative phosphorylation system triggered by MPP+, characterized by deficient ATP production. In conclusion, our findings provide the first evidence on the ability of rutin to maintain Ca2+ homeostasis, inhibit ER stress, and protect the mitochondria in MPP+-treated SH-SY5Y cells.

SPF enhancement provided by rutin in a multifunctional sunscreen.

Unprotected chronic exposure to solar radiation can contribute to premature skin cancer and sunscreens are a key factor to avoid those detrimental effects. Currently, there is a growing interest in the photoprotector and antioxidant potential of bioactive substances, such as rutin, that could increase the sun protection factor (SPF) value and, also, donate multifunctional characteristics to sunscreens. Recent in vitro findings indicated that rutin, when incorporated into sunscreens, can provide antioxidant activity and SPF improvement. However, clinical studies are fundamental to determine this activity, due to the lack of repeatability of in vitro methodology and low correlation with the in vivo data. We aimed at evaluating the clinical safety and in vivo SPF of rutin by comparing sunscreen formulations containing 0.1% (w/w) rutin, 3.0% (w/w) butyl methoxydibenzoylmethane and 8.0% (w/w) octyl dimethyl PABA (2-ethylhexyl 4-(dimethylamino)benzoato) with a similar bioactive-free preparation. Additionally, skin hydration, in vitro SPF and in vitro antioxidant activity of rutin, in association with the ultraviolet (UV) filters, were investigated. The safety profile of the formulations under sun-exposed skin conditions qualified the formulas for clinical efficacy assays. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) test confirmed the antioxidant properties of rutin, revealing around 40% increase in radical scavenging potential when the bioactive compound was present. Rutin in combination with the UV filters robustly elevated the clinical SPF around 70%, when compared with the bioactive-free formulation. To date, this is the first report in the specialized literature of an in vivo SPF measurement of a rutin-containing photoprotective preparation, supporting the claim that rutin is an effective and safe bioactive compound to be used in multifunctional sunscreens.

The effect of rutin on cisplatin-induced oxidative cardiac damage in rats.

OBJECTIVE: Cisplatin is an anticancer drug used for treating childhood solid tumors. Symptoms related to cisplatin-induced cardiovascular adverse effects may be mild or severe. Rutin (vitamin P1) has many properties, including as antioxidant, anticancer, antidiabetic, antimicrobial, antiulcer, and tissue renewal properties. Therefore, we aimed to biochemically, histopathologically, and immunohistochemically demonstrate the effect of rutin on cisplatin-induced cardiotoxicity in rats. METHODS: The rats included in our study were divided into four groups: Healthy group (HE), 5-mg/kg cisplatin group (CP), 50 mg/kg rutin+5-mg/kg cisplatin (CR-50), 100-mg/kg rutin+5-mg/kg cisplatin (CR-100) group. RESULTS: CP group administered cisplatin had significantly increased blood, serum, and cardiac tissue malondialdehyde (MDA), interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), troponin I, creatine kinase (CK), and CK-MB levels compared to the HE group, whereas there was a significant decrease in the total glutathione (tGSH) levels. Rutin was observed to prevent the increase in MDA, IL-1ß, TNF-α, troponin I, CK, and CK-MB levels as well as prevent the decrease in tGSH levels more significantly when administered at a 100-mg/kg dose than at a 50-mg/kg dose. Histopathologically, cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte, edema, and cells with pyknotic nuclei were observed in the CP group. Rutin was shown to prevent cisplatin-induced cardiac damage more effectively when used at a100-mg/kg dose than at a 50-mg/kg dose. CONCLUSION: These results suggest that rutin is useful for preventing cisplatin-related cardiovascular damage.

Protective effects of rutin on lipopolysaccharide-induced heart injury in mice.

Rutin has a wide range of beneficial health properties in the amelioration of multi-organ injury owing to its various biological effects. The aim of this study was to investigate the effects of rutin on lipopolysaccharide (LPS)-induced heart injury and clarify its potential cardioprotective mechanism. The mouse model of heart injury was intraperitoneal infection with LPS, and rutin was orally administered for 8 consecutive days. One day after LPS injection, heart histopathology, cardiac marker enzymes and cardiac fibrosis related genes were determined to evaluate the cardioprotective effects of rutin. In addition, oxidative parameters and inflammatory cytokines were tested to explore its possible underlying mechanism. The presented results showed that rutin significantly improved morphological changes of myocardium and relieved cardiac marker enzymes [creatine kinase (CK) and lactate dehydrogenase (LDH)] level to protect heart in LPS-induced sepsis. And more, rutin observably mitigated fibrosis related genes [matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9)] expression in the heart to prevent against LPS-induced cardiac fibrosis. In addition, rutin markedly increased antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] activity, and improved oxidative production [malondialdehyde (MDA) and H2O2] level to balance the oxidation and anti-oxidation systems in the heart. Lastly, rutin dramatically ameliorated [tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)] activity to restrain inflammatory responses in the heart. In conclusion, rutin possessed anti-oxidant and anti-inflammatory properties to improve LPS-induced heart injury, which suggested rutin could be used as a potential cardioprotective medicine in sepsis.