Short-Term Effects of Supplemental L-Arginine, Diosmin, Troxerutin, and Hesperidin in Diabetic Patients: A Pilot Study.

BACKGROUND AND AIMS: Inflammatory, oxidative stress, and endothelial dysfunction play a key role in the pathogenesis of long-term cardiovascular complications in patients with diabetes. The present observational prospective study is aimed at evaluating the effects of micronutrients and phytochemicals contained in the dietary supplement Flebotrofine® (AMNOL Chimica Biologica) on biochemical markers of inflammation, endothelial dysfunction, and glycemic control in patients with diabetes. METHODS: 105 type 1 or type 2 diabetes patients regularly took a daily dose of the dietary supplement Flebotrofine® for three consecutive months, and haematological and biochemical parameters were checked at baseline, after three months of treatment, and one month after its suspension. Statistical comparison of the laboratory parameters was performed using the two-tailed ANOVA test for repeated samples with a statistical significance level set at p < 0.05. RESULTS: The daily use of Flebotrofine® did not change the glycemic metabolic compensation of enrolled patients. After three months of regular Flebotrofine® intake, the plasma levels of the antioxidant ß-carotene and of arginine were significantly higher compared with the baseline values, with a decrease in the ADMA/arginine ratio. In contrast, apolipoprotein B, ApoB/ApoA1 ratio, and platelet and leukocyte counts significantly dropped. CONCLUSION: The daily use of Flebotrofine® might be a valid supplement of arginine, the precursor of NO, and essential in the prevention of endothelial dysfunction. The regular intake of arginine and phytochemicals also improved the antioxidant and antithrombotic profile of enrolled patients. Therefore, Flebotrofine® could be a useful dietary supplement to prevent long-term complications in patients with diabetes.

Neuroprotective effects of troxerutin and cerebroprotein hydrolysate injection on the neurovascular unit in a rat model of Middle cerebral artery occlusion.

Purpose: Cerebral ischemic stroke, caused by obstruction of the blood flow to the brain, initiates a complex cascade of pathophysiological changes. The aim of the present study was to assess the protective role and the underlying mechanism of troxerutin and cerebroprotein hydrolysate (TCH) injections for five days in rats subjected to middle cerebral artery occlusion (MCAO).Materials and Methods: Male Sprague-Dawley rats treated with either TCH or a vehicle (0.9% saline) via intraperitoneal injection were examined one or three days after MCAO.Results: TCH alleviated neurological deficits and reduced infarct volume, innate immune response, blood-brain barrier destruction, and suppressed cell apoptosis. The therapeutic effects of TCH were achieved by diminished neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), and increased endothelial nitric oxide synthase (eNOS). Furthermore, L-NAME showed an inhibitory effect against TCH after MCAO on eNOS expression, NO and peroxynitrite production, neurobehavioral score, and infarct volume.Conclusions: The results indicate that injection of TCH has multifaceted neuroprotective effects against MCAO via regulation of the various NOS isoforms.

Troxerutin protects against DHT-induced polycystic ovary syndrome in rats.

The exact pathogenesis of polycystic ovary syndrome (PCOS), the most common neuroendocrine disorder in women of reproductive age, has not been fully elucidated. Recent studies suggested that chronic inflammation and neurotransmitter disorder involved in the progress of PCOS. Troxerutin, a natural flavonoid, was reported to possess neuroprotective effect in several disease models by inhibiting inflammation or enhancing neurotrophic factor. In this study, we investigated the possible protective effect and mechanism of troxerutin in a dihydrotestosterone (DHT)-induced rat model of PCOS. The PCOS rat models were treated with troxerutin at a dose of 150 mg/kg or 300 mg/kg for up to 4 weeks. Results showed that 300 mg/kg troxerutin significantly decreased the body weight gain and improved the pathological changes of ovary induced by DHT. Meanwhile, the elevated gonadotrophin-releasing hormone (GnRH), gonadotrophin and testosterone in the serum of PCOS rats were reduced with the treatment of troxerutin. The expression of kisspeptin and NKB in arcuate nucleus and their receptors kiss1r and NK3r in GnRH positive neurons of median eminence were markedly decreased in troxerutin-treated rats. Of note, the GnRH inhibitory regulator GABA and stimulatory regulator glutamate were also restored to the normal level by troxerutin. The present study indicated that troxerutin may exhibit a protective effect in PCOS rat model via regulating neurotransmitter release.

Can troxerutin pretreatment prevent testicular complications in prepubertal diabetic male rats?

OBJECTIVE: The vast majority of type 1 diabetes leads to a higher prevalence of reproductive system's impairments. Troxerutin has attracted much attention owing to its favorable properties, including antihyperglycemic, anti-inflammatory, and antiapoptotic effects. This investigation was proposed to evaluate whether pretreatment with troxerutin could prevent apoptosis-induced testicular disorders in prepubertal diabetic rats. METHODS: Fifty prepubertal male Wistar rats were randomly allocated into five groups: control (C), troxerutin (TX), diabetic (D), diabetic+troxerutin (DTX), and diabetic+insulin (DI). Diabetes was induced by 55 mg/kg of streptozotocin applied intraperitoneally. In TX and DTX groups, 150 mg/kg troxerutin was administered by oral gavage. Diabetic rats in DI group received 2-4 U NPH insulin subcutaneously. Troxerutin and insulin treatments were begun immediately on the day of diabetes confirmation. After 30 days, the testicular lipid peroxidation and antioxidant activity, apoptosis process, and stereology as well as serum glucose and insulin levels were assessed. RESULTS: The results showed that diabetes caused a significant increase in the blood glucose, the number of TUNEL positive cells and tubules, and the malondialdehyde level as well as a significant decrease in serum insulin level compared to controls. The stereological analysis also revealed various alterations in diabetic rats compared to controls. Troxerutin treatment improved these alterations compared to the diabetic group. CONCLUSION: Troxerutin-pretreatment may play an essential role in the management of the type-1 diabetes-induced testicular disorders by decreasing blood glucose and modulating apoptosis.

Troxerutin downregulates C/EBP-ß gene expression via modulating the IFNγ-ERK1/2 signaling pathway to ameliorate rotenone-induced retinal neurodegeneration.

Troxerutin, a natural flavonoid guards against oxidative stress and apoptosis with a high capability of passing through the blood-brain barrier. Our aim was to investigate the role of troxerutin in experimentally induced retinal neurodegeneration by modulating the interferon-gamma (IFNγ)-extracellular signal-regulated kinases 1/2 (ERK1/2)-CCAAT enhancer-binding protein ß (C/EBP-ß) signaling pathway. Three groups of rats (10 each group) were included. Group I (control group), group II (rotenone treated group): the rats were injected subcutaneously with a single rotenone dosage of 3 mg/kg repeated every 48 hours for 60 days to trigger retinal neurodegeneration. Group III (troxerutin-treated group): rats received troxerutin (150 mg/kg/day) by oral gavage 1 hour before rotenone administration. A real-time polymerase chain reaction technique was applied to measure messenger RNA (mRNA) levels of retinal C/EBP-ß. Enzyme-linked immunosorbent assay technique was utilized to assay tumor necrosis factor-α (TNF-α), IFNγ, and ERK1/2 levels. Finally, reactive oxygen species (ROS), as well as carbonylated protein (CP) levels, were assessed spectrophotometrically. Improved retinal neurodegeneration by downregulation of C/EBP-ß mRNA gene expression, also caused a significant reduction of TNF-α, IFNγ, ERK1/2 as well as ROS and CP levels compared with the diseased group. These findings could hold promise for the usage of troxerutin as a protective agent against rotenone-induced retinal neurodegeneration.

Troxerutin suppresses the inflammatory response in advanced glycation end-product-administered chondrocytes and attenuates mouse osteoarthritis development.

As a chronic degenerative joint disease, osteoarthritis (OA) is clinically characterized by a high incidence, long-term pain, and limited joint activity but without effective preventative therapy. Troxerutin (Tx) is a natural flavonoid, also called vitamin P4, which is widely present in plants consumed as part of our daily diet, such as cereals, various fruits and vegetables, tea, and coffee, and possesses various biological activities, especially an anti-inflammatory effect. Here, we aimed to investigate the potential chondroprotection of Tx in experimental OA development. In in vitro studies, human chondrocytes were isolated and exposed in advanced glycation end-products (AGEs) to simulate OA development. It was found that Tx pretreatment inhibited the AGE-induced production of pro-inflammatory factors in chondrocytes, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Meanwhile, AGE-medicated extracellular matrix (ECM) degradation was decreased in Tx-pretreated chondrocytes. Furthermore, we found that Tx pretreatment suppressed the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in AGE-exposed chondrocytes. In vivo, Tx treatment prevented the narrowing of the joint space, the calcification of cartilage, and the loss of proteoglycans in the mouse OA model. In brief, Tx is considered as a potential therapeutic agent for OA.

Troxerutin down-regulates KIM-1, modulates p38 MAPK signaling, and enhances renal regenerative capacity in a rat model of gentamycin-induced acute kidney injury.

Gentamycin is an aminoglycoside antibiotic that is widely employed for controlling Gram negative bacterial infections including that caused by the antibiotic-resistant Pseudomonas species. The clinical use of gentamycin is substantially limited by its side effects particularly acute kidney injury (AKI). The aim of the current study was to investigate the protective effect of the plant flavonoid troxerutin (150 mg kg-1 day-1 for 15 days) against gentamycin-induced AKI using Wistar rats as an experimental mammalian model. The results of the present work revealed that troxerutin significantly improved renal function as demonstrated by the increase in the glomerular filtration rate and the decrease in the levels of urinary albumin, urinary albumin to creatinine ratio, serum creatinine, and blood urea nitrogen (p < 0.001). In addition, troxerutin significantly attenuated gentamycin-induced renal tissue injury as indicated by the decreased protein expression of the renal tubular injury marker KIM-1, the attenuation of the renal histopathological changes, and the modulation of the oxidative stress markers as reflected by the decrease in the levels of lipid and protein oxidative modifications and the increase in the levels of reduced glutathione and total antioxidant capacity (p < 0.001). Furthermore, troxerutin down-regulated the levels of inflammatory cytokines (IL-10, TNF-α, and IL-6), attenuated apoptotic cell death, and enhanced the renal tissue regenerative capacity as demonstrated by the increase in the protein expression of the proliferating cell nuclear antigen, PCNA (p < 0.001). Collectively, the results of the current study highlight, for the first time, the ameliorating effects of troxerutin against gentamycin-induced AKI in rats that is potentially mediated via the modulation of p38 MAPK signaling as well as via antioxidant, anti-inflammatory and anti-apoptotic activities.

Troxerutin subdues hepatic tumorigenesis via disrupting the MDM2-p53 interaction.

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide that lacks proper medical prognosis and treatment. In the present study, the anti-tumoral potential of troxerutin (TX), an ethnomedicine, was examined in relation to its effects on the promoter 2-acetylaminofluorene (2-AAF) in N-nitrosodiethylamine (NDEA) initiated HCC, as compared to its effects on HCC induced by NDEA alone. Liver samples from each experimental group were collected and evaluated for histological, biochemical and cellular characterization. The protein expressions of apoptotic and cell proliferation markers were determined via immunohistochemistry and western blotting. Molecular docking was also performed to delineate the inhibitory mechanism of TX on HCC. The results show that only higher doses of TX showed a significant reduction in the incidence of hepatic nodule formation, and they also counteracted NDEA plus 2-AAF induced alterations in the enzymic status. The frequencies of glutathione-S-transferase and proliferating cell nuclear antigen, markers of S phase progression, were markedly reduced during TX treatment. TX also modulated the imbalance in the MDM2-p53 interaction. The molecular docking results confirmed the interaction of TX with the upstream kinases that regulate apoptosis. This study provides evidence that a copious dose of TX is required to counteract the differential mitoinhibitory effect of 2-AAF in NDEA initiated hepatomas, and TX exhibits an anti-tumoral effect via suppressing oxidative stress, regulating liver function enzymes, inhibiting inflammatory responses and modulating MDM2-p53 interactions, thus inducing apoptosis, and thereby suggesting that TX may provide promising therapeutic effects for the chemoprevention of HCC.

Flavonoid mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) in the treatment of I-III degree hemorroidal disease: a double-blind multicenter prospective comparative study.

PURPOSE: We evaluated the efficacy of new flavonoids mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) to reduce bleeding from I-III degrees hemorrhoidal disease in the short and medium time. METHODS: One hundred fifty-four consecutive patients with hemorrhoidal disease recruited in four colorectal units were enrolled to the study. Exclusion criteria were allergy to the flavonoids, inflammatory bowel disease, obstructed defecation syndrome, pregnancy and puerperium, associated anal disease or hemorrhoidal thrombosis, proctologic surgical procedures within 1 year before recruitment, contemporary cancer or HIV, previous pelvic radiotherapy, patients receiving oral anticoagulant therapy, or contemporary administration of other therapy for hemorrhoids. Patients with inability to understand the study or mental disorders were also excluded. RESULTS: Seventy-eight were randomized to receive the mixture of diosmin, troxerutin, rutin, hesperidin, and quercetin (study group, SG), and 76 a mixture of diosmin in combination with hesperidin, diosmetin, isoroifolin, and linarin in purified micronized fraction (control group, CG). Bleeding, number of pathological piles, and Golligher's grade were assessed at each scheduled visit and compared using the Chi-square test. During the study period, bleeding improved after 1 and 6 months both in the SG (79.5 and 70.5%) and in the CG (80.2 and 75%) without significant differences between two groups. Satisfaction degree after 6 months was greater in the patients of the SG (4.05) towards the CG (3.25): this result was statistical significant (p 0.003). CONCLUSIONS: Use of flavonoids mixture (diosmin, troxerutin, rutin, hesperidin, quercetin) is a safe and effective mean of managing bleeding from hemorrhoidal disease and minimal adverse events are reported.

Troxerutin cerebroprotein hydrolysate injection ameliorates neurovascular injury induced by traumatic brain injury - via endothelial nitric oxide synthase pathway regulation.

BACKGROUND: Neurovascular dysfunction caused by traumatic brain injury (TBI) is characterized by cerebralvascular damage, blood-brain barrier (BBB) breakdown, brain edema, etc. This study was designed to assess the protective role of 5 days troxerutin cerebroprotein hydrolysate (TCH) injection treatment against TBI, as well as the potential mechanism. METHODS: The weight-drop model of TBI in male Sprague-Dawley rats was chosen to induce TBI model, rats either with TCH or a vehicle via intraperitoneal injection were examined 3 days after TBI. RESULTS: TCH resulted in alleviation of neurological deficits, reduction of infarct volume, improvement of regional cerebral blood flow (rCBF), amelioration of neuronal death, astrocyte proliferation, endothelial cell loss, and BBB dysintegrity. These effects of TCH treatment against TBI were through endothelial nitric oxide synthase (eNOS) coupling/decoupling status adjustment, which not only increased nitric oxide (NO) level, but also decreased peroxynitrate level expression. CONCLUSIONS: All the results indicated that TCH injection has multifaceted protective effects of neurovascular unit (NVU) against TBI via eNOS pathway regulation.

The efficiency of O-(beta-hydroxyethyl)-rutosides in reducing the incidence of superficial venous insufficiency in patients with calf muscle pump dysfunction.

Objective We aimed to evaluate the efficiency of O-(beta-Hydroxyethyl)-rutosides (Oxerutin) in reducing the incidence of venous system disease among patients with calf muscle pump dysfunction secondary to immobilization due to lower-limb fractures. Methods A total of 60 patients with lower-limb fractures and immobilized in plaster casts were included in this study randomized into control (n = 30; mean: 30.37 ± 6.03 years; 73.3% males; no treatment) and experiment (n = 30; mean: 31.67 ± 4.76 years; 66.6% males; Oxerutin, 500 mg po q12hr) treatment groups. Doppler ultrasound was performed to evaluate the effect of oxerutin on the alterations in the venous circulation. Results Patients in the control group were determined to be more commonly affected from the below-knee immobilization in terms of venous dysfunction in the great saphenous vein in the below-knee region when compared with the patients in the oxerutin treatment group (46.7 vs. 13.3%, respectively; p = 0.011). Incidence of reflux in the small saphenous vein was more common in the control group during the healing period when compared with the experiment group (40.0 vs. 10.0%, respectively; p = 0.017). None of the patients developed venous thrombosis. Conclusions In conclusion, the impairment of the lower extremity muscle pump should be considered as an important risk factor for venous disease, and should be evaluated. O-(beta-Hydroxyethyl)-rutosides during 6-8 week cast immobilization for a lower limb fracture may be an effective prophylactic regimen in reducing the incidence of reflux in the below-knee superficial veins.

Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice.

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.

Development and in vitro-in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin.

OBJECTIVE: The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability. METHODS: The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7 mg/kg) in male Wistar rats. RESULTS: The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20 nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution. CONCLUSION: These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.

Phosphorylation of GSK-3ß and reduction of apoptosis as targets of troxerutin effect on reperfusion injury of diabetic myocardium.

Diabetes has various interactions with ischemic heart diseases. Troxerutin, a flavonoid, owns outstanding pharmacological potentials in cardiovascular medicine. The purpose of this study was to investigate the effects of troxerutin on phosphorylation of GSK-3ß protein and apoptosis induced by myocardial ischemia-reperfusion injury in healthy and diabetic hearts. Male Wistar rats (n=36, 250-300 g) were randomly divided into four groups: healthy, diabetic, healthy-troxerutin and diabetic-troxerutin. Diabetes was induced by a single injection of streptozotocin (50 mg/kg; ip) and the diabetic period was lasted for ten weeks. Six weeks after induction of diabetes, troxerutin-treated groups received 150 mg/kg/day troxerutin by oral gavage for 4 weeks. The rats' hearts were transferred to the Langendorff apparatus and then subjected to 30 min regional ischemia followed by 45 min reperfusion. Supernatants of the left ventricle were used to measure the levels of cardiac troponin-I (cTnI) by ELISA, total and phosphorylated form of GSK-3ß by western blotting and tissue apoptosis by TUNEL assay. Troxerutin administration significantly decreased the cTnI levels in healthy and diabetic groups, as compared to the corresponding controls (P<0.05). In addition, troxerutin significantly increased the level of phosphorylated form and the ratio of phosphorylated to total form of GSK-3ß in diabetic and control groups (P<0.05). Tissue apoptosis level and apoptotic index also showed a significant decrease after administration of troxerutin in control and diabetic groups (P<0.05). The findings indicated that the attenuation of GSK-3ß activity and subsequent reduction of apoptosis by troxerutin play significant roles in its cardioprotection on reperfusion injuries.

Troxerutin reverses fibrotic changes in the myocardium of high-fat high-fructose diet-fed mice.

A previous study from our laboratory showed that troxerutin (TX) provides cardioprotection by mitigating lipid abnormalities in a high-fat high-fructose diet (HFFD)-fed mice model of metabolic syndrome (MS). The present study aims to investigate the reversal effect of TX on the fibrogenic changes in the myocardium of HFFD-fed mice. Adult male Mus musculus mice were grouped into four and fed either control diet or HFFD for 60 days. Each group was divided into two, and the mice were either treated or untreated with TX (150 mg/kg bw, p.o) from the 16th day. HFFD-fed mice showed marked changes in the electrocardiographic data. Increased levels of myocardial superoxide, p22phox subunit of NADPH oxidase, transforming growth factor (TGF), smooth muscle actin (α-SMA), and matrix metalloproteinases (MMPs)-9 and -2, and decreased levels of tissue inhibitors of MMPs-1 and -2 were observed. Furthermore, degradation products of troponin I and myosin light chain-1 were observed in the myocardium by immunoblotting. Rise in collagen was observed by hydroxyproline assay, while fibrotic changes were noticed by histology and Western blotting. Hypertrophy of cardiomyocytes and myocardial calcium accumulation were also observed in HFFD-fed mice. TX treatment exerted cardioprotective and anti-fibrotic effects in HFFD-fed mice by improving cardiac contractile function, reducing superoxide production and by favorably modifying the fibrosis markers. These findings suggest that TX could be cardioprotective through its antioxidant and antifibrogenic actions. This new finding could pave way for translation studies to human MS.

Flavonoids mixture (diosmin, troxerutin, hesperidin) in the treatment of acute hemorrhoidal disease: a prospective, randomized, triple-blind, controlled trial.

BACKGROUND: The role of a mixture of phlebotonics in the treatment of acute hemorrhoid crisis is investigated to test their efficacy. METHODS: One hundred and thirty-four consecutive patients with an acute hemorrhoidal crisis recruited in five colorectal units entered the study. Sixty-six of them were randomized to receive a mixture of diosmin, troxerutin and hesperidin (group A), and 68 a placebo (group B). The main symptoms, the use of oral painkillers and the Bristol scale score were recorded at each scheduled visit and compared using both Student's t test for independent samples and the ANOVA models for repeated measures. The presence of edema, prolapse and thrombosis were also recorded and compared using the Chi-square test. Furthermore, the trend of proportions during the time of the evaluations was assessed by the Chi-square test for linear trend. RESULTS: Pain, bleeding and the proportion of patients who reported persistence of edema and thrombosis decreased significantly after 12 days of treatment in group A. After 6 days, the number of paracetamol tablets taken by patients in group A was significantly lower than the amount of flavonoid mixture. CONCLUSIONS: The use of a mixture of diosmin, troxerutin and hesperidin is a safe and effective mean of managing symptoms of acute hemorrhoidal disease. Furthermore, in patients receiving treatment, there was faster control and lower persistence of edema and thrombosis.

A systematic review of the efficacy and tolerability of hydroxyethylrutosides for improvement of the signs and symptoms of chronic venous insufficiency.

WHAT IS KNOWN AND OBJECTIVE: Rutoside (rutin; quercetin rutinoside) is a glycoside found in various plant products, including apples, citrus fruits and cranberries. Hydroxyethylrutosides (HR) are semisynthetic derivatives sold as standardized products for the treatment of chronic venous insufficiency (CVI). Commercially available products include Relvène(®) (France), Venoruton(®) (Switzerland) and Paroven(®) (United Kingdom). However, the evidence for their efficacy is inconclusive. The aim of this systematic review was to evaluate the evidence of efficacy and tolerability of hydroxyethylrutosides for CVI. METHODS: We searched electronic databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and publisher databases, conference proceedings and references lists for randomized controlled trials published in English and non-English languages. We also performed hand searches for additional trials. We included all trials that assessed the effectiveness of HR for CVI. Comparisons include HR (with or without compression bandaging) vs. placebo (with or without compression bandaging) or HR vs. compression bandaging alone. Two review authors independently selected studies, extracted data and assessed risks of bias in the included trials. RESULTS AND DISCUSSION: The search identified 1474 records. Only 15 trials involving 1643 participants met our inclusion criteria. A meta-analysis based on similar studies that compared HR with placebo showed that HR significantly reduced symptoms of pain (SMD -1·07, 95% CI -1·44 to -0·70), symptoms of heavy legs (OR 0·50; 95% CI 0·28-0·91) and cramps (SMD -1·07, 95% CI -1·45 to -0·69). No serious adverse effect due to HR was reported. WHAT IS NEW AND CONCLUSION: The findings showed that HR produced modest improvements in several symptoms of CVI. However, all the included trials were of limited quality, and therefore, better-quality trials are still required to draw firm conclusions on the usefulness of HR for CVI.

Effect of troxerutin on insulin signaling molecules in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic adult male rat.

Troxerutin is a trihydroxyethylated derivative of the flavonoid, rutin. It has been reported to possess the hepatoprotective, nephroprotective, antioxidant, anti-inflammatory, and antihyperlipidemic activities. Troxerutin treatment reduced the blood glucose and glycosylated hemoglobin levels in high-cholesterol-induced insulin-resistant mice and in type-2 diabetic patients. However, the mechanism by which it exhibits antidiabetic property was unknown. Therefore, the present study was designed to evaluate the effect of troxerutin on insulin signaling molecules in gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic rats. Wistar male albino rats were selected and divided into five groups. Group I: Control. Group II: High fat and sucrose-induced type-2 diabetic rats. Group III: Type-2 diabetic rats treated with troxerutin (150 mg/kg body weight/day orally). Group IV: Type-2 diabetic rats treated with metformin (50 mg/kg body weight/day orally). Group V: Normal rats treated with troxerutin (150 mg/kg body weight/day orally). After 30 days of treatment, fasting blood glucose, oral glucose tolerance, serum lipid profile, and the levels of insulin signaling molecules, glycogen, glucose uptake, and oxidation in gastrocnemius muscle were assessed. Diabetic rats showed impairment in insulin signaling molecules (IR, p-IRS-1(Tyr632), p-Akt(Ser473), ß-arrestin-2, c-Src, p-AS160(Thr642), and GLUT4 proteins), glycogen concentration, glucose uptake, and oxidation. Oral administration of troxerutin showed near normal levels of blood glucose, serum insulin, lipid profile, and insulin signaling molecules as well as GLUT4 proteins in type-2 diabetic rats. It is concluded from the present study that troxerutin may play a significant role in the management of type-2 diabetes mellitus, by improving the insulin signaling molecules and glucose utilization in the skeletal muscle.

[Potentials for the conservative therapy in the complex treatment of varicocele in adolescents].

The article presents the results of the evaluation of the influence of varicocele on the reproductive system of adolescents from the perspective of involvement of periprostatic venous plexus and prostatovesicular complex in the pathological process. The study involved 90 adolescents 16-18 years old with left varicocele and disturbances in ejaculate parameters, of which 60 had pelvic congestion. Patients and control group received a comprehensive treatment, including preoperative trophic and flebotonic therapy, laparoscopic surgical clipping of the internal spermatic vein and post-operative rehabilitation. Patients of the study group along with this treatment received prostatotropic drug Vitaprost. According to the results of study, it was found that in patients with varicocele, attention should pay to the status of the venous outflow from the pelvic organs, which leads to the pelvic congestion and causes degenerative changes in the prostate in half of cases, which in turn negatively affects the spermogram parameters and increases the risk of subfertility. The use of prostatotropic drugs in the treatment of patients suffering from varicoceles with pelvic congestion is appropriate and pathogenetically justified, as it promotes a more rapid restoration of the structure and function of the prostate.

Troxerutin counteracts domoic acid-induced memory deficits in mice by inhibiting CCAAT/enhancer binding protein ß-mediated inflammatory response and oxidative stress.

The C/EBP ß is a basic leucine zipper transcription factor that regulates a variety of biological processes, including metabolism, cell proliferation and differentiation, and immune response. Recent findings show that C/EBP ß-induced inflammatory responses mediate kainic acid-triggered excitotoxic brain injury. In this article, we show that protein kinase C ζ enhances K-ras expression and subsequently activates the Raf/MEK/ERK1/2 pathway in the hippocampus of domoic acid (DA)-treated mice, which promotes C/EBP ß expression and induces inflammatory responses. Elevated production of TNF-α impairs mitochondrial function and increases the levels of reactive oxygen species by IκB kinase ß/NF-κB signaling. The aforementioned inflammation and oxidative stress lead to memory deficits in DA-treated mice. However, troxerutin inhibits cyclin-dependent kinase 1 expression, enhances type 1 protein phosphatase α dephosphorylation, and abolishes MEK/ERK1/2/C/EBP ß activation, which subsequently reverses the memory impairment observed in the DA-treated mice. Thus, troxerutin is recommended as a potential candidate for the prevention and therapeutic treatment of cognitive deficits resulting from excitotoxic brain damage and other brain disorders.