troxerutin and Inflammation

The aim of this article was first to review the complex pathophysiological mechanisms responsible for symptoms and signs of primary chronic venous disease (CVD) that allow the identification of targets for pharmacological treatment. The results of CVD treatment with venoactive drugs (VADs) were emphasised and presented in the form of recommendations. The last section raises key questions to be answered to improve protocols for good clinical trials and to draw up future guidelines on these agents.. The literature has been reviewed here using PubMed and Embase.. Venous hypertension appears to underlie all clinical manifestations of primary CVD. Inflammation is key in wall remodelling, valve failure and subsequent venous hypertension. Changes in the haemodynamics of veins are transmitted to the microcirculation, resulting in capillary alteration leading to oedema, skin changes and eventually venous ulceration. Venous symptoms may be the result of interplays between pro-inflammatory mediators and nerve fibres located in the venous wall. Therefore, venous inflammation constitutes a promising therapeutic target for pharmacological intervention, and some available VADs could attenuate various elements of venous inflammation. Based on recent studies, reviews and guidelines, tentative recommendations for the use of VADs were proposed and strong recommendations were given to two of them (micronised purified flavonoid fraction and oxerutins).. VADs should be accorded a better role in the management of CVD. However, larger and more definitive clinical trials are needed to improve the existing recommendations.

Topics: Anticoagulants; Blood Viscosity; Capillaries; Capillary Permeability; Capillary Resistance; Chronic Disease; Diosmin; Edema; Humans; Hydroxyethylrutoside; Inflammation; Lymphatic System; Pain; Skin Diseases; Vasodilator Agents; Veins; Venous Insufficiency

Troxerutin, a bioflavonoid with marked immune-modulatory and antioxidant features, has been proven to ameliorate experimental cardiotoxicity, hepatotoxicity, and neurodegeneration. However, its impact on methotrexate (MTX)-induced nephrotoxicity has not been investigated. In the current work, we aimed to investigate the potential of troxerutin to combat MTX-triggered renal injury, exploring immune cell infiltration, inflammation, autophagy, and apoptosis, with emphasis on the HMGB1/RAGE/NF-κB, AMPK/mTOR, and Nrf2/HO-1 pathways.. Troxerutin (150 mg/kg/day) was administered by oral gavage and the renal tissues were examined with the aid of biochemical assays, ELISA, histology, and immunohistochemistry.. Troxerutin mitigated MTX-induced renal dysfunction by significantly lowering creatinine, BUN, and KIM-1 alongside immune-cell infiltration and histopathologic aberrations. These favorable effects were mediated by inhibition of HMGB1/RAGE/NF-κB cascade via downregulating the protein expression of HMGB1, RAGE, and nuclear NF-κBp65 alongside its downstream signals, including COX-2 and TNF-α. Moreover, troxerutin activated the autophagy flux as evidenced by upregulating renal Beclin 1, lowering p62 SQSTM1 accumulation, and activation of AMPK/mTOR pathway, seen by increasing p-AMPK/total AMPK and lowering p-mTOR/total mTOR signals. In tandem, troxerutin combated renal apoptotic changes as proven with lowering caspase-3 activity, Bax expression, and Bax/Bcl-2 ratio and upregulating the proliferation signal PCNA. Additionally, the oxidative insult was attenuated by troxerutin, as evidenced by lowering NOX-1 and lipid peroxides, replenishing GSH, GPx, and SOD antioxidants, and activating Nrf2/HO-1 pathway.. Troxerutin attenuated MTX-triggered renal injury via inhibition of inflammation and apoptosis alongside activation of autophagy. Thus, it may serve as an adjunct modality for the management of MTX-linked nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Apoptosis; Autophagy; Disease Models, Animal; Humans; Hydroxyethylrutoside; Inflammation; Male; Methotrexate; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction; Vasoconstrictor Agents

Screening potential compounds for improving ulcerative colitis (UC) from clinical medication is an effective strategy for drug repurposing. We applied bioinformatics and network pharmacology to the drug screening process in this study, which helped us to screen out troxerutin that could improve UC. Troxerutin belongs to flavonoids and is used clinically as an anticoagulant and thrombolytic agent. This study found a new pharmacological activity of troxerutin, that is, it had a significant improvement effect on UC in mice. Experimental results of

Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Hydroxyethylrutoside; Inflammation; Mice

Obesity is a chronic low-grade inflammatory state associated with immune cell infiltration into the adipose tissue (AT). We hypothesize that the anti-obesity and anti-inflammatory effects of troxerutin (TX) are mediated through inhibition of elastase.. To determine the inhibitory effect of TX on elastase. Differentiated 3T3-L1 adipocytes were pretreated with TX, elastatinal (ELAS) or sodium salicylate (SAL) before exposure to TNFα. Lipid accumulation, reactive oxygen species (ROS) generation and oxidant-antioxidant balance were examined. The mRNA and protein expression of TNFα, interleukin-6, monocyte chemoattractant protein-1, adiponectin, leptin, resistin, chemerin, and elastase were analyzed. Elastase inhibition by TX and ELAS in a cell free system and docking studies for HNE with TX and ELAS were performed.. TX, ELAS or SAL pretreatment had lowered lipid droplets formation and TG content. TX suppressed ROS generation, oxidative stress and improved antioxidant status. The expression of inflammatory cytokines and elastase was downregulated while that of adiponectin was upregulated by TX. The concentration required to produce 50% inhibition. TNFα induces inflammation of 3T3-L1 cells through elastase activation. TX inhibits elastase activity, downregulates expression and binds with elastase.. The antioxidant and anti-inflammatory activities of TX in AT could be of relevance in the management of obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Cytokines; Hydroxyethylrutoside; Inflammation; Leukocyte Elastase; Lipid Metabolism; Mice; Obesity; Oxidative Stress; Reactive Oxygen Species; Serine Proteinase Inhibitors

Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in-depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA-induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up-regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin-induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin-induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA-induced nephrosis and associated systemic energy metabolism disorders.-Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.

Topics: Adipose Tissue, Brown; Animals; CLC-2 Chloride Channels; Energy Metabolism; Hydroxyethylrutoside; Inflammation; Kidney; Lipid Metabolism; Male; Mice; Mice, Inbred ICR; Ochratoxins; Respiration

This study was conducted to clarify the potential mechanisms of Troxerutin neuroprotection against Lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting the SIRT1/SIRT3 signaling pathway. To establish a model, a single dose of LPS (500μg/kg body weight) was injected to male Wistar rats intraperitoneally. Troxerutin (100 mg/kg body weight) was injected intraperitoneally for 5 days after induction of the model. Cognitive and behavioral evaluations were performed using Y-maze, single-trial passive avoidance, and novel object recognition tests. The expression of inflammatory mediators, SIRT1/SIRT3, and P53 was measured using the ELISA assay. Likewise, the expression levels of SIRT1/SIRT3 and NF-κB were determined using Western blot assay. Brain acetyl-cholinesterase activity was determined by utilizing the method of Ellman. Reactive oxygen species (ROS) was detected using Fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA). Furthermore, malondialdehyde (MDA) levels were determined. A single intraperitoneal injection of LPS was led to ROS production, acute neuroinflammation, apoptotic cell death, and inactivation of the SIRT1/SIRT3 signaling pathway. Likewise, ELISA assay demonstrated that post-treatment with Troxerutin considerably suppressed LPS-induced acute neuroinflammation, oxidative stress, apoptosis and subsequently memory impairments by targeting SIRT1/SIRT3 signaling pathway. Western blot assay confirmed ELISA results about SIRT1/SIRT3 and NF-κB proteins. These results suggest that Troxerutin can be a suitable candidate to treat neuroinflammation caused by neurodegenerative disorders.

Topics: Animals; Avoidance Learning; Behavior, Animal; Hippocampus; Hydroxyethylrutoside; Inflammation; Lipopolysaccharides; Male; Malondialdehyde; Maze Learning; Neuroprotective Agents; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Sirtuin 1; Sirtuin 3

Protective effects of ischemic postconditioning in myocardial ischemia/reperfusion (I/R) injury have been ever demonstrated, but the exact mechanisms remain unclear. Because of their multiplex activities, using natural pharmaceuticals seems to be clinically interesting. The aim of present study was to investigate the effects of troxerutin preconditioning and ischemic postconditioning on inflammatory responses after myocardial I/R injury in a rat model. Twenty-four Wistar rats were divided into four groups as the control, troxerutin receiving (TXR), postconditioning receiving (PostC), and combined therapy (TXR + PostC). Rats' isolated hearts underwent 30-min LAD regional ischemia followed by 45-min reperfusion. Troxerutin was orally administered for a month before I/R. Ischemic PostC was applied by alternative three cycles of 30-s R/I at the onset of reperfusion. The coronary effluent and ischemic left ventricular samples were used to determine the activities of creatine kinase (CK), intercellular adhesion molecule-1 (ICAM-1), interlukin-1beta (IL-1β), tumor-necrosis factor (TNF-α), and also histopathological studies. Pretreatment of rats with troxerutin significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels and ICAM-1 activity after I/R insult compared to those of control I/R hearts (P < 0.05). Application of PostC showed similar impacts on those parameters. In fact, anti-inflammatory mechanisms of both treatments were associated with their protective effects against myocardial damages causing from I/R injury. Pretreatment with troxerutin as well as postconditioning can induce cardioprotection through prevention of the cell-cell interaction and release of inflammatory mediators, minimizing I/R pathological changes in myocardial cells. These two treatments may share same mechanisms in their actions since they showed no significant additive effects.

Topics: Animals; Heart Ventricles; Hydroxyethylrutoside; Inflammation; Inflammation Mediators; Ischemic Postconditioning; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Premedication; Rats; Rats, Wistar; Transplantation Conditioning

The C/EBP β 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 β-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 β expression and induces inflammatory responses. Elevated production of TNF-α impairs mitochondrial function and increases the levels of reactive oxygen species by IκB kinase β/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 β 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.

Topics: Animals; Butadienes; CCAAT-Enhancer-Binding Protein-beta; CDC2 Protein Kinase; Gene Knockdown Techniques; Genes, ras; Hippocampus; Hydroxyethylrutoside; Inflammation; Inflammation Mediators; Kainic Acid; Male; Memory Disorders; Mice; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidases; Nitriles; Oxidative Stress; Phosphoprotein Phosphatases; Phosphorylation; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

An experimental investigation was made of the influence of 0-(beta-hydroxyethyl)-rutin (HR) on the effect of indomethacin (1, 2 or 4 mg/kg i.p.) in inhibiting rat paw oedema. HR was given once daily during a 6-day pretreatment, with the final dose 90 minutes before the inflammatory reaction was induced. In the group of HR-pretreated rats which also received indomethacin in a dose of 2 or 4 mg/kg, the extent of the carrageenin-oedema was diminished significantly in comparison to that in experimental animals treated merely with indomethacin.

Topics: Animals; Anticoagulants; Carrageenan; Drug Synergism; Edema; Hydroxyethylrutoside; Indomethacin; Inflammation; Male; Rats; Rats, Sprague-Dawley