scholarly journals Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7695
Author(s):  
Yiming Wang ◽  
Weikaixin Kong ◽  
Liang Wang ◽  
Tianyu Zhang ◽  
Boyue Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Serum Uric Acid ◽  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Connectivity Map ◽  
Stress Injury ◽  
Ckd Stage ◽  
Lowering Drug

Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3–4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.

scholarly journals Protective Effect of Uric Acid on ox-LDL-Induced HUVECs Injury via Keap1-Nrf2-ARE Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Yajuan Lin ◽  
Yunpeng Xie ◽  
Zhujing Hao ◽  
Hailian Bi ◽  
Yang Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Nuclear Translocation ◽  
Density Lipoprotein ◽  
Endothelial Damage ◽  
The Body ◽  
Inflammatory Factors ◽  
Cell Phenotype ◽  
Mrna Levels

Uric acid is an effective antioxidant. Oxidized low-density lipoprotein (ox-LDL) is derived from circulating LDL and promotes atherosclerosis. The Keap1-Nrf2-ARE pathway is a key body pathway involved in protection against internal and external oxidative damages. The role of uric acid on vascular endothelial function damaged by ox-LDL, and its effect on the Keap1-Nrf2-ARE pathway has not been fully explored. HUVECs were treated with different concentrations of uric acid and ox-LDL to explore the effect of uric acid in vitro. Cell phenotype was determined by cytometry and Western blot. Nuclear translocation of Nrf2 was determined by immunofluorescence. Coimmunoprecipitation was used to determine the level of Nrf2 ubiquitination. A microfluidic device was used to mimic the vascular environment in the body, and the level of mRNA levels of inflammatory factors was determined by RT-PCR. The findings of this study show that suitable uric acid can significantly reduce endothelial damage caused by ox-LDL, such as oxidative stress, inflammation, and increased adhesion. In addition, uric acid reduced Nrf2 ubiquitination and increased nuclear translocation of Nrf2 protein, thus activating the Keap1-Nrf2-ARE pathway and playing a protective role. Interestingly, the effects of UA were significantly inhibited by administration of Brusatol, an inhibitor of Nrf2. In summary, suitable concentrations of uric acid can alleviate the oxidative stress level of endothelial cells through Nrf2 nuclear translocation and further protect cells from damage.

scholarly journals Sesamin Enhances Nrf2-Mediated Protective Defense against Oxidative Stress and Inflammation in Colitis via AKT and ERK Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-20 ◽  
Author(s):  
Xupeng Bai ◽  
Xiaoli Gou ◽  
Peiheng Cai ◽  
Chuncao Xu ◽  
Lin Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Nuclear Translocation ◽  
Physical Symptoms ◽  
Luciferase Reporter ◽  
Related Factor ◽  
Aminosalicylic Acid ◽  
Stress Injury ◽  
Erk Activation

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) with high incidence and prevalence in many countries. Patients with UC usually suffer from a lifetime of debilitating physical symptoms. Therefore, developing effective therapeutic strategy that can manage this disease better and improve patients’ life quality is in urgent need. Sesamin (SSM) is a lignan derived from sesame seeds. In this study, the protective effect of SSM against UC and the underlying mechanism were investigated in vitro and in vivo. Our data showed that SSM protected Caco-2 cells from H2O2-induced oxidative stress injury via GSH-mediated scavenging of reactive oxygen species (ROS). Dual luciferase reporter assay showed that the transcriptional activity of nuclear factor erythroid-related factor 2 (Nrf2) was significantly increased by SSM, and the ability of SSM to activate Nrf2-targeted genes was further confirmed in Caco-2 cells using western blot and quantitative real-time PCR (qRT-PCR). In contrast, Nrf2 knockdown abolished the protective effect of SSM. Additionally, we found that SSM also activated advanced protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in Caco-2 cells, while either AKT or ERK inhibition can prevent SSM-mediated nuclear translocation of Nrf2. Furthermore, SSM displayed a better protective effect against dextran sulfate sodium- (DSS-) induced UC compared with 5-aminosalicylic acid (5-ASA) in C57BL/6 mice. The enhanced Nrf2 signaling and activated AKT/ERK were also observed in the colon of mice after SSM administration. These results first demonstrate the protective effect of SSM against UC and indicate that the effect is associated with AKT/ERK activation and subsequent Nrf2 signaling enhancement. This study provides a new insight into the medicinal value of SSM and proposes it as a new natural nutrition for better managing the symptoms of UC.

scholarly journals Association between Serum Uric Acid and Oxidative Stress in Korean Adults

2018 ◽  
Vol 39 (5) ◽  
pp. 295-299 ◽  
Author(s):  
Eun Jeong Ok ◽  
Kiyoung Kim ◽  
Sat Byul Park
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
Serum Uric Acid ◽  
Korean Adults ◽  
And Oxidative Stress

scholarly journals The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiwei Liu ◽  
Yang Yi ◽  
Chuanfu Zhang ◽  
Baojuan Zhou ◽  
Lin Liao ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Mtor Pathway ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Mtorc1 Pathway ◽  
Hk2 Cells

Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.

scholarly journals Biochemical Interactions Between Polymeric Resins Used for Occlusal Splints and Saliva A pilot study comparing the CAD/CAM technology and the conventional approach

2019 ◽  
Vol 56 (2) ◽  
pp. 409-412 ◽  
Author(s):  
Marina Melescanu-Imre ◽  
Mihaela Pantea ◽  
Alexandra Totan ◽  
Ana Maria Cristina Tancu ◽  
Maria Greabu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uric Acid ◽  
In Vitro Study ◽  
Acrylic Resin ◽  
Occlusal Splints ◽  
Oral Environment ◽  
Cad Cam ◽  
3D Printed ◽  
Polymeric Resins

The CAD/CAM technology has been successfully integrated in clinical and laboratory aspects of dental medicine. The present in vitro study focuses on the biochemical interactions between saliva and three types of polymeric resins for occlusal splints. Dental material samples were produced from 3D printed, milled and self-cured resins and were incubated with saliva samples from 20 healthy volunteers. The results showed that the 3D printed and milled polymeric resins did not produce any significant changes in oxidative stress parameters (uric acid, TAC, GGT, OXSR-1) or inflammatory markers (IL-2, IL-6). On the other hand, the self-cured acrylic resin produced a significant decrease in the salivary TAC and uric acid, the most important antioxidants in saliva, affecting the capacity of saliva to protect the oral environment against oxidative stress.

scholarly journals Rhubarb-Aconite Decoction (RAD) Drug-Containing Serum Alleviated Endotoxin-Induced Oxidative Stress Injury and Inflammatory Response in Caco-2 Cells In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xiao-hong Du ◽  
Qing-jun Chen ◽  
Jian-bo Song ◽  
Yan Xie ◽  
Yan Zhi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Calcium Ion ◽  
Lipid Peroxide ◽  
Intestinal Injury ◽  
Intracellular Free Calcium ◽  
Free Calcium ◽  
Stress Injury ◽  
Oxidative Stress Injury

Rhubarb-Aconite Decoction (RAD), a famous Chinese medicine prescription, has been widely used for treating intestinal injury. However, the effect of RAD on intestinal epithelial cells is unclear. The aim of this study was to investigate the effects of RAD drug-containing serum on the oxidative stress injury and inflammatory response induced by endotoxin (ET) in Caco-2 cells in vitro. Lipid peroxide malondialdehyde (MDA), lactate dehydrogenase (LDH), caspase-11, tumor necrosis factor-α(TNF-α), interleukin-3(IL-3), and cytokeratin (CK)18, adenosine triphosphate (ATP) activity, and intracellular free calcium ion levels were measured. The results showed that ET triggered the activation of caspase-11 and the massive release of TNF-α, increased the inhibitory rate of cell growth, MDA, and LDH expressions in Caco-2 cells. Moreover, RAD drug-containing serum could inhibit caspase-11 activation, decrease the release of TNF-α and IL-3, reduce intracellular free calcium ion, and enhance CK 18 expression and ATP activity. These novel findings demonstrated that ET-induced oxidative stress injury and inflammatory response of Caco-2 cells were improved by RAD drug-containing serum, indicating that RAD may be a good choice for the treatment of intestinal injury.

scholarly journals P1597USE OF FEBUXOSTAT IN HYPERURICEMIC PATIENTS UNDERGOING DIALYSIS: TOLERABILITY AND EFFICACY IN INDIAN POPULATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sourabh Sharma ◽  
Neha Sharma
Keyword(s):  
Adverse Event ◽  
Uric Acid ◽  
Adverse Events ◽  
Serum Uric Acid ◽  
Skin Rash ◽  
Uric Acid Level ◽  
Acid Level ◽  
Serum Uric Acid Level ◽  
Vascular Events ◽  
Ckd Stage

Abstract Background and Aims Hyperuricemia is associated with increased vascular events in chronic kidney disease (CKD). Febuxostat is an effective alternative treatment in this subset but there is scarcity of data on its use in patients undergoing dialysis. The aim of our study was to evaluate efficacy and safety profile of febuxostat in hyperuricemic Indian patients on dialysis. Method Fifty four patients with CKD stage 5D and hyperuricemia were included in the study from Jul 2018 to Mar 2019. Febuxostat was started and patients followed-up over 6 months for decline in uric acid and any adverse events. Results Out of 54 cases, 30 were males (55.56%). Mean age was 51.28±16.9 years. Thirty two cases were diabetic (59.26) and all cases were on two or more antihypertensives. Nine cases were suffering from gout at time of inclusion and mean serum creatinine in these cases was 10.47 mg/dl. Symptomatic cases responded to treatment within 2 weeks of therapy. Mean serum uric acid level at 3 months post-treatment (4.65±0.96 mg/dL) was significantly reduced compared from pre-treatment level (8.34± 1.18 mg/dL) [p<0.01]. Serum uric acid level remained significantly low for 6 months without deterioration in eGFR. Blood pressure remained well controlled during therapy period and only four cases required increment of antihypertensive medication. Out of 54 cases, five stopped medication due to adverse events. Out of them, three cases were on peritoneal dialysis. Three cases developed skin rash which subsided once drug was withheld. Most common side effect was nausea (7/54) and headache (6/54). Conclusion Febuxostat at a low dose of 40 mg/dl is well tolerated among dialysis population. It effectively declines serum uric acid level. Gastrointestinal side effects are most common adverse event which corresponds to non-dialysis population. There was no higher risk of skin rash or other major adverse event in this subset. It is also worth mentioning that hyperuricemia is associated with significant vascular events and all cases included in study were hypertensive.

scholarly journals The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Peng Wang ◽  
Qian Luo ◽  
Hui Qiao ◽  
Hui Ding ◽  
Yonggang Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Morris Water Maze Test ◽  
Oxidative Stress Biomarkers ◽  
Neuroprotective Effects ◽  
Stress Injury

Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects.

scholarly journals Protective Effects and Mechanisms of Recombinant Human Glutathione Peroxidase 4 on Isoproterenol-Induced Myocardial Ischemia Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Chang Liu ◽  
Bozhao Li ◽  
Qi Yan ◽  
Shaopeng Niu ◽  
Yiding Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Glutathione Peroxidase ◽  
In Vitro Model ◽  
Cardiomyocyte Apoptosis ◽  
Protective Effects ◽  
Stress Injury ◽  
Oxidative Stress Injury ◽  
Vitro Model

Ischemic heart disease (IHD) is a cardiovascular disease with high fatality rate, and its pathogenesis is closely related to oxidative stress. Reactive oxygen species (ROS) in oxidative stress can lead to myocardial ischemia (MI) injury in many ways. Therefore, the application of antioxidants may be an effective way to prevent IHD. In recent years, glutathione peroxidase 4 (GPx4) has received increasing attention due to its antioxidant effect. In a previous study, we used the new chimeric tRNAUTuT6 to express highly active recombinant human GPx4 (rhGPx4) in amber-less Escherichia coli. In this study, we established an isoproterenol- (ISO-) induced MI injury model in rats and an in vitro model to research the protective effect and mechanism of rhGPx4 on MI injury. The results showed that rhGPx4 could reduce the area of myocardial infarction and ameliorate the pathological injury of heart tissue, significantly reduce ISO-induced abnormalities on electrocardiogram (ECG) and cardiac serum biomarkers, protect mitochondrial function, and attenuate cardiac oxidative stress injury. In an in vitro model, the results also confirmed that rhGPx4 could inhibit ISO-induced oxidative stress injury and cardiomyocyte apoptosis. The mechanism of action of rhGPx4 involves not only the inhibition of lipid peroxidation by eliminating ROS but also keeping a normal level of endogenous antioxidant enzymes by eliminating ROS, thereby preventing oxidative stress injury in cardiomyocytes. Additionally, rhGPx4 could inhibit cardiomyocyte apoptosis through a mitochondria-dependent pathway. In short, rhGPx4, a recombinant antioxidant enzyme, can play an important role in the prevention of IHD and may have great potential for application.

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