Extension of Drosophila Lifespan by Astragalus polysaccharide through a Mechanism Dependent on Antioxidant and Insulin/IGF-1 Signaling

Historical literature and pharmacological studies demonstrate that Astragalus polysaccharide (APS) has anti-inflammatory and antioxidative effects. Studies into the longevity effects of APS are limited, and the molecular mechanism of lifespan extension by APS is not elucidated yet. Here, the longevity effect of APS was investigated in Drosophila melanogaster by feeding dose-dependent APS. APS significantly extended the lifespan and improved the reproduction. Meanwhile, APS increased locomotion, TAG level, and starvation resistance and reduced the mortality rate induced by hydrogen peroxide. The activities of superoxide dismutase (SOD) and catalase (CAT) were increased in flies treated with APS diet. Moreover, APS significantly enhanced expressions of antioxidant genes (Sod1, Sod2, and Cat), dFoxO, and 4E − BP, decreased the expressions of insulin-like peptides (dilp2, dilp3, and dilp5), and longevity gene MTH. Together, these results indicate that APS can prolong the lifespan by regulating antioxidant ability and insulin/IGF-1 signaling and also enhance the reproduction ability in Drosophila. APS may be explored as a novel agent for slowing the aging process and improving reproduction.

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Salvianolic Acid A Protects the Kidney against Oxidative Stress by Activating the Akt/GSK-3β/Nrf2 Signaling Pathway and Inhibiting the NF-κB Signaling Pathway in 5/6 Nephrectomized Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2853534 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 7

Author(s):

Hong-feng Zhang ◽

Jia-hong Wang ◽

Yan-li Wang ◽

Cheng Gao ◽

Yan-ting Gu ◽

...

Keyword(s):

Oxidative Stress ◽

Western Blot ◽

Signaling Pathway ◽

Kidney Injury ◽

Dependent Manner ◽

Salvianolic Acid ◽

Nrf2 Signaling Pathway ◽

Antioxidative Effects ◽

Dose Dependent

Salvianolic acid A (SAA) is a bioactive polyphenol extracted from Salviae miltiorrhizae Bunge, which possesses a variety of pharmacological activities. In our previous study, we have demonstrated that SAA effectively attenuates kidney injury and inflammation in an established animal model of 5/6 nephrectomized (5/6Nx) rats. However, there has been limited research regarding the antioxidative effects of SAA on chronic kidney disease (CKD). Here, we examined the antioxidative effects and underlying mechanisms of SAA in 5/6Nx rats. The rats were injected with SAA (2.5, 5, and 10 mg·kg-1·d-1, ip) for 28 days. Biochemical, flow cytometry, and Western blot analyses showed that SAA significantly increased the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and catalase (CAT) and lowered the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and NADPH oxidase 4 (NOX-4) in a dose-dependent manner in 5/6Nx rats and in H2O2-induced HK-2 cells in vitro. Moreover, SAA enhanced the activation of the protein kinase B/glycogen synthase kinase-3β/nuclear factor-erythroid-2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathway in a dose-dependent manner and subsequently increased the expression of heme oxygenase-1 (HO-1) in the kidney of 5/6Nx rats, which were consistent with those obtained in H2O2-induced HK-2 cells in vitro shown by Western blot analysis. Furthermore, SAA significantly increased the expression of intranuclear Nrf2 and HO-1 proteins compared to HK-2 cells stimulated by LPS on the one hand, which can be enhanced by QNZ to some extent; on the other hand, SAA significantly lowered the expression of p-NF-κB p65 and ICAM-1 proteins compared to HK-2 cells stimulated by H2O2, which can be abrogated by ML385 to some extent. In conclusion, our results demonstrated that SAA effectively protects the kidney against oxidative stress in 5/6Nx rats. One of the pivotal mechanisms for the protective effects of SAA on kidney injury was mainly related with its antioxidative roles by activating the Akt/GSK-3β/Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway.

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Selenylation, Characterization and Cytotoxic Activity of Seleno-Astragalus Polysaccharide

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.411-414.3146 ◽

2013 ◽

Vol 411-414 ◽

pp. 3146-3149 ◽

Cited By ~ 2

Author(s):

Yu Bin Ji ◽

Fang Dong ◽

Miao Yu

Keyword(s):

Cytotoxic Activity ◽

Human Breast Cancer ◽

Human Breast ◽

X Ray Diffraction ◽

X Ray ◽

Astragalus Polysaccharide ◽

Series Of Experiments ◽

Dose Dependent ◽

Mcf 7

This paper investigated the selenylation, characterization and cytotoxic activity of seleno-Astragalus polysaccharide. Firstly, Se-APS was synthesized under reaction time at 8 h, reaction temperature at 80 °C, ratio of Na2SeO3 to APS at 1.0 g/g and water bath shaking rate at 40 r/min. Then, a series of experiments were designed to investigate the characterization and cytotoxicity of Se-APS. The result indicated that the characterization of Se-APS was significantly different from APS, except for X-ray diffraction. Additionally, MTT assay conformed that Se-APS could significantly inhibit the proliferation of human breast cancer MCF-7 cells in dose-dependent and time-dependent manners.

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Gypenosides modulate NCX calcium flux, insulin secretion and cytoprotection in BRIN-BD11 pancreatic β-cells

10.1101/2021.01.29.428823 ◽

2021 ◽

Author(s):

Chinmai Patibandla ◽

Xinhua Shu ◽

Angus M Shaw ◽

Sharron Dolan ◽

Steven Patterson

Keyword(s):

Insulin Secretion ◽

Calcium Flux ◽

Dependent Manner ◽

Sodium Calcium Exchanger ◽

Β Cells ◽

Antioxidant Genes ◽

Reverse Mode ◽

Independent Mechanism ◽

Antioxidant Gene Expression ◽

Dose Dependent

AbstractGypenosides are saponins extracted from the plant Gynostemma pentaphyllum, suggested to have antidiabetic and anti-obesity potential. However, its mechanism of action is not fully understood. The present study aimed to investigate the cytoprotective and insulin stimulatory effects of gypenosides using the rat BRIN-BD11 β-cell line. Gypenosides provided a significant cytoprotective effect against palmitate-, peroxide- and cytokine-induced cytotoxicity, with upregulation of antioxidant genes Nrf2, Cat, Sod1, and Gpx1. Acutely, gypenosides enhanced intracellular calcium ([Ca2+]i) and insulin secretion in a dose-dependent manner. The presence of the sodium/calcium exchanger (NCX) reverse mode inhibitor SN-6 blocked the gypenosides mediated increase in [Ca2+]I but not the insulin secretion. These findings indicate that gypenosides may enhance [Ca2+]i by activating the reverse mode of NCX channels and a possible calcium-independent mechanism involved in their insulin secretion. Gypenosides also upregulate the antioxidant gene expression and protect against oxidative stress and lipotoxicity, providing the rationale for their observed antidiabetic actions.

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In vitro Evaluation of Ureteral Contractility: A Comparative Assessment of Human, Porcine and Sheep Ureteral Response to Vardenafil

Urologia Internationalis ◽

10.1159/000358601 ◽

2014 ◽

Vol 94 (2) ◽

pp. 234-239 ◽

Cited By ~ 1

Author(s):

Iason Kyriazis ◽

Panagiotis Kallidonis ◽

Ioannis Georgiopoulos ◽

Abdulrahman Al-Aown ◽

George Sakellaropoulos ◽

...

Keyword(s):

Animal Models ◽

Science Studies ◽

Organ Bath ◽

Pharmaceutical Agent ◽

Amplitude Increase ◽

Pharmacological Studies ◽

Relaxant Response ◽

Dose Dependent ◽

Different Doses

Objectives: Basic science studies of ureteral physiology and pathophysiology are commonly performed on animal ureters due to several limitations associated with human ureteral sampling. In this work we question whether animal ureters are good replicas of human ureteral behavior for pharmacological studies. Materials and Methods: Ureteral rings from human, porcine and ovine ureters underwent the same organ bath protocol. After stimulation with KCl, ureters were subjected to different doses of vardenafil. Basic contractility and ureteral response to vardenafil were analyzed. Results: A different pattern of basic contractility was evidenced between species. Vardenafil administration induced a dose-dependent reduction in KCl-induced amplitude increase in human ureters and a dose-dependent reduction in autonomic contractile rhythm of porcine and ovine ureters. Although animal ureters could predict the relaxant response of human samples to vardenafil, its effect would have been overestimated using only animal models. Conclusions: Human ureteral investigations cannot entirely be replaced by existing animal models since results of the latter will vary significantly according to the tested pharmaceutical agent.

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Jiang Tang Xiao Ke Granule, a Classic Chinese Herbal Formula, Improves the Effect of Metformin on Lipid and Glucose Metabolism in Diabetic Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/1592731 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Yi Zhang ◽

Hong An ◽

Si-Yuan Pan ◽

Dan-Dan Zhao ◽

Jia-Cheng Zuo ◽

...

Keyword(s):

Combination Treatment ◽

Serum Triglyceride ◽

Lipid Lowering ◽

Dependent Manner ◽

Hepatic Glucose ◽

Antioxidative Effects ◽

Antioxidant Stress ◽

Dose Dependent ◽

Lipid Lowering Effect

In the present study, the hypoglycemic, hypolipidemic, and antioxidative effects of metformin (MET) combined with Jiang Tang Xiao Ke (JTXK) granule derived from the “Di Huang Tang” were evaluated in mice with type 2 diabetes mellitus (DM) induced by high-fat diet/streptozotocin. DM mice were orally treated with MET (0.19 g/kg) either alone or combined with different doses (1.75, 3.5, or 7 g/kg) of JTXK for 4 weeks. Results showed that the serum and hepatic glucose, lipids, and oxidative stress levels were elevated in DM mice, when compared with the normal mice. MET treatment decreased FBG and serum glucagon levels of DM mice. Combination treatment with MET and JTXK 3.5 g/kg increased the hypoglycemia and insulin sensitivity at 4 weeks when compared with the DM mice treated with MET alone. However, neither MET nor MET/JTXK treatment could completely reverse the hyperglycemia in DM mice. JTXK enhanced the serum triglyceride (TG) and hepatic lipid-lowering effect of MET in a dose-dependent manner in DM mice. JTXK 1.75 and 3.5 g/kg improved the hepatoprotective effect of MET in DM mice. Synergistic effect of combination treatment with MET and JTXK on antioxidant stress was also found in DM mice compared with MET alone.

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Chikusetsu saponin V attenuates H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells through Sirt1/PGC-1α/Mn-SOD signaling pathways

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0262 ◽

2016 ◽

Vol 94 (9) ◽

pp. 919-928 ◽

Cited By ~ 20

Author(s):

Jingzhi Wan ◽

Lili Deng ◽

Changcheng Zhang ◽

Qin Yuan ◽

Jing Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Signaling Pathways ◽

Vital Role ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Human Neuroblastoma ◽

Ros Accumulation ◽

Antioxidative Effects ◽

Dose Dependent

Oxidative stress plays a vital role in the pathogenesis of neurodegenerative diseases. Chikusetsu saponin V (CsV), the most abundant member of saponins from Panax japonicus (SPJ), has attracted increasing attention for its potential to treat neurodegenerative diseases. However, the mechanisms are unclear. Our study intended to investigate the antioxidative effects of CsV in human neuroblastoma SH-SY5Y cells. Our data showed that CsV attenuated H2O2-induced cytotoxicity, inhibited ROS accumulation, increased the activities of superoxide dismutase (SOD) and GSH, and increased mitochondrial membrane potential dose-dependently. Further exploration of the mechanisms showed that CsV exhibited these effects through increasing the activation of oxidative-stress-associated factors including Sirt1, PGC-1α, and Mn-SOD. Moreover, CsV inhibited H2O2-induced down-regulation of Bcl-2 and up-regulation of Bax in a dose-dependent manner and, thus, increased the ratio of Bcl-2/Bax. In conclusion, our study demonstrated that CsV exhibited neuroprotective effects possibly through Sirt1/PGC-1α/Mn-SOD signaling pathways.

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Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells

Cells ◽

10.3390/cells8101159 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1159 ◽

Cited By ~ 7

Author(s):

Bhavana Chhunchha ◽

Eri Kubo ◽

Dhirendra P. Singh

Keyword(s):

Cell Death ◽

Antioxidant Defense ◽

Antioxidant Response ◽

Therapeutic Interventions ◽

Related Factor ◽

Antioxidant Genes ◽

Peroxiredoxin 6 ◽

Dose Levels ◽

Dose Dependent ◽

Higher Doses

Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like Peroxiredoxin 6 (Prdx6) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN (>6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of Prdx6 expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-CA/GCCC-3) in the Prdx6 promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as Prdx6 via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy.

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Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/6943053 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Xian Wen Tan ◽

Mrinal Bhave ◽

Alan Yean Yip Fong ◽

Eiji Matsuura ◽

Kazuko Kobayashi ◽

...

Keyword(s):

Oxidative Stress ◽

Rice Bran ◽

Rice Variety ◽

Cytotoxic Effects ◽

Antioxidative Effects ◽

Preliminary Study ◽

Cytotoxicity Effects ◽

Dose Dependent ◽

Antioxidant Enzyme Catalase ◽

Antioxidant Effects

This study was aimed at preliminarily assessing the cytoprotective and antioxidative effects of rice bran extracts (RBEs) from a Sarawak local rice variety (local name: “BJLN”) and a commercial rice variety, “MR219,” on oxidative stress in rat H9c2(2-1) cardiomyocytes. The cardiomyocytes were incubated with different concentrations of RBE and hydrogen peroxide (H2O2), respectively, to identify their respective IC50values and safe dose ranges. Two nonlethal and close-to-IC50doses of RBE were selected to evaluate their respective effects on H2O2induced oxidative stress in cardiomyocytes. Both RBEs showed dose-dependent cytotoxicity effects on cardiomyocytes. H2O2induction of cardiomyocytes pretreated with RBE further revealed the dose-dependent cytoprotective and antioxidative effects of RBE via an increase in IC50values of H2O2. Preliminary analyses of induction effects of RBE and H2O2on cellular antioxidant enzyme, catalase (CAT), also revealed their potential in regulating these activities and expression profile of related gene on oxidative stress in cardiomyocytes. Pretreated cardiomyocytes significantly upregulated the enzymatic activity and expression level of CAT under the exposure of H2O2induced oxidative stress. This preliminary study has demonstrated the potential antioxidant effects of RBE in alleviating H2O2-mediated oxidative injuries via upregulation in enzymatic activities and expression levels of CAT.

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Disparity of selenourea and selenocystine on methaemoglobinemia in non-diabetics and diabetics

The Journal of Biochemistry ◽

10.1093/jb/mvaa115 ◽

2020 ◽

Author(s):

Debashree Das ◽

Souvik Sen ◽

Kamalika Sen

Keyword(s):

Reactive Oxygen Species ◽

P Value ◽

Dependent Manner ◽

Oxygen Species ◽

Blood Samples ◽

Peak Intensity ◽

Medicinal Properties ◽

Dose Dependent ◽

Protein Part ◽

Novel Agent

Abstract Organoselenium drugs like selenourea (SeU) and selenocystine (SeC) are found to exhibit several medicinal properties and have reported roles in the field of cancer prevention. However, studies related to their interactions with the major erythroid protein, haemoglobin (HbA) are still in dearth despite being of prime importance. In view of this, it was considered essential to investigate the interaction of these two anticancer drugs with Hb. Both the drugs showed significant changes in absorption spectra of Hb at wavelength of maximum absorption (λmax) 630 nm. SeU itself had no effect on the absorbance value at 630 nm with respect to time even with 400 µM concentration. However, it was rapidly converted to nanoselenium in presence of nitrite and there was an increase in the absorbance rate at 630 nm from 3.39 × 10−3 min−1 (without nitrite) to 8.94 × 10−3 min−1 in presence of nitrite (200 µM) owing to the generation of reactive oxygen species in the medium. Although the generation and increase in peak intensity at 630 nm in Hb generally indicates the formation and rise in the levels of methaemoglobin (metHb), nanoselenium was observed to follow a different path. Instead of causing oxidation of Fe2+ to Fe3+ responsible for metHb formation, nanoselenium was found to interact with the protein part, thereby causing changes in its secondary structure which is reflected in the increasing absorbance at 630 nm. SeC, however, showed a different effect. It was shown to act as a novel agent to reduce nitrite-induced metHb formation in a dose-dependent manner. The efficiency of SeC was again found to be less in diabetic blood samples as compared to the non-diabetic ones. For similar ratio of metHb to SeC (1:8), % reduction of metHb was found to be 27.46 ± 0.82 and 16.1 ± 2.4 for non-diabetic and diabetic samples, respectively, with a two tailed P-value much <0.05 which implies that the data are highly significant.

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P070 Efficacy of a novel non-covalent oral small molecule Nrf2 activator in a rat model of Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.199 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S174-S174

Author(s):

C Murray ◽

N Cooper ◽

C L Lucas ◽

A S Manso ◽

N C Ray ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Antioxidant Response ◽

Antioxidant Genes ◽

Nrf2 Pathway ◽

Markers Of Inflammation ◽

Inflammatory Bowel ◽

Nrf2 Activator ◽

Dose Dependent

Abstract Background Inflammatory Bowel Disease (IBD) is characterised by chronic inflammation and increased oxidative stress in the intestinal mucosa of patients. NF-E2-related factor 2 (Nrf2) plays a key role in the antioxidant response by regulating the transcription of antioxidant genes as well as reducing expression of inflammatory mediators. A role for the Nrf2 pathway in IBD has been demonstrated in rodent models previously but these studies have predominantly used compounds such as Dimethyl Fumarate that are covalent Nrf2 activators that have the potential for significant off-target activities. C4X Discovery has identified C4X_6746, a novel potent and selective non-covalent Nrf2 activator, that disrupts the interaction between Nrf2 and its repressor Keap1 and is being investigated as an oral treatment for inflammatory disorders. Methods Male Han Wistar rats were given 3% Dextran Sodium Sulphate (DSS) in drinking water for 8 days in order to induce colitis and were dosed once daily by oral gavage with vehicle, C4X_6746 (0.3, 3 or 30 mg/kg) or Cyclosporine A (CsA, 20 mg/kg). The Disease Activity Index (DAI) was assessed daily based on stool consistency, faecal blood and body weight. On study termination, the colon weight and length were measured, and additional endpoints assessed (colon macroscopic score, histology, colon markers of inflammation and antioxidant response). Results C4X_6746 caused a dose-dependent decrease in the DAI with 30 mg/kg showing similar efficacy to the reference comparator CsA. C4X_6746 (3 and 30 mg/kg) resulted in a statistically significant reduction in the colon weight:length ratio and the macroscopic score. The compound also reduced the DSS-induced histological changes including inflammatory cell infiltrate, epithelial damage and mucosal architecture changes. Analysis of the colon tissue showed that C4X_6746 reduced inflammation (MPO activity) and upregulated the antioxidant response (SOD activity, ratio of reduced:oxidised glutathione). Efficacy of C4X_6746 in the model correlated with the dose-dependent induction of NQO1 mRNA in the colon and blood as a biomarker for Nrf2 pathway activation. Conclusion The efficacy of C4X_6746 in the rat DSS model supports development of non-covalent oral Nrf2 activators to significantly reduce oxidative tissue damage and chronic inflammation in IBD.

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