scholarly journals Endothelial dysfunction in insulin-resistant rats is associated with oxidative stress and COX pathway dysregulation

2009 ◽  
pp. 499-509
Author(s):  
A Oudot ◽  
D Behr-Roussel ◽  
S Compagnie ◽  
S Caisey ◽  
O Le Coz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Vascular Dysfunction ◽  
Pressor Response ◽  
In Vitro Study ◽  
Cardiovascular Complications ◽  
Insulin Resistant ◽  
Pathway Dysregulation

Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1α were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.

scholarly journals Vascular Dysfunction Induced by Mercury Exposure

2019 ◽  
Vol 20 (10) ◽  
pp. 2435 ◽  
Author(s):  
Tetsuya Takahashi ◽  
Takayoshi Shimohata
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Brain Parenchyma ◽  
Transport Systems ◽  
Mehg Exposure ◽  
In Vivo Models ◽  
The Central Nervous System ◽  
The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

scholarly journals Protection of the vascular endothelium in experimental situations

2011 ◽  
Vol 4 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Ružena Sotníková ◽  
Jana Nedelčevová ◽  
Jana Navarová ◽  
Viera Nosáľová ◽  
Katarína Drábiková ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Endothelium ◽  
Vascular Dysfunction ◽  
Antioxidant Properties ◽  
Pharmacological Intervention ◽  
Ros Production ◽  
Nitric Oxide Radical ◽  
Endothelium Dependent Relaxation

Protection of the vascular endothelium in experimental situationsOne of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 foundin vitrowere partly confirmedin vivo.Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effectin vivo.

scholarly journals Honokiol Alleviates Methionine-Choline Deficient Diet-Induced Hepatic Steatosis and Oxidative Stress in C57BL/6 Mice by Regulating CFLAR-JNK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Ting Zhai ◽  
Wei Xu ◽  
Yayun Liu ◽  
Kun Qian ◽  
Yanling Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Regulatory Gene ◽  
Deficient Diet ◽  
Jnk Pathway ◽  
Beneficial Effects ◽  
Protein Levels ◽  
And Oxidative Stress

Background. Honokiol (HNK) has been reported to possess various beneficial effects in the context of metabolic disorders, including fatty liver, insulin resistance, and oxidative stress which are closely related to nonalcoholic steatohepatitis (NASH), however with no particular reference to CFLAR or JNK. Methods. C57BL/6 mice were fed methionine-choline-deficient (MCD) diet and administered simultaneously with HNK (10 and 20 mg/kg once a day, ig) for 6 weeks, and NCTC1469 cells were pretreated, respectively, by oleic acid (OA, 0.5 mmol/L) plus palmitic acid (PA, 0.25 mmol/L) for 24 h, and adenovirus-down Cflar for 24 h, then exposed to HNK (10 and 20 μmol/L) for 24 h. Commercial kits, H&E, MT, ORO staining, RT-qPCR, and Western blotting were used to detect the biomarkers, hepatic histological changes, and the expression of key genes involved in NASH. Results. The in vivo results showed that HNK suppressed the phosphorylation of JNK (pJNK) by activating CFLAR; enhanced the mRNA expression of lipid metabolism-related genes Acox, Cpt1α, Fabp5, Gpat, Mttp, Pparα, and Scd-1; and decreased the levels of hepatic TG, TC, and MDA, as well as the levels of serum ALT and AST. Additionally, HNK enhanced the protein expression of oxidative stress-related key regulatory gene NRF2 and the activities of antioxidases HO-1, CAT, and GSH-Px and decreased the protein levels of prooxidases CYP4A and CYP2E1. The in vivo effects of HNK on the expression of CLFAR, pJNK, and NRF2 were proved by the in vitro experiments. Moreover, HNK promoted the phosphorylation of IRS1 (pIRS1) in both tested cells and increased the uptake of fluorescent glucose 2-NBDG in OA- and PA-pretreated cells. Conclusions. HNK ameliorated NASH mainly by activating the CFLAR-JNK pathway, which not only alleviated fat deposition by promoting the efflux and β-oxidation of fatty acids in the liver but also attenuated hepatic oxidative damage and insulin resistance by upregulating the expression of NRF2 and pIRS1.

A novel small molecule A2A adenosine receptor agonist, indirubin-3′-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes

2019 ◽  
Vol 476 (16) ◽  
pp. 2371-2391 ◽  
Author(s):  
Saynaz A. Choudhary ◽  
Nikita Bora ◽  
Dipanjan Banerjee ◽  
Leena Arora ◽  
Anindhya Sundar Das ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adenosine Receptor ◽  
In Vitro Study ◽  
A2a Adenosine Receptor ◽  
Insulin Resistant ◽  
Adenosine Receptor Agonist ◽  
Inflammatory State

Abstract Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A2A adenosine receptor (A2AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A2AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3′-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates A2AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of in silico virtual screening of potential anti-diabetic candidates and in vitro study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through A2AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the A2AAR antagonist, SCH 58261 or siRNA mediated knockdown of A2AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.

scholarly journals Solid Lipid Nanoparticles of Myricitrin Have Antioxidant and Antidiabetic Effects on Streptozotocin-Nicotinamide-Induced Diabetic Model and Myotube Cell of Male Mouse

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Akram Ahangarpour ◽  
Ali Akbar Oroojan ◽  
Layasadat Khorsandi ◽  
Maryam Kouchak ◽  
Mohammad Badavi
Keyword(s):  
Oxidative Stress ◽  
C2c12 Cell ◽  
In Vitro Study ◽  
Homogenization Method ◽  
Solid Lipid ◽  
Muscle Tissues ◽  
Diabetic Model ◽  
Cellular Apoptosis

Type 2 diabetes mellitus (T2DM) may occur via oxidative stress. Myricitrin is a plant-derived antioxidant, and its solid lipid nanoparticle (SLN) may be more potent. Hence, the present study was conducted to evaluate the effects of myricitrin SLN on streptozotocin-nicotinamide- (STZ-NA-) induced T2DM of the mouse and hyperglycemic myotube. In this experimental study, cold homogenization method was used to prepare SLN. Then, 120 adult male NMRI mice were divided into 7 groups: control, vehicle, diabetes (received STZ 65 mg/kg 15 min after injected NA 120 mg/kg), diabetes + SLN containing myricitrin 1, 3, and 10 mg/kg, and diabetes + metformin. For in vitro study, myoblast (C2C12) cell line was cultured and divided into 6 groups (n=3): control, hyperglycemia, hyperglycemia + SLN containing myricitrin 1, 3, and, 10 μM, and hyperglycemia + metformin. After the last nanoparticle treatment, plasma samples, pancreas and muscle tissues, and myotubes were taken for experimental assessments. Diabetes increased lipid peroxidation and reduced antioxidant defense along with the hyperglycemia, insulin resistance, and pancreas apoptosis. Hyperglycemia induced oxidative stress, antioxidant impairment, and cellular apoptosis. Myricitrin SLN improved diabetes and hyperglycemia complications in the in vivo and in vitro studies. Therefore, SLN of myricitrin showed antioxidant, antidiabetic, and antiapoptotic effects in the mouse and myotube cells.

scholarly journals Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Na Zhang ◽  
Lingyan Wang ◽  
Qi Duan ◽  
Laixiang Lin ◽  
Mohamed Ahmed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Urinary Iodine ◽  
In Vitro Study ◽  
Superoxide Production ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Superoxide ◽  
Iodine Level ◽  
Significant Difference

Purpose. We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid.Methods. Eight-week-old MT-I/II knockout (MT-I/II KO) mice and background-matched wild-type (WT) mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx) 3 expression were measured.Results. In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P>0.05), while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P>0.05).Conclusions. Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes.

scholarly journals Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance

Reproduction ◽  
2008 ◽  
Vol 136 (3) ◽  
pp. 335-344 ◽  
Author(s):  
Erica Louden ◽  
Maggie M Chi ◽  
Kelle H Moley
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Ampk Activation ◽  
Embryonic Cells ◽  
Insulin Resistant

Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

Abstract 630: Novel Chimeric Anti-proteoglycan Antibody Inhibits Arterial Retention of Proatherogenic Lipoproteins in a Rat Model of Insulin Resistance

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yosdel Soto ◽  
Rabban Mangat ◽  
Ana M Vázquez ◽  
Spencer D Proctor
Keyword(s):  
Insulin Resistance ◽  
Monoclonal Antibody ◽  
Ex Vivo ◽  
Dependent Manner ◽  
Insulin Resistant ◽  
Remnant Lipoproteins ◽  
Preferential Binding ◽  
Carotid Vessels

Background: The response-to-retention hypothesis for atherosclerosis describes subendothelial retention of apolipoprotein B-containing lipoproteins mediated by proteoglycans (PG). Further we know that diabetes is also associated with both increased circulating chylomicron remnants and remodeling of proatherogenic PGs. We have recently reported antiatherogenic properties of a novel chimeric monoclonal antibody (chP3R99) that recognizes PG sulfated molecules. Hypothesis: chP3R99 monoclonal antibody may interfere with the interaction of atherogenic lipoproteins with arterial sulfated PGs during insulin resistance. Methods and Results: chP3R99 antibody recognized sulfated glycosaminoglycans by ELISA showing a preferential binding to chondroitin sulfate. Also, chP3R99 blocked the interaction of proatherogenic lipoproteins with this glycosaminoglycan in vitro in a dose-dependent manner and its intravenous injection into healthy Sprague-Dawly rats (n=6, 1 mg/animal) inhibited LDL (4 mg/kg; intraperitoneally) aortic retention. To further assess this property in an insulin resistant condition, carotid arteries from control and JCR:LA-cp rats (n=4) were perfused ex vivo with apoB48 containing remnant lipoproteins (prepared via rabbit hepatectomy procedure), with or without Cy3-LDL (150 μg/mL) for 20 minutes. Confocal microscopy analysis revealed an increased arterial retention of both remnants (3.6 fold) and LDL (2.8 fold) in carotid vessels from insulin resistant rats relative to control. However, chP3R99 pre-perfusion resulted in decreased retention of remnants (-30%) and LDL (-60%) associated arterial cholesterol. Data suggests that the chP399 antibody may interfere with the arterial attachment of both remnants and LDL in vivo, but with differential efficacy. Conclusions: Relative to LDL, remnant lipoproteins had preferential accumulation in arterial vessels from insulin resistant rats ex vivo , which could then be inhibited by acute pre-exposure to the chP3R99 antibody. These in vivo data support the concept for an innovative approach to target the retention of proatherogenic lipoproteins in a pre-clinical setting.

scholarly journals Alpha-1-antitrypsin suppresses oxidative stress in preeclampsia by inhibiting the p38MAPK signaling pathway: An in vivo and in vitro study

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0173711 ◽  
Author(s):  
Ya-Ling Feng ◽  
Yong-Xiang Yin ◽  
Jian Ding ◽  
Hua Yuan ◽  
Lan Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
In Vitro Study ◽  
Vitro Study ◽  
P38mapk Signaling ◽  
Alpha 1 Antitrypsin

scholarly journals Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 580-591 ◽  
Author(s):  
Gareth E. Lim ◽  
Guan J. Huang ◽  
Nina Flora ◽  
Derek LeRoith ◽  
Christopher J. Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Oral Glucose ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Resistant ◽  
L Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Phosphatidylinositol 3

Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 ± 58%. Insulin resistance was induced by 24 h pretreatment with 10−7m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion. Insulin is a novel secretagogue of the incretin hormone, glucagon-like peptide-1 (GLP-1), and L cell insulin resistance impairs heterologous secretagogue-induced GLP-1 secretion in vitro and in vivo.

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