scholarly journals Narrow-Leafed Lupin (Lupinus angustifolius L.) Seeds Gamma-Conglutin is an Anti-Inflammatory Protein Promoting Insulin Resistance Improvement and Oxidative Stress Amelioration in PANC-1 Pancreatic Cell-Line

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 12 ◽  
Author(s):  
Elena Lima-Cabello ◽  
Juan D. Alché ◽  
Sonia Morales-Santana ◽  
Alfonso Clemente ◽  
Jose C. Jimenez-Lopez
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Insulin Signalling ◽  
Pancreatic Cell ◽  
Protein Levels ◽  
Stress Amelioration ◽  
Inflammatory Protein ◽  
Insulin Signalling Pathway ◽  
Anti Inflammatory

(1) Background: Inflammation molecular cues and insulin resistance development are some of the main contributors for the development and advance of the pathogenesis of inflammatory-related diseases; (2) Methods: We isolated and purified γ-conglutin protein from narrow-leafed lupin (NLL or blue lupin) mature seeds using affinity-chromatography to evaluate its anti-inflammatory activities at molecular level using both, a bacterial lipopolysaccharide (LPS)-induced inflammation and an insulin resistance pancreatic cell models; (3) Results: NLL γ-conglutin achieved a plethora of functional effects as the strong reduction of cell oxidative stress induced by inflammation through decreasing proteins carbonylation, nitric oxide synthesis and inducible nitric oxide synthase (iNOS) transcriptional levels, and raising glutathione (GSH) levels and modulation of superoxide dismutase (SOD) and catalase enzymes activities. γ-conglutin induced up-regulated transcriptomic and protein levels of insulin signalling pathway IRS-1, Glut-4, and PI3K, improving glucose uptake, while decreasing pro-inflammatory mediators as iNOs, TNFα, IL-1β, INFγ, IL-6, IL-12, IL-17, and IL-27; (4) Conclusion: These results suggest a promising use of NLL γ-conglutin protein in functional foods, which could also be implemented in alternative diagnosis and therapeutic molecular tools helping to prevent and treat inflammatory-related diseases.

scholarly journals Melatonin and Microglia

2021 ◽  
Vol 22 (15) ◽  
pp. 8296
Author(s):  
Rüdiger Hardeland
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Signal Transduction ◽  
Endothelial Cells ◽  
Bacterial Infections ◽  
Melatonin Receptors ◽  
Sterile Inflammation ◽  
High Complexity ◽  
Anti Inflammatory ◽  
Multiple Signaling

Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT1 and MT2 melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia.

scholarly journals Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

2011 ◽  
Vol 301 (5) ◽  
pp. H2093-H2101 ◽  
Author(s):  
Baptiste Kurtz ◽  
Helene B. Thibault ◽  
Michael J. Raher ◽  
John R. Popovich ◽  
Sharon Cawley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mitochondrial Respiration ◽  
Pressure Overload ◽  
Lv Remodeling ◽  
Stress Levels ◽  
Nitric Oxide Synthase 3 ◽  
And Function ◽  
Oxide Synthase

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

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.

scholarly journals Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Giuseppe Verdile ◽  
Kevin N. Keane ◽  
Vinicius F. Cruzat ◽  
Sandra Medic ◽  
Miheer Sabale ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Insulin Signalling ◽  
Contributory Factor ◽  
Protein Accumulation ◽  
Age Related ◽  
Impaired Insulin ◽  
And Oxidative Stress

Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β(Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.

scholarly journals Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

2017 ◽  
Vol 41 (6) ◽  
pp. 2419-2431 ◽  
Author(s):  
Lin Dou ◽  
Shuyue Wang ◽  
Libo Sun ◽  
Xiuqing Huang ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphatase ◽  
Insulin Signalling ◽  
Critical Role ◽  
Transcriptional Regulator ◽  
Signalling Pathway ◽  
Hepatic Insulin Resistance ◽  
Luciferase Assay ◽  
Insulin Signalling Pathway ◽  
Tnf Α

Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

scholarly journals Galantamine alleviates oxidative stress alongside anti-inflammatory and cardio-metabolic effects in subjects with the metabolic syndrome in a randomized trial

2020 ◽  
Author(s):  
Carine Teles Sangaleti ◽  
Keyla Yukari Katayama ◽  
Kátia De Angelis ◽  
Tércio Lemos de Moraes ◽  
Amanda Aparecida Araújo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Autonomic Regulation ◽  
Metabolic Effects ◽  
Antioxidant Enzyme Activities ◽  
Low Grade ◽  
The Metabolic Syndrome ◽  
Inflammatory State ◽  
Anti Inflammatory

AbstractBackgroundThe metabolic syndrome (MetS) is an obesity-driven disorder with pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered autonomic regulation, are important components of MetS pathophysiology. We recently reported that galantamine, an acetylcholinesterase inhibitor and an FDA-approved drug (for Alzheimer’s disease) alleviates the inflammatory state in MetS subjects. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS.MethodsThe effects of galantamine treatment, 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n=22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment.ResultsGalantamine treatment significantly increased antioxidant enzyme activities, including SOD (+1.65 USOD/mg protein, [95% CI 0.39 to 2.92], P=0.004) and CAT (+0.93 nmol/mg, [95% CI 0.34 to 1.51], P=0.011), decreased lipid peroxidation (thiobarbituric acid reactive substances, -5.45 pmol/mg, [95% CI -10.97 to 0.067], P=0.053) and systemic nitrite levels (-0.05 nit/mg protein, [95% CI -0.21 to 0.10], P=0.038) compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment.ConclusionLow-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with galantamine to ameliorate MetS pathophysiology.

scholarly journals The Role of TGFβ Ligands and Signalling on Insulin Resistance in Skeletal Muscle in Women With PCOS

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A443-A444
Author(s):  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Rhiannon K Patten ◽  
Andrew J McAinch ◽  
Raymond J Rodgers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Whole Body ◽  
Insulin Signalling Pathway ◽  
Cultured Myotubes ◽  
Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.

scholarly journals Reversible insulin resistance helps Bactrian camels survive fasting

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fucheng Guo ◽  
Rendalai Si ◽  
Quanyun Li ◽  
Le Hai ◽  
Li Yi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signalling ◽  
Serum Insulin ◽  
Fasting Period ◽  
Insulin Levels ◽  
Insulin Tolerance ◽  
Insulin Signalling Pathway ◽  
Bactrian Camels ◽  
Three Stages ◽  
Branched Chain

AbstractCamels have hunger tolerance and can adapt to the severe environment of the desert. Through the comparison of insulin signalling pathway genes in different tissues in different eating periods (feeding, fasting and recovery feeding), it was found that IRS1, PIK3CB, PIK3R1 and SLC2A4 expression was significantly downregulated in the fore hump and hind hump during the fasting period. In addition, there was no difference in serum insulin levels among the three stages. However, the serum leptin and adiponectin levels decreased significantly during fasting. Additionally, insulin tolerance tests during the three stages showed that camels were insensitive to insulin during fasting. Further study of the serum metabolites showed that serum branched-chain and aromatic amino acid levels increased during the fasting period. Finally, analysis of microbial diversity in camel faeces at different stages showed that during the fasting period, the proportion of Firmicutes and Actinobacteria increased, while that of Bacteroides and the butyrate-producing bacterium Roseburia decreased. The results of this study show that fasting is accompanied by changes in the activation of insulin pathways in various camel tissues, normal insulin levels, and increased lipolysis and insulin resistance, which return to normal after eating.

scholarly journals Global proteomic analysis of insulin receptor interactors in glomerular podocytes

2020 ◽  
Vol 5 ◽  
pp. 202
Author(s):  
Salman B. Hosawi ◽  
Jonathan D. Humphries ◽  
Richard J. Coward ◽  
David Knight ◽  
Martin J. Humphries ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Time Course ◽  
Insulin Signalling ◽  
Label Free ◽  
Insulin Resistant ◽  
Filtration Barrier ◽  
Proteomic Approach ◽  
Insulin Signalling Pathway ◽  
Organ Systems

Background: Insulin signalling contributes to diverse cellular activities including protein synthesis, proliferation and cell survival. Insulin resistance describes the inability of cells to activate the insulin signalling pathway effectively; leading to pathological effects in multiple organ systems including the kidney. In diabetic kidney disease, there is progressive glomerular dysfunction and recent studies have demonstrated that the kidney podocyte is a direct target for insulin action. In this study we defined the literature-based insulin receptor (INSR) interactome and utilised an unbiased proteomic approach to examine INSR interactors in podocytes. Methods: Human podocytes expressing the INSR were characterised under basal and insulin resistant conditions. The INSR was isolated by whole cell immunoprecipitation following a time course stimulation of 2, 7, and 15 minutes with of 100nM insulin. The resulting INSR complexes were analysed by label-free mass spectrometry (MS) to detect protein interactors. Results: We identified 27 known, direct INSR interactors in addition to novel interactors including doublecortin domain-containing protein 2 (DCDC2). The interaction of DCDC2 with the INSR was confirmed by immunoprecipitation and immunofluorescence, and under insulin resistant conditions, DCDC2 had increased association with the INSR. siRNA knockdown of DCDC2 in podocytes resulted in cell morphological change and altered INSR localisation. Conclusion: This study provides insight into the complexity of INSR interactors in podocytes and highlights DCDC2 as a novel INSR binding protein. Involvement of this novel interactor in insulin signalling and podocyte biology may explain how insulin resistance alters morphology and integrity of the glomerular filtration barrier.

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