Context-Dependent Regulation of Nrf2/ARE Axis on Vascular Cell Function during Hyperglycemic Condition

2020 ◽  
Vol 16 (8) ◽  
pp. 797-806 ◽  
Author(s):  
Tharmarajan Ramprasath ◽  
Allen John Freddy ◽  
Ganesan Velmurugan ◽  
Dhanendra Tomar ◽  
Balakrishnan Rekha ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Dysfunction ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Antioxidant Genes ◽  
Increased Risk ◽  
Context Dependent

: Diabetes mellitus is associated with an increased risk of micro and macrovascular complications. During hyperglycemic conditions, endothelial cells and vascular smooth muscle cells are exquisitely sensitive to high glucose. This high glucose-induced sustained reactive oxygen species production leads to redox imbalance, which is associated with endothelial dysfunction and vascular wall remodeling. Nrf2, a redox-regulated transcription factor plays a key role in the antioxidant response element (ARE)-mediated expression of antioxidant genes. Although accumulating data indicate the molecular mechanisms underpinning the Nrf2 regulated redox balance, understanding the influence of the Nrf2/ARE axis during hyperglycemic condition on vascular cells is paramount. This review focuses on the context-dependent role of Nrf2/ARE signaling on vascular endothelial and smooth muscle cell function during hyperglycemic conditions. This review also highlights improving the Nrf2 system in vascular tissues, which could be a potential therapeutic strategy for vascular dysfunction.

Molecular mechanisms for vascular complications of targeted cancer therapies

2016 ◽  
Vol 130 (20) ◽  
pp. 1763-1779 ◽  
Author(s):  
Srila Gopal ◽  
Kenneth B. Miller ◽  
Iris Z. Jaffe
Keyword(s):  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Complications ◽  
Vascular Complication ◽  
Cancer Therapies ◽  
Vegf Inhibitors ◽  
Increased Risk ◽  
Anti Cancer ◽  
Targeted Cancer Therapies

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.

scholarly journals Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

2017 ◽  
Vol 6 (3) ◽  
pp. 121-128 ◽  
Author(s):  
Xuhua Mao ◽  
Hucheng Chen ◽  
Junmin Tang ◽  
Liangliang Wang ◽  
Tingting Shu
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Mrna Levels ◽  
Β Cell ◽  
Min6 Cells ◽  
Hepcidin Expression ◽  
Insulin Synthesis

Objective Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. Design We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. Methods MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. Results Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. Conclusions Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.

scholarly journals Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice

2021 ◽  
Vol 3 (9) ◽  
pp. 1202-1216
Author(s):  
Alexandra Aliluev ◽  
Sophie Tritschler ◽  
Michael Sterr ◽  
Lena Oppenländer ◽  
Julia Hinterdobler ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Hormone Secretion ◽  
Cell Types ◽  
Acid Synthesis ◽  
Enteroendocrine Cell ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Ppar Signaling ◽  
Obesogenic Diet

AbstractExcess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr–Igf1r–Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.

Abstract P031: Enhanced Cardiac Progenitor Cell Function and Differentiation in a Naturally Derived Extracellular Matrix

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Kristin M French ◽  
Jessica A DeQuach ◽  
Karen L Christman ◽  
Michael E Davis
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Progenitor Cells ◽  
Troponin I ◽  
Cell Function ◽  
Cultured Cells ◽  
Current Treatment ◽  
Gene Expressions ◽  
Antioxidant Genes ◽  
Functional Studies

Cardiovascular disease, including myocardial infarction, is a leading cause of death worldwide. Though several pharmacological treatments for severe dysfunction exist, much recent work has focused on the transplantation of adult-derived stem and progenitor cells. Early acute functional improvements have been noted, however long-term clinical efficacy is hampered by poor cell survival and engraftment. While the current treatment is infusion into the coronary artery, biomaterials may play an important role in modulating implanted cell function. This work aims to establish the role that a naturally derived extracellular matrix plays in the differentiation of cardiac progenitor cells (CPCs) and their potentially protective enzymatic systems. To test this hypothesis, we cultured rat CPCs in a naturally derived porcine ECM (pECM) and compared it to Collagen I. Quantitative real-time PCR was used to assess expression of cardiac, endothelial and smooth muscle markers. Additionally, angiotensin receptor (AT1R and AT2R) and antioxidant gene expressions were evaluated to determine the protective qualities of pECM. Preliminary data at 2 days following LIF removal demonstrate an increase in the expression of cardiac lineage markers (Nkx-2.5, Gata-4, α-MHC, and troponin I) in pECM compared to collagen. Smooth muscle markers, smooth muscle α-actin and sm22α as well as the endothelial marker Flk1 were also increased in pECM samples. Increased expression was also seen for antioxidant genes GPX1, SOD1, SOD2 and catalase in pECM cultured cells. Culturing in pECM for 7 days demonstrated an increase in Flt-1 and α-myosin heavy chain, indicating a potential increase in cardiogenesis. Moreover a 60% reduction in AT1R gene expression was observed with no significant change in AT2R expression. Our data demonstrate that culturing CPCs in naturally derived matrices may provide protection and enhance differentiation compared to collagen (present in high amounts in scarred myocardium). Future work will further elucidate this protective effect of AT1R downregulation and antioxidant increases in functional studies. In conclusion, pECM may be a potential cell delivery scaffold in post-MI treatment given its protective nature and improved differentiation influence.

scholarly journals FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4424
Author(s):  
Jung-Hwa Han ◽  
Suji Kim ◽  
Suji Kim ◽  
Heejung Lee ◽  
So-Young Park ◽  
...  
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Ros Generation ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Interacting Protein ◽  
Cell Dysfunction

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications.

scholarly journals The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

2015 ◽  
Vol 36 (3) ◽  
pp. 407-420 ◽  
Author(s):  
Hiroki Sekine ◽  
Keito Okazaki ◽  
Nao Ota ◽  
Hiroki Shima ◽  
Yasutake Katoh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Antioxidant Response ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Antioxidant Gene Expression

The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption ofMed16significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles inMed16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent inMed16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.

scholarly journals Potential role of Toll-like receptors in programming of vascular dysfunction

2013 ◽  
Vol 125 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Jennifer A. Thompson ◽  
R. Clinton Webb
Keyword(s):  
Oxidative Stress ◽  
Gestational Age ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Current Evidence ◽  
Postnatal Life ◽  
Ongoing Research ◽  
The Metabolic Syndrome ◽  
Prenatal Factors ◽  
Increased Risk

The developmental origins of the metabolic syndrome have been established through the consistent observation that small-for-gestational age and large-for-gestational age fetuses have an increased risk for hypertension and related metabolic disorders later in life. These phenotypes have been reproduced in various species subjected to a range of intrauterine insults and ongoing research is directed towards understanding the underlying molecular mechanisms. Current evidence suggests that the creation of a pro-inflammatory and pro-oxidant intrauterine milieu is a common thread among prenatal factors that have an impact upon fetal size. Furthermore, studies demonstrate that a shift in fetal redox status consequent to environmental cues persists after birth and drives the progression of vascular dysfunction and hypertension in postnatal life. TLR (Toll-like receptor) signalling has emerged as a key link between inflammation and oxidative stress and a pathogenic contributor to hypertension, insulin resistance and obesity, in both human patients and animal models of disease. Thus TLR activation and dysregulation of its signalling components represent potential molecular underpinnings of programmed hypertension and related disorders in those subjected to suboptimal intrauterine conditions, yet their contributions to developmental programming remain unexplored. We propose that danger signals mobilized by the placenta or fetal tissues during complicated pregnancy activate the fetal innate immune system through TLRs and thereby potentiate the generation of ROS (reactive oxygen species) and orchestrate fetal adaptive responses, including changes in gene expression, which later translate to vascular dysfunction. Furthermore, we suggest that, after birth, continual activation of TLR signalling propagates vascular oxidative stress and thereby accelerates the advancement of hypertension and heart failure.

scholarly journals Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice

2021 ◽  
Vol 22 (19) ◽  
pp. 10788
Author(s):  
Jie Zhao ◽  
Xiaotong Lv ◽  
Yan Huo ◽  
Xiaodi Hu ◽  
Xiaochen Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Reductase Activity ◽  
Cell Receptor ◽  
Antioxidant Response ◽  
Related Factor ◽  
Hepatic Inflammation ◽  
Antioxidant Genes ◽  
Jnk Signaling ◽  
Mrna Stabilization ◽  
Signaling Activation

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 μmol/g tissue in WT mice vs. 0.85 ± 0.14 μmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.

Activation of autophagy through modulation of 5′-AMP-activated protein kinase protects pancreatic β-cells from high glucose

2010 ◽  
Vol 425 (3) ◽  
pp. 541-551 ◽  
Author(s):  
Diana Han ◽  
Byungho Yang ◽  
L. Karl Olson ◽  
Alexander Greenstein ◽  
Seung-Hoon Baek ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Survival ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

Chronic hyperglycaemia is detrimental to pancreatic β-cells by causing impaired insulin secretion and diminished β-cell function through glucotoxicity. Understanding the mechanisms underlying β-cell survival is crucial for the prevention of β-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic β-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5′-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic β-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic β-cells. Greater knowledge of the molecular mechanisms linking autophagy and β-cell survival may unveil novel therapeutic targets needed to preserve β-cell function.

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