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 Effect of Resveratrol on Metabolic Syndrome

2021 ◽  
Vol 6 (5) ◽  
pp. 408-413
Author(s):  
N. A. Markhon ◽  
◽  
V. М. Baibakov ◽  
V. A. Kosse ◽  
I. V. Lyulko ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Antioxidant Properties ◽  
Beneficial Effects ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Wide Range ◽  
Prevention And Treatment

The purpose of the study is to analyze the sources of modern literature of domestic and foreign researchers on the prospects of resveratrol in the prevention and treatment of metabolic syndrome. Metabolic syndrome is a clinical manifestation characterized by many comorbidities, including hyperglycemia, abdominal obesity, hypertension, and dyslipidemia. All components of metabolic syndrome are involved in the induction of low-quality inflammation and oxidative stress, characteristic of this symptom complex. Metabolic syndrome is associated with an increased risk of cardiovascular disease and early mortality, which has a significant impact on health care costs. Finding an effective and alternative therapeutic strategy, which is natural and has no side effects, can be a useful tool in the fight against metabolic syndrome. This review focuses on the potential beneficial effects of a polyphenolic natural compound – resveratrol – on various molecular targets with programming for the development of disorders associated with metabolic syndrome and its comorbidities. A number of data on the effects of resveratrol on body weight, insulin sensitivity, glucose tolerance, lipid profile, blood pressure, oxidative stress indicate that this compound has a wide range of beneficial effects on human health, and also has a beneficial effect on metabolic syndrome. A numerous data on the improvement of homeostasis, glucose, lipids, fat reduction, blood pressure, oxidative stress may demonstrate how resveratrol may be useful in the prevention and treatment of metabolic syndrome and related disorders due to its anti-inflammatory, antiplatelet and antioxidant properties. Resveratrol can be used either early as a reprogramming agent or later as a part of the treatment of metabolic syndrome. A few of the main molecular mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are given in the article. Conclusion. Presented review of literature outlined the potential of resveratrol as supplementary or alternative medicine. Thus, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions. The article considers some molecular level targets for resveratrol in terms of its effect on the metabolic syndrome, such as adenosine monophosphate-activated protein kinase, SIRT1 protein, the main switch of the cellular defense system (Nrf2), nuclear factor-kappa B, estrogen receptor and the like

Abstract MP58: Tissue And Sex Specific Effects Of Gstm1 Deletion In Mouse Models

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yves Wang ◽  
Nhu Nguyen ◽  
Keith Nehrke ◽  
Paul S Brookes ◽  
Thu H Le
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Properties ◽  
Iri Model ◽  
Increased Risk ◽  
Study Gene Expression

The glutathione S-transferase ( Gst ) gene family encodes antioxidant enzymes. In humans, a common null allele deletion variant of GST μ-1 ( GSTM1 ) is highly prevalent across populations and is associated with increased risk and progression of various diseases. Using a Gstm1 knockout (KO) mouse model, we previously showed that KO mice with angiotensin II-induced hypertension (HTN) have increased kidney injury compared to wild-type (WT) controls, mediated by elevated oxidative stress. In the same mouse model, we have recently reported that in a Langendorff-perfused cardiac ischemia-reperfusion injury (IRI) model, where damage is also mediated by oxidative stress, male KO hearts are protected while females are not. Here, we investigated the molecular mechanisms for this difference in male hearts. WT and KO mice of both sexes were studied at 12-20 weeks of age. Hearts were snap frozen at baseline and after 25 min of global ischemia, and kidneys were collected at baseline and 4 weeks following HTN induction. A panel of 18 Gst genes were probed by qPCR from baseline hearts and kidneys of both sexes. Global metabolites were assayed using Metabolon, Inc. from hearts of both sexes and kidneys of males, at both baseline and diseased states. Analysis by qPCR (n = 3/group) showed that male, but not female, KO hearts had upregulation of other Gst s. In contrast, no significant differences between were found in male kidneys. Metabolomics (n = 6/group) detected 695 metabolites in hearts and 926 in kidneys. There were increases in several metabolites in KO vs. WT hearts including those with antioxidant properties. Notably, increases in carnosine and anserine were observed in KO male hearts but not in female hearts, while that of other antioxidant-related metabolites were observed in hearts of both sexes, but not in kidneys. HTN induced significant increases in metabolites in KO vs. WT kidneys in the pathways related to and linking methionine, cysteine, and glutathione, which were not observed in hearts. In this study, gene expression and metabolites suggest that the mechanisms compensating for the loss of GSTM1 are both tissue and sex specific. The resulting differences in antioxidant enzymes and metabolites may explain the unexpected protection for male Gstm1 KO hearts in IRI.

scholarly journals Vascular Dysfunction in Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3055
Author(s):  
Megan A. Opichka ◽  
Matthew W. Rappelt ◽  
David D. Gutterman ◽  
Justin L. Grobe ◽  
Jennifer J. McIntosh
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Treatment Options ◽  
Cardiovascular Disorder ◽  
Endothelial Damage ◽  
Spiral Artery ◽  
Mitochondrial Stress ◽  
Inflammatory State ◽  
Life Threatening

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

scholarly journals Increased Oxidative Stress in Prepubertal Children Born Small for Gestational Age

2007 ◽  
Vol 92 (4) ◽  
pp. 1372-1378 ◽  
Author(s):  
Angelika Mohn ◽  
Valentina Chiavaroli ◽  
Marina Cerruto ◽  
Annalisa Blasetti ◽  
Cosimo Giannini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Antioxidant Status ◽  
Lag Phase ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Prepubertal Children ◽  
Increased Risk

Abstract Context: Low birth weight is associated with an increased risk of metabolic and cardiovascular diseases in adulthood. The development of insulin resistance (IR) seems to play a pivotal role; no data on the oxidant-antioxidant status are available in this risk group. Objective: This study is an assessment of oxidant-antioxidant status in prepubertal children born small for gestational age (SGA) in comparison to healthy controls and the relationship to IR. Design: This cross-sectional study compares indexes of IR and oxidant-antioxidant status in three different groups (SGA+, SGA−, controls), with analysis by post hoc and Pearson correlation. Setting: The study was conducted in the Academic Department of Pediatrics. Participants: A total of 19 SGA+ and 16 SGA− children were compared with 13 controls. Intervention: No intervention was used. Main Outcome Measures: Indexes of IR (glucose to insulin ratio, homeostasis model assessment of IR) were evaluated, and markers of oxidative stress (lag phase, malonildialdehyde, vitamin E) were measured. Results: Homeostasis model assessment of IR was significantly higher in SGA+ than SGA− children (1.32 ± 0.9 vs. 0.69 ± 0.47; P = 0.03) and controls (0.71 ± 0.37; P = 0.04). Glucose to insulin ratio was significantly lower in SGA+ than SGA− children (12.41 ± 5.01 vs. 26.54 ± 17.18; P = 0.02) and controls (26.96 ± 20.70; P = 0.04). Lag phase was significantly shorter in SGA+ than SGA− children (24.3 ± 4.38 vs. 35.59 ± 11.29 min; P = 0.003) and controls (45.28 ± 7.69 min; P = 0.0001) and in SGA− than controls (P = 0.01). Malonildialdehyde was significantly higher in SGA+ than SGA− children (0.79 ± 0.3 vs. 0.6 ± 0.1 nmol/mg; P = 0.03) and controls (0.36 ± 0.04 nmol/mg; P = 0.0001) and in SGA− children than controls (P = 0.02). Vitamin E was significantly reduced in SGA+ children than controls (27.54 ± 7.9 vs. 43.23 ± 11.32 μmol/liter; P = 0.002). Conclusion: Oxidative stress is present in both SGA+ and SGA− children, with a continuous alteration in relation to IR. Therefore, catch-up growth might exert the greatest influence in the development of future diseases.

scholarly journals The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2810-2819 ◽  
Author(s):  
Taichi Sugizaki ◽  
Mitsuhiro Watanabe ◽  
Yasushi Horai ◽  
Nao Kaneko-Iwasaki ◽  
Eri Arita ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Insulin Signaling ◽  
Metabolic Diseases ◽  
In Vitro Study ◽  
Liver X Receptor ◽  
Gene Expressions ◽  
The Metabolic Syndrome ◽  
Increased Risk

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

Homocysteine and thrombosis: from basic science to clinical evidence

2005 ◽  
Vol 94 (11) ◽  
pp. 907-915 ◽  
Author(s):  
Jan Brożek ◽  
Andrzej Szczeklik ◽  
Anetta Undas
Keyword(s):  
Molecular Mechanisms ◽  
Platelet Reactivity ◽  
Current Evidence ◽  
Factor V ◽  
Dna Hypomethylation ◽  
Homocysteine Concentration ◽  
Increased Risk ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
Artery Disease

SummaryHomocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.

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.

scholarly journals Biomarkers of Oxidative Stress for Neonatal Lung Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Giuliana Ferrante ◽  
Giuseppe Carota ◽  
Giovanni Li Volti ◽  
Mario Giuffrè
Keyword(s):  
Oxidative Stress ◽  
Lung Disease ◽  
Arterial Oxygen Tension ◽  
Ease Of Use ◽  
Arterial Oxygen ◽  
Current Evidence ◽  
Antioxidant Systems ◽  
Postnatal Life ◽  
Neonatal Lung ◽  
Biomarkers Of Oxidative Stress

The transition from prenatal to postnatal life causes a significant increase in arterial oxygen tension and the activation of metabolic pathways enabling the newborn's adaptation to the extra-uterine environment. The balance between pro-oxidant and anti-oxidant systems is critical to preserve cellular functions. Indeed, oxidative stress (OS) occurs when the production of free radicals is not balanced by the activity of intracellular antioxidant systems, contributing to cellular and tissue damage. Perinatal OS may have serious health consequences during the postnatal period and later in life. Namely, OS has been recognized as the major cause of lung injury in newborns, especially those preterm born, due to their immature lung and antioxidant systems. The development of OS biomarkers has gained increasing research interest since they may provide useful insights about pathophysiological pathways underlying OS-mediated pulmonary diseases in newborns. Moreover, their implementation in clinical settings may help to early identify high risk-newborns and to provide targeted treatment. Ideally, a biomarker should demonstrate ease of use, biological validity and reproducibility, high sensitivity and specificity. However, none of the clinically validated biomarkers so far have been qualified for neonatal lung disease. Additionally, the complex technical procedures and the high cost of such determinations have hampered the use of OS biomarkers in clinical practice. This review aims to evaluate the current evidence on the application of biomarkers of oxidative stress for neonatal lung disease and exploring the most relevant issues affecting their implementation in practice, as well as the associated evidence gaps and research limitations.

scholarly journals Nutraceuticals as a potential adjunct therapy toward improving vascular health in CKD

2019 ◽  
Vol 317 (5) ◽  
pp. R719-R732 ◽  
Author(s):  
Nicholas T. Kruse
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Health ◽  
Fully Integrated ◽  
Beneficial Effects ◽  
Increased Risk ◽  
Health Related ◽  
No Bioavailability ◽  
Mitochondria Targeting

Chronic kidney disease (CKD) is a major public health epidemic and increases risk for developing cardiovascular disease (CVD). Vascular dysfunction is a major independent risk factor toward increased risk for CVD in CKD. Several mechanisms have been postulated to result in vascular dysfunction in CKD, including oxidative stress-mediated inflammation by redox imbalance and reduced nitric oxide (NO) bioavailability and synthesis. Therefore, strategies that decrease oxidative stress and/or increase NO bioactivity may have major clinical implications toward improving vascular health and reducing the burden of CVD in CKD. Nutraceutical therapy in the form of polyphenols, dietary nitrates, or selective mitochondria-targeting therapies has recently been shown to improve vascular function by reducing oxidative stress and/or increasing NO bioavailability and synthesis. This review, therefore, highlights these three emerging nutraceuticals recently implicated in pathophysiological improvement of vascular function in CKD. This review also describes those pathophysiological mechanisms thought to be responsible for the beneficial effects on the vasculature and possible experimental considerations that may exist within human CKD populations. It is clear throughout this review that human-based mechanistic preclinical and health-related clinical studies are lacking regarding whether nutraceuticals do indeed improve vascular function in patients with CKD. As such, a comprehensive, detailed, and fully integrated understanding of nutraceuticals and vasculature function is necessary in patients with CKD. Many opportunities exist for original mechanistic and therapeutic discoveries and investigations on select nutraceuticals and their impact on vascular outcomes in patients with CKD, and these will remain exciting avenues of research in the future.

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