Correction: Differential Effects of Prenatal Stress in 5-Htt Deficient Mice: Towards Molecular Mechanisms of Gene × Environment Interactions

Epidemiological and clinical studies over the past two decades have provided strong evidence that genetic elements interacting with environmental components can individually and collectively influence one’s susceptibility to cancer. In addition to tumorigenic properties, numerous environmental factors, such as nutrition, chemical carcinogens, and tobacco/alcohol consumption, possess pro-invasive and pro-metastatic cancer features. In contrast to traditional cancer treatment, modern therapeutics not only take into account an individual’s genetic makeup but also consider gene–environment interactions. The current review sharpens the focus by elaborating on the impact that environmental factors have on the pathogenesis and progression of head and neck cancer and the underlying molecular mechanisms involved. Recent advances, challenges, and future perspectives in this area of research are also discussed. Inhibiting key environmental drivers of tumor progression should yield survival benefits for patients at any stage of head and neck cancer.

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HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6620873 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhenling Zhang ◽

Lijing Zhang ◽

Qiuping Zhang ◽

Bojia Liu ◽

Fang Li ◽

...

Keyword(s):

Molecular Mechanisms ◽

Intestinal Barrier ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Barrier Integrity ◽

Tnf Α ◽

Intestinal Barrier Integrity ◽

Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

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Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils

AJP Cell Physiology ◽

10.1152/ajpcell.00336.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. C494-C501 ◽

Cited By ~ 3

Author(s):

Wenli Liu ◽

Yueqin Liu ◽

Hongzhen Li ◽

Griffin P. Rodgers

Keyword(s):

Hydrogen Peroxide ◽

Nadph Oxidase ◽

Molecular Mechanisms ◽

Oxidase Inhibitor ◽

Superoxide Production ◽

Wild Type ◽

Escherichia Coli Bacteria ◽

Induced Apoptosis ◽

Nadph Oxidase Activation ◽

Deficient Mice

Neutrophils increase production of reactive oxygen species, including superoxide, hydrogen peroxide (H2O2), and hydroxyl radical, to destroy invading microorganisms under pathological conditions. Conversely, oxidative stress conditions, such as the presence of H2O2, induce neutrophil apoptosis, which helps to remove neutrophils after inflammation. However, the detailed molecular mechanisms that are involved in the latter process have not been elucidated. In this study, we investigated the potential role of olfactomedin 4 (Olfm4) in H2O2-induced superoxide production and apoptosis in mouse neutrophils. We have demonstrated that Olfm4 is not required for maximal-dosage PMA- and Escherichia coli bacteria-induced superoxide production, but Olfm4 contributes to suboptimal-dosage PMA- and H2O2-induced superoxide production. Using an NADPH oxidase inhibitor and gp91phox-deficient mouse neutrophils, we found that NAPDH oxidase was required for PMA-stimulated superoxide production and that Olfm4 mediated H2O2-induced superoxide production through NADPH oxidase, in mouse neutrophils. We have shown that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-induced apoptosis compared with neutrophils from wild-type mice. We also demonstrated that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-stimulated mitochondrial damage and membrane permeability, and as well as reduced caspase-3 and caspase-9 activity, compared with neutrophils from wild-type mice. Moreover, the cytoplasmic translocation of the proapoptotic mitochondrial proteins Omi/HtrA2 and Smac/DIABLO in response to H2O2was reduced in neutrophils from Olfm4-deficient mice compared with neutrophils from wild-type mice. Our study demonstrates that Olfm4 contributes to H2O2-induced NADPH oxidase activation and apoptosis in mouse neutrophils. Olfactomedin 4 might prove to be a potential target for future studies on inflammatory neutrophil biology and for inflammatory disease treatment.

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Abstract 353: Chronic Polarization of Low-grade Inflammatory Monocytes During the Pathogenesis of Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.353 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Liwu Li ◽

Shuo Geng

Keyword(s):

High Fat Diet ◽

Immunohistochemical Staining ◽

Molecular Mechanisms ◽

Molecular Switches ◽

Low Grade ◽

High Fat ◽

Inflammatory Monocytes ◽

Severe Atherosclerosis ◽

Low Grade Inflammation ◽

Deficient Mice

Background: Chronic inflammation mediated by low-grade inflammatory monocytes may serve as a key culprit for atherosclerosis. However, the cellular and molecular mechanisms responsible for the low-grade inflammatory polarization of monocytes are not well understood. We hypothesize that the selective clearance of homeostatic molecular switches may pre-dispose innate monocytes for the establishment of non-resolving low-grade inflammation. Methods and Results: By comparing high-fat-diet (HFD) fed ApoE deficient mice chronically challenged with either PBS or a subclinical dose endotoxin, we observed that subclinical endotoxin potently induced the establishment of low-grade inflammation, as manifested in elevated levels of systemic inflammatory mediators, accumulation of low-grade inflammatory circulating monocytes and neutrophils, as well as lipids. Immunohistochemical staining of liver and aorta tissues revealed significantly elevated steatosis and atherosclerosis in ApoE deficient mice chronically challenged with subclinical dose of endotoxin. At the mechanistic level, the polarization of low-grade inflammatory monocytes were due to the down-regulation and removal of key homeostatic molecules such as IRAK-M and Tollip. ApoE and IRAK-M double deficient mice had enhanced inflammatory polarization of innate monocytes, and developed severe atherosclerosis. Conclusions: Our data suggest that the clearance of homeostatic suppressors such as IRAK-M and Tollip may cause the memory establishment of low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis. Key words: Low-grade inflammation, monocyte polarization, innate memory, atherosclerosis

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Abstract 263: Differential Effects of 17ß-Estradiol and 16a-Hydroxyestrone in Oxidative Stress and Proliferative Responses in Human Pulmonary Artery Smooth Muscle Cells - Implications in Pulmonary Arterial Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a263 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Katie Y Hood ◽

Augusto C Montezano ◽

Margaret R MacLean ◽

Rhian M Touyz

Keyword(s):

Oxidative Stress ◽

Pulmonary Arterial Hypertension ◽

Cell Growth ◽

Arterial Hypertension ◽

Molecular Mechanisms ◽

Antioxidant Systems ◽

Ros Generation ◽

Ros Production ◽

Differential Effects ◽

Pulmonary Arterial

Women develop pulmonary arterial hypertension (PAH) more frequently than men. This may relate, in part, to metabolism of 17β-estradiol (E2), leading to formation of the deleterious metabolite, 16α-hydroxyestrone (16α OHE1), which plays a role in the remodelling of pulmonary arteries. Molecular mechanisms whereby 16αOHE1 influences PASMC remodelling are unclear but ROS may be important, since oxidative stress has been implicated in the pathogenesis of PAH. We hypothesised that E2 and 16αOHE1 leads to Nox-induced ROS production, which promotes PASMC damage. Cultured PASMCs were stimulated with either E2 (1nM) or 16αOHE1 (1nM) in the presence/absence of EHT1864 (100μM, Rac1 inhibitor) or tempol (antioxidant; 10μM). ROS production was assessed by chemiluminescence (O2-) and Amplex Red (H2O2). Antioxidants (thioredoxin, peroxiredoxin 1 and NQ01), regulators of Nrf2 (BACH1, Nrf2) and, marker of cell growth (PCNA) were determined by immunoblotting. E2 increased O2- production at 4h (219 ± 30% vs vehicle; p<0.05), an effect blocked by EHT1864 and tempol. E2 also increased H2O2 generation (152 ± 4%; p<0.05). Thioredoxin, NQ01 and peroxiredoxin1 (71 ± 6%; 78 ± 9%; 69 ± 8%; p<0.05 respectively) levels were decreased by E2 as was PCNA expression (72 ± 2%; p<0.05). 16αOHE1 exhibited a rapid (5 min) and exaggerated increase in ROS production (355 ± 41%; p<0.05), blocked by tempol and EHT1864. This was associated with an increase in Nox4 expression (139 ± 11% vs vehicle, p<0.05). 16αOHE1 increased BACH1, (129 ± 3%; p<0.05), a competitor of Nrf2, which was decreased (92 ± 2%). In contrast, thioredoxin expression was increased by 16aOHE1 (154 ± 22%; p<0.05). PCNA (150 ± 5%) expression was also increased after exposure to 16αOHE1. In conclusion, E2 and 16αOHE1 have differential effects on redox processes associated with PASMC growth. Whereas E2 stimulates ROS production in a slow and sustained manner without effect on cell growth, 16αOHE1 upregulates Nox4 with associated rapid increase in ROS generation and downregulation of antioxidant systems, affecting proliferation. Our findings suggest that E2 -derived metabolites may promote a pro-proliferative PASMC phenotype through Nox4-derived ROS generation. These deleterious effects may impact on vascular remodeling in PAH.

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Gene-Environment Interaction in the Determination of Levels of Plasma Fibrinogen

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615917 ◽

1999 ◽

Vol 82 (08) ◽

pp. 818-825 ◽

Cited By ~ 17

Author(s):

Le-Anh Luong ◽

Hugh Montgomery ◽

Ian Day ◽

Vidya Mohamed-Ali ◽

John Yudkin ◽

...

Keyword(s):

Risk Factors ◽

Healthy Subjects ◽

Large Scale ◽

Molecular Mechanisms ◽

Smoking Habit ◽

Plasma Fibrinogen ◽

Environment Interaction ◽

Gene Environment ◽

Genotype Information

IntroductionThis review will focus on the inflammatory risk factors that may influence changes in plasma fibrinogen levels and that may influence an individual’s risk of ischemic heart disease (IHD). These inflammatory risk factors occur to a different extent in individuals as their environment changes. Although a specific genotype may be associated, in healthy subjects, with modest differences in levels of a risk factor for thrombosis, this effect may be larger or smaller in subgroups of subjects. Documenting such gene-environment interactions is important if genotype information is ever to be used in a clinical or diagnostic setting. Understanding the molecular mechanisms of such interactions is vital to the development of novel therapeutic approaches to reduce risk of myocardial infarction (MI).We review some of the gene-environment interactions detected to date for the G-455A β-fibrinogen gene promoter polymorphism. Carriers of the A allele, representing roughly 20% of the population, consistently have, on average, 7% to 10% higher fibrinogen levels than those with the genotype GG. Data will be presented to demonstrate interaction between situations of inflammatory stimulation (e.g., smoking habit, presence of ischemic disease, and level of physical exercise) in the determination of the magnitude of the effect of the A allele on plasma fibrinogen levels.The cytokine interleukin-6 (IL-6) is the likely link between inflammatory processes and IHD. Recently we have identified a functional G/C polymorphism at -174bp in the IL-6 promoter, with the G allele being a 2 to 4 times stronger promoter upon stimulation with interleukin-1 (IL-1) or lipopolysaccharide (LPS). In a small study of healthy subjects, the C allele was associated with significantly lower mean plasma levels of IL-6, an effect which may be protect against the development of IHD. Finally, we describe a rapid throughput genotyping method that is useful for large-scale genetic epidemiology studies.

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