Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases.

Reactive Oxygen Species in Metabolic and Inflammatory Signaling.

Phenolic compounds including phenolic acids, flavonoids and proanthocyanidins are widely distributed in plants as a protective mechanism against biotic and abiotic stresses. Fruits, vegetables, grains, spices and herbs are the richest source of dietary polyphenols. High intake of these foods has been linked to lowered risk of most common degenerative and chronic diseases that are known to be caused by oxidative stress. This review intends to summarize briefly recent progress on the chemistry and biochemistry of dietary polyphenols, their antioxidant and anti-inflammatory activities, and the underlying molecular mechanisms of their involvement in inflammation mediated metabolic diseases are also discussed. Perspectives for future research are also briefly discussed.

Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects

Background/Aims: The serum- and glucocorticoid-inducible kinase Sgk1 contributes to cardiac remodeling and development of heart failure, which is paralelled by Sg

/pdf/sgk1-dependent-stimulation-of-cardiac-na-h-exchanger-nhe1-by-1u0suc69c6.pdf

Sgk1-Dependent Stimulation of Cardiac Na+/H+ Exchanger Nhe1 by Dexamethasone

Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.

http://smallmoleculetechnologies.com/wp-content/uploads/2015/02/Small-Molecule-Technologies-Peer-Review-Articles-Kim-2014-new-insights-mechanisms-polyphenols-beyond-antioxidant-properties.pdf

New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate.

Significance: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1–7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. Critical Issues: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very im...

/pdf/the-role-of-sirtuins-in-antioxidant-and-redox-signaling-3tpkc5qq1a.pdf

The Role of Sirtuins in Antioxidant and Redox Signaling

Resveratrol, a natural polyphenol abundantly found in grape skins and red wine, possesses diverse biochemical and physiological actions, including anti-inflammatory, anti-oxidation, anti-proliferation and promotion of differentiation, and chemopreventive effects. Recently, it is attracting increased attention due to its health benefits, especially in common age-related diseases such as cardiovascular disease, cancer, type 2 diabetes, and neurological conditions. In this review, we discuss the latest cellular and molecular findings that account for the beneficial actions of resveratrol. J. Cell. Biochem. 113: 752–759, 2012. © 2011 Wiley Periodicals, Inc.

Cellular and molecular effects of resveratrol in health and disease

Resveratrol protects cardiomyocytes from hypoxia-induced apoptosis through the SIRT1-FoxO1 pathway.

Cardiac hypertrophy is one of the most commonly cardiovascular diseases in clinical practice. Despite the extensive studies, the pathophysiology of cardiac hypertrophy, however, remains incompletely understood. Studies have demonstrated that insulin signaling may be involved in cardiac growth and protein synthesis. More recently, a growing body of evidence suggests that insulin signaling is associated with the development of cardiac hypertrophy. The evidence for the hypotheses included that (1) several studies have demonstrated insulin is an important regulator of physiological cardiac growth; (2) PI3K-Akt pathway has been investigated as a participant in the cardiac hypertrophic program; (3) negative regulators of insulin signaling show beneficial effects on cardiac hypertrophy development; and (4) insulin signaling interaction with angiotensin II in cardiac hypertrophy. Although the studies suggest that the association between insulin signaling and cardiac hypertrophy, the exact pathogenesis of insulin signaling in cardiac hypertrophy development remains elusive and requires further investigation. Insulin signaling may provide a scientific basis for further research on the underlying mechanisms of cardiac hypertrophy and may target for pharmacological interruption of cardiac hypertrophy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1755-5922.2009.00120.x

Insulin Signaling: A Possible Pathogenesis of Cardiac Hypertrophy

Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord‑derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin‑induced rat model of DCM. Male Lewis rats (aged 8‑weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1x106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle‑injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor‑β1 (TGF‑β1), tumor necrosis factor‑α (TNF‑α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF‑α, extracellular‑signal regulated kinase 1/2 (ERK1/2) and TGF‑β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF‑α and the TGF‑β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM.

/pdf/human-umbilical-cord-mesenchymal-stem-cells-alleviate-qnn2c4s5by.pdf

Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF‑α and TGF‑β1/ERK1/2 signaling pathways

Calorie restriction (CR) has been shown to increase longevity and mitigate age‑associated diseases in various organisms. Numerous studies have identified that sirtuin 1 (SIRT1) is upregulated by CR. However, the expression of SIRT isoforms 2‑7 in response to CR in cardiomyocytes has yet to be elucidated. Therefore, the present study aimed to investigate the cellular localization and expression of SIRT1‑7 in cardiomyocytes. Twenty SD rats were fed either ad libitum (AL) or a CR diet (60% of AL) for three weeks. In addition, H9c2 cells were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with either normal‑ (4.5 g/l) or low‑ (1 g/l) glucose concentrations for 24 h, representing control or CR cells, respectively. CR rats were observed to have significantly lower heart and body weights (BWs) than control rats. Moreover, immunohistochemical analyzes revealed that SIRT1, 3‑5 and 7 demonstrated similar localization patterns in H9c2 cells and rat cardiac tissues, with SIRT1 and 7 predominantly located in the nucleus and SIRT3‑5 in the cytoplasm. This was in contrast with SIRT2, which was detected exclusively in the cytoplasm in rat cardiac tissues, but was found predominantly in the nucleus in H9c2 cells. The converse was observed for SIRT6. Quantitative polymerase chain reaction revealed that the mRNA expression of SIRT1‑4 and ‑7 was increased in the CR group. Western blot analysis further revealed that the protein expression of SIRT1‑4 and ‑7 was significantly increased in the cardiac tissues of rats in the CR group. These results suggest that CR may attenuate age‑associated changes through reducing BW. Moreover, short‑term CR may activate SIRT1 as well as SIRT2‑4 and ‑7 expression in cardiomyocytes in vivo and in vitro.

https://www.spandidos-publications.com/10.3892/mmr.2014.1944/download

Short‑term calorie restriction activates SIRT1‑4 and ‑7 in cardiomyocytes in vivo and in vitro.

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