The role of triiodothyronine-induced substrate cycles in the hepatic response to overnutrition: thyroid hormone as an antioxidant

Overnutrition, by generating reactive oxygen species (ROS), produces oxidative stress - an important cause of cellular injury. In the liver, overnutrition begins in the perivenous hepatocytes. To prevent injury, cells must protect themselves against ROS accumulation. Overnutrition also activates the enzyme deiodinase-1 (D1), which catalyzes the conversion of T4 to T3. D1 is primarily located in the PV region of the liver. Thyroid hormone is known to generate substrate cycling. The hypothesis of this paper is that a nutrient-induced increase in intracellular T3 acts as an antioxidant by inducing substrate cycles that reduce ROS accumulation. These cycles do this by: (i) reducing ROS formation by hydrolyzing excess ATP, thus enhancing oxidative phosphorylation and reducing the proton motive force on the electron transport chain (ETC), and; (ii) enhancing the removal (reduction) of ROS by producing the NADPH required for regeneration of reduced glutathione, a potent endogenous antioxidant. Oxidative stress is an important factor in the etiology of a number of hepatic injuries, including nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. In the latter, the frequency of mutations in thyroid hormone receptors (TRs) supports the concept that thyroid hormone acts as a tumor suppressor by reducing oxidative stress. This paper reviews the substrate cycles involved in this process. It also describes other mechanisms that permit rapid availability of T3 to cells undergoing oxidative stress.     

Inflammatory and oxidative stress in rotavirus infection

Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.     

Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke

Stroke is one of the leading causes of mortality and morbidity in advanced countries of the world. Despite the fact that reactive oxygen and nitrogen species (ROS and RNS) are the by-products of normal metabolic processes and mediate important physiological processes, they can inflict damage to the cell if produced in excess due to oxidative stress. In the present review, we focus on the cellular and molecular aspects of ROS and RNS generation and its role in the pathogenesis of stroke produced by hypoxia-reperfusion (H-R) phenomena that elicit oxidative stress. We outline the reasons for the vulnerability of the brain to ischaemic insult, chronic infection and inflammation as well as the natural defence mechanisms against radical mediated injury. We deal with the effect of ROS and RNS on intracellular signaling pathways together with the phenomena of apoptosis, mitochondrial injury and survival associated with these pathways. The intracellular signaling mechanisms influenced by reactive species can have significant effects on the outcome of the condition. Future studies should focus on understanding the molecular mechanisms involved in the action of anti-radicals agents, and their mode of action.     

Skin aging and oxidative stress: Equol’s anti-aging effects via biochemical and molecular mechanisms

Oxygen in biology is essential for life. It comes at a cost during normal cellular function, where reactive oxygen species (ROS) are generated by oxidative metabolism. Human skin exposed to solar ultra-violet radiation (UVR) dramatically increases ROS production/oxidative stress. It is important to understand the characteristics of human skin and how chronological (intrinsic) aging and photo-aging (extrinsic aging) occur via the impact of ROS production by cascade signaling pathways. The goal is to oppose or neutralize ROS insults to maintain good dermal health. Botanicals, as active ingredients, represent one of the largest categories used in dermatology and cosmeceuticals to combat skin aging. An emerging botanical is equol, a polyphenolic/isoflavonoid molecule found in plants and food products and via gastrointestinal metabolism from precursor compounds. Introductory sections cover oxygen, free radicals (ROS), oxidative stress, antioxidants, human skin aging, cellular/molecular ROS events in skin, steroid enzymes/receptors/hormonal actions and genetic factors in aging skin. The main focus of this review covers the characteristics of equol (phytoestrogenic, antioxidant and enhancement of extracellular matrix properties) to reduce skin aging along with its anti-aging skin influences via reducing oxidative stress cascade events by a variety of biochemical/molecular actions and mechanisms to enhance human dermal health.     

Caveolin-1, cellular senescence and age-related diseases

According to the "free radical theory" of aging, normal aging occurs as the result of tissue damages inflicted by reactive oxygen species (ROS) when ROS production exceeds the antioxidant capacity of the cell. ROS induce cellular dysfunctions such as stress-induced premature senescence (SIPS), which is believed to contribute to normal organismal aging and play a role in age-related diseases. Consistent with this hypothesis, increased oxidative damage of DNA, proteins, and lipids have been reported in aged animals and senescent cells accumulate in vivo with advancing age. Caveolin-1 acts as a scaffolding protein that concentrates and functionally regulates signaling molecules. Recently, great progress has been made toward understanding of the role of caveolin-1 in stress-induced premature senescence. Data show that caveolin-mediated signaling may contribute to explain, at the molecular level, how oxidative stress promotes the deleterious effects of cellular senescence such as aging and age-related diseases. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of SIPS and their relevance to the biology of aging.     

Significance of ROS in oxygen sensing in cell systems with sensitivity to physiological hypoxia

Reactive oxygen species (ROS) are oxygen-containing molecular entities which are more potent and effective oxidizing agents than is molecular oxygen itself. With the exception of phagocytic cells, where ROS play an important physiological role in defense reactions, ROS have classically been considered undesirable byproducts of cell metabolism, existing several cellular mechanisms aimed to dispose them. Recently, however, ROS have been considered important intracellular signaling molecules, which may act as mediators or second messengers in many cell functions. This is the proposed role for ROS in oxygen sensing in systems, such as carotid body chemoreceptor cells, pulmonary artery smooth muscle cells, and erythropoietin-producing cells. These unique cells comprise essential parts of homeostatic loops directed to maintain oxygen levels in multicellular organisms in situations of hypoxia. The present article examines the possible significance of ROS in these three cell systems, and proposes a set of criteria that ROS should satisfy for their consideration as mediators in hypoxic transduction cascades. In none of the three cell types do ROS satisfy these criteria, and thus it appears that alternative mechanisms are responsible for the transduction cascades linking hypoxia to the release of neurotransmitters in chemoreceptor cells, contraction in pulmonary artery smooth muscle cells and erythropoietin secretion in erythropoietin producing cells.     

Tumour,Oxidative Stress and Host T Cell Response: Cementing the Dominance

Reactive oxygen species (ROS) and free radicals are produced intrinsically during normal cellular metabolic processes or extrinsically due to ionizing radiations, UV rays, xenobiotic insult, etc. ROS are important signal mediators and are used by the immune system to destroy pathogens, but as these are highly reactive, they also have the capacity to cause DNA damage and alter protein and lipid components of a cell. As a result, cells have evolved a tight regulation of internal redox environment that involves a balanced interplay between free radicals produced and quenched by cellular antioxidants and enzyme systems. Any deregulation of this subtle balance can result in oxidative stress that can lead to various pathological conditions including cancer. Oxidative stress can be a cause of neoplasia, or it can be induced by a growing tumour itself. The link existing between oxidative stress and inflammation is also very strong. Suppressed cellular immune system, especially effector T cell system, is a characteristic of tumour‐bearing host. Both the direct oxidative stress caused by tumour cell(s) and oxidative stress mediators present in tumour microenvironment play a significant role in the suppression of effector T cell function and induction of T cell death. This review discusses in detail the complex interplay between tumour–stroma–immune system in the light of oxidative stress that dominates every phase of cancer including initiation, progression and establishment. This review also addresses in detail the mechanisms of oxidative stress‐induced T cell dysfunction in tumour‐bearing host and also briefly points out the possible therapeutic interventions.     

Examination of the requirement for ucp-4, a putative homolog of mammalian uncoupling proteins, for stress tolerance and longevity in C. elegans

Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and damage cellular components. According to the free radical theory of aging, oxidative damage from mitochondrial ROS is a major cause of cellular decline during aging. Mitochondrial uncoupling proteins (UCPs) uncouple ATP production from electron transport and can be stimulated by free radicals, suggesting UCPs may perform a cytoprotective function. The nematode, Caenorhabditis elegans, contains one UCP-like protein, encoded by the ucp-4 gene. We have investigated the genetic requirement for ucp-4 in normal aging and stress resistance. Consistent with the hypothesis that ucp-4 encodes a putative uncoupling protein, animals lacking ucp-4 function contained elevated ATP levels. However, the absence of ucp-4 function did not affect adult lifespan or survival in the presence of thermal or oxidative stress. Together, these results demonstrate that ucp-4 is a negative regulator of ATP production in C. elegans, but is not required for normal lifespan.     

On the biodegradability of polyethylene glycol,polypeptoids and poly(2-oxazoline)s

Despite being the gold standard of hydrophilic biomaterials and well known sensitivity of polyethylene glycol (PEG) against oxidative degradation, very little information on the decomposition of PEG under biological oxidative stress can be found in the literature. Poly(2-oxazoline)s (POx) and polypeptoids (POI), two pseudo-polypeptides, have attracted some attention for the use as biomaterials and alternative to PEG with an altered stability against oxidative degradation. All three polymer families are supposedly non-biodegradable, which could be seen as one of their main disadvantages. Here, we present evidence that PEG, POx and POI are degradable by oxidative degradation under biologically relevant conditions. Transition metal catalysed generation of reactive oxygen species (ROS) leads to a pronounced time and concentration dependent degradation of all polymers investigated. While we do not envision oxidative degradation to be of relevance in the short-term usage of these polymers, mid- and long-term biodegradability in vivo appears feasible. Moreover, influence in ROS mediated signalling cascades may be one mechanism how synthetic polymers influence complex cellular processes.     

Emerging roles of cardiolipin remodeling in mitochondrial dysfunction associated with diabetes,obesity, and cardiovascular diseases

Cardiolipin (CL) is a phospholipid exclusively localized in inner mitochondrial membrane where it is required for oxidative phosphorylation, ATP synthesis, and mitochondrial bioenergetics. The biological functions of CL are thought to depend on its acyl chain composition which is dominated by linoleic acids in metabolically active tissues. This unique feature is not derived from the de novo biosynthesis of CL, rather from a remodeling process that involves in phospholipases and transacylase/acyltransferase. The remodeling process is also believed to be responsible for generation of CL species that causes oxidative stress and mitochondrial dysfunction. CL is highly sensitive to oxidative damages by reactive oxygen species (ROS) due to its high content in polyunsaturated fatty acids and location near the site of ROS production. Consequently, pathological remodeling of CL has been implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, heart failure, neurodegeneration, and aging that are characterized by oxidative stress, CL deficiency, and abnormal CL species. This review summarizes recent progresses in molecular, enzymatic, lipidomic, and metabolic studies that support a critical regulatory role of pathological CL remodeling as a missing link between oxidative stress and mitochondrial dysfunction in metabolic diseases and aging.     

Stress-responsive protein kinases in redox-regulated apoptosis signaling

Both extra- and intracellular stimuli elicit a wide variety of responses, such as cell survival, proliferation, differentiation, and apoptosis, through regulation of cell signaling. Recent studies have revealed that stress-responsive signal transduction pathways are strictly regulated by the intracellular redox state. The redox state of the cell is a consequence of the precise balance between the levels of oxidizing and reducing equivalents, such as reactive oxygen species (ROS) and endogenous antioxidants. The generation of ROS fluctuates in response to alterations of both external and internal environment and, in turn, triggers specific signaling cascades, including mitogen-activated protein kinases, which determine cell survival or cell death. This review focuses on the regulatory mechanisms of stress-responsive protein kinases and their involvement in oxidative stress-induced apoptosis. It also provides recent findings on the molecular mechanisms by which redox signaling cross-talks with stress-responsive protein kinase cascades.     

Mechanisms of cell death in oxidative stress

Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-kappaB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.     

Signaling pathways in mitochondrial dysfunction and aging

Mitochondria are central players in the determination of cell life and death. They are essential for energy production, since most cellular ATP is produced in their matrix by the oxidative phosphorylation pathway. At the same time, mitochondria are the main regulators of apoptotic cell death, mediating both extrinsic (cell-surface receptor mediated) and intrinsic apoptotic pathways. Reactive oxygen species (ROS) accumulate as side products of the electron transport chain, causing mitochondrial damage. Non-functional mitochondria accumulate in aged individuals, and cell homeostasis is maintained by removing damaged mitochondria by an autophagic process called “mitophagy”. In addition, mitochondrial ROS represent signaling molecules leading to autophagy, consisting in the bulk degradation of cytosolic portions. When cell homeostasis is perturbed, and cytosolic components are damaged, autophagy represents a defense mechanism aimed at removing non-functional proteins and organelles. If this is not sufficient, cell death occurs with distinct morphological hallmarks from apoptosis. This binary choice integrates a number of critical information converging on a number of common regulatory elements. In this review, the focus will be placed on the central role of mitochondria in the cross-talk between autophagy and apoptosis, highlighting the signaling pathways and molecular machinery impinging on these organelles.     

Reactive oxygen species and synaptic plasticity in the aging hippocampus

Aging is associated with a general decline in physiological functions including cognitive functions. Given that the hippocampus is known to be critical for certain forms of learning and memory, it is not surprising that a number of neuronal processes in this brain area appear to be particularly vulnerable to the aging process. Long-term potentiation (LTP), a form of synaptic plasticity that has been proposed as a biological substrate for learning and memory, has been used to examine age-related changes in hippocampal synaptic plasticity. A current hypothesis states that oxidative stress contributes to age-related impairment in learning and memory. This is supported by a correlation between age, memory impairment, and the accumulation of oxidative damage to cellular macromolecules. However, it also has been demonstrated that ROS are necessary components of signal transduction cascades during normal physiological processes. This review discusses the evidence supporting the dual role of reactive oxygen species (ROS) as cellular messenger molecules in normal LTP, as well their role as damaging toxic molecules in the age-related impairment of LTP. In addition, we will discuss parallel analyses of LTP and behavioral tests in mice that overexpress antioxidant enzymes and how the role of antioxidant enzymes and ROS in modulating these processes may vary over the lifespan of an animal.     

Characterization of reactive oxygen species in diaphragm

Reactive oxygen species (ROS) exist as natural mediators of metabolism to maintain cellular homeostasis. However, ROS production may significantly increase in response to environmental stressors, resulting in extensive cellular damage. Although several potential sources of increased ROS have been proposed, exact mechanisms of their generation have not been completely elucidated. This is particularly true for diaphragmatic skeletal muscle, the key muscle used for respiration. Several experimental models have focused on detection of ROS generation in rodent diaphragm tissue under stressful conditions, including hypoxia, exercise, and heat, as well as ROS formation in single myofibres. Identification methods include direct detection of ROS with confocal or fluorescent microscopy and indirect detection of ROS through end product analysis. This article explores implications of ROS generation and oxidative stress, and also evaluates potential mechanisms of cellular ROS formation in diaphragmatic skeletal muscle.     

活性氧在宫颈癌形成中的作用

活性氧是需氧细胞在代谢过程中产生的,当活性氧累积过多时会对细胞造成伤害,产生氧化应激。机体有自身的一套抗氧化应激系统,保护细胞免受损伤。随着活性氧研究的不断深入,它在肿瘤发生发展过程中的重要作用已被证实,体内活性氧与抗氧化应激系统的失衡是肿瘤形成的关键因素。宫颈癌作为一种妇科常见的恶性肿瘤,其形成机制尚不明了。近年来,活性氧在宫颈癌形成中的临床研究和体外研究成为国内外学者探讨的热点。       

Activation of extracellular signal-regulated kinase in MDBK cells infected with bovine viral diarrhea virus

Our efforts to identify the cellular signaling cascades triggered by bovine viral diarrhea virus (BVDV) infection in MDBK cells revealed marked activation of extracellular signal-regulated kinase 1/2 (ERK). Enhanced phosphorylation of ERK was detected following infection with cytopathogenic (cp) BVDV, but not with noncytopathogenic BVDV. It appears that cp BVDV-induced ERK phosphorylation is caused by oxidative stress, because ERK phosphorylation was inducible by treatment with hydrogen peroxide or serum deprivation and was attenuated by addition of antioxidants. These results indicate that BVDV infection influences the ERK signaling pathway via oxidative stress, depending on the biotype.     

The role of mitochondrial uncoupling proteins in lifespan

The increased longevity in modern societies raised the attention to biological interventions that could promote a healthy aging. Mitochondria are main organelles involved in the production of adenosine triphosphate (ATP), the energetic substrate for cellular biochemical reactions. The production of ATP occurs through the oxidative phosphorylation of intermediate substrates derived from the breakdown of lipids, sugars, and proteins. This process is coupled to production of oxygen reactive species (ROS) that in excess will have a deleterious role in cellular function. The damage promoted by ROS has been emphasized as one of the main processes involved in senescence. In the last decades, the discovery of specialized proteins in the mitochondrial inner membrane that promote the uncoupling of proton flux (named uncoupling proteins–UCPs) from the ATP synthase shed light on possible mechanisms implicated in the buffering of ROS and consequently in the process of aging. UCPs are responsible for a physiological uncoupling that leads to decrease in ROS production inside the mitochondria. Thus, induction of uncoupling through UCPs could decrease the cellular damage that occurs during aging due to excess of ROS. This review will focus on the evidence supporting these mechanisms.     

NADPH oxidases of the brain: distribution, regulation, and function

The NADPH oxidase is a multi-subunit enzyme that catalyzes the reduction of molecular oxygen to form superoxide (O(2)(-)). While classically linked to the respiratory burst in neutrophils, recent evidence now shows that O(2)(-) (and associated reactive oxygen species, ROS) generated by NADPH oxidase in nonphagocytic cells serves myriad functions in health and disease. An entire new family of NADPH Oxidase (Nox) homologues has emerged, which vary widely in cell and tissue distribution, as well as in function and regulation. A major concept in redox signaling is that while NADPH oxidase-derived ROS are necessary for normal cellular function, excessive oxidative stress can contribute to pathological disease. This certainly is true in the central nervous system (CNS), where normal NADPH oxidase function appears to be required for processes such as neuronal signaling, memory, and central cardiovascular homeostasis, but overproduction of ROS contributes to neurotoxicity, neurodegeneration, and cardiovascular diseases. Despite implications of NADPH oxidase in normal and pathological CNS processes, still relatively little is known about the mechanisms involved. This paper summarizes the evidence for NADPH oxidase distribution, regulation, and function in the CNS, emphasizing the diversity of Nox isoforms and their new and emerging role in neuro-cardiovascular function. In addition, perspectives for future research and novel therapeutic targets are offered.