How cigarette smoking may increase the risk of anxiety symptoms and anxiety disorders : a critical review of biological pathways

Multiple studies have demonstrated an association between cigarette smoking and increased anxiety symptoms or disorders, with early life exposures potentially predisposing to enhanced anxiety responses in later life. Explanatory models support a potential role for neurotransmitter systems, inflammation, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophins and neurogenesis, and epigenetic effects, in anxiety pathogenesis. All of these pathways are affected by exposure to cigarette smoke components, including nicotine and free radicals. This review critically examines and summarizes the literature exploring the role of these systems in increased anxiety and how exposure to cigarette smoke may contribute to this pathology at a biological level. Further, this review explores the effects of cigarette smoke on normal neurodevelopment and anxiety control, suggesting how exposure in early life (prenatal, infancy, and adolescence) may predispose to higher anxiety in later life. A large heterogenous literature was reviewed that detailed the association between cigarette smoking and anxiety symptoms and disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress, mitochondrial function, neurotransmitter systems, neurotrophins and neurogenesis. Some preliminary data were found for potential epigenetic effects. The literature provides some support for a potential interaction between cigarette smoking, anxiety symptoms and disorders, and the above pathways; however, limitations exist particularly in delineating causative effects. The literature also provides insight into potential effects of cigarette smoke, in particular nicotine, on neurodevelopment. The potential treatment implications of these findings are discussed in regards to future therapeutic targets for anxiety. The aforementioned pathways may help mediate increased anxiety seen in people who smoke. Further research into the specific actions of nicotine and other cigarette components on these pathways, and how these pathways interact, may provide insights that lead to new treatment for anxiety and a greater understanding of anxiety pathogenesis

Bacoside A: Role in Cigarette Smoking Induced Changes in Brain

Cigarette smoking (CS) is a major health hazard that exerts diverse physiologic and biochemical effects mediated by the components present and generated during smoking. Recent experimental studies have shown predisposition to several biological consequences from both active and passive cigarette smoke exposure. In particular, passive smoking is linked to a number of adverse health effects which are equally harmful as active smoking. A pragmatic approach should be considered for designing a pharmacological intervention to combat the adverse effects of passive smoking. This review describes the results from a controlled experimental condition, testing the effect of bacoside A (BA) on the causal role of passive/secondhand smoke exposure that caused pathological and neurological changes in rat brain. Chronic exposure to cigarette smoke induced significant changes in rat brain histologically and at the neurotransmitter level, lipid peroxidation states, mitochondrial functions, membrane alterations, and apoptotic damage in rat brain. Bacoside A is a neuroactive agent isolated from Bacopa monnieri. As a neuroactive agent, BA was effective in combating these changes. Future research should examine the effects of BA at molecular level and assess its functional effects on neurobiological and behavioral processes associated with passive smoke

Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling.

The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein-protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling

Antioxidants in Health and Disease

Antioxidants in Health and Disease discusses the effects of dietary antioxidants and antioxidant supplementation in humans. It reviews the latest evidence-based research in the area, principally through prospective cohort studies and randomized controlled trials. The book assesses major dietary antioxidants and discusses their use in diseases such as cancer, diabetes, stroke, coronary heart disease, HIV/AIDS, and neurodegenerative and immune diseases. The use of antioxidants in health is also discussed along with common adverse effects associated with antioxidant use. Separating myth from fact, this book gives you insight into the true role of antioxidants in health and disease

Antioxidants in Health and Disease

Antioxidant use in health promotion and disease prevention either through dietary intake or supplementation is controversial. This book reviews the latest evidence-based research in the area, principally through prospective cohort studies and randomized controlled trials. It assesses major dietary antioxidants and discusses their use in diseases such as cancer, diabetes, stroke, coronary heart disease, HIV/AIDS, and neurodegenerative and immune diseases. The use of antioxidants in health is also discussed along with common adverse effects associated with antioxidant use

Effect of smoking and smoking cessation on muscle and vascular function-a pilot study

Smoking is a preventable risk factor for the development of chronic diseases in the lungs, brain, heart and kidneys, but smoking can also affect vascular and muscle function. It has been observed, for instance, that the smokers suffer from an earlier onset skeletal muscle fatigue that may at least partly be caused by toxins, such as carbon monoxide (CO), in the blood. The impact of smoking and smoking cessation on skeletal muscle and vascular function however are unknown. Methodology. After obtaining ethical approval and informed written consent, we investigated the impact of smoking and 2 weeks smoking cessation on muscle and arterial function in 13 participants (8 smokers (S); 5 controls (C)). We measured blood CO with a smokelyser and nicotine using an ELISA. In the right femoral artery (FA) we measured flow and vasodilation induced by contractile activity and a short occlusion with 2D US. The muscle strength, fatigability of the right Vastus lateralis muscle were determined with a dynamometer. Results. The blood CO (S: 4 ± 0.9%; C: 0.0 ± 0.0 %, P < 0.003) and cotinine levels (179 ± 24 vs 27 ± 16 ng·ml-1, P < 0.001) were significantly higher, whereas maximal torque (208 ± 21 vs 259 ± 14 Nm, P < 0.03), flow (548 ± 42 vs 714 ± 80 ml·min-¹ P < 0.01) and FA diameter (6.8 ± 0.3 vs 7.6 ± 0.2 mm, P < 0.01) were significantly lower in smokers than non-smokers. After 2 weeks of smoking cessation, CO decreased to 0.3 ± 0.2% (P < 0.01) and cotinine to 30 ± 13 ng·ml-1 (P < 0.02) while there were no significant changes in FA diameter, flow, maximal torque or fatigue resistance. Conclusion Our data suggests that the reduced muscle and arterial function in smokers does not revert to normal after a short cessation period, although CO/Cotinine levels decline and may require a longer cessation period, supplemented with antioxidants to stabilize, improve or recover function

Thrombospondin: An emerging keystone in skeletal muscle structure and function

Our objective was to elucidate the effects of TSP-1 on skeletal muscle structure and function, and its potential role in the progression of skeletal muscle dysfunction. The central hypothesis was that TSP-1 is a critical negative regulator of skeletal muscle angiogenesis. In chapter 3, we used a TSP-1 mimetic delivered by mini osmotic pumps to show that TSP-1 can reduce capillarity across three distinct muscle types. We found that those given the mimetic had a 35% decrease in soleus capillarity, a 20% decrease in the gastrocnemius, and an 11% decrease in the plantaris. This confirmed the critical role that TSP-1 plays in physiological skeletal muscle angiogenesis. Despite previous evidence showing that TSP-1 is an important regulator of apoptosis in tumorigenesis, we found no apoptosis in the skeletal muscle of those animals treated with the TSP-1 mimetic, as measured by TUNEL staining or cell death ELISA. Further, again using this same mimetic, in chapters 3 and 4 we failed to find any change in whole body exercise, as measured by maximal running speed, or direct muscle function as measured by ex vivo muscle simulation, in relation to the TSP-1 induced capillary rarefaction. This may further support the notion that it is not simply one factor that controls exercise capacity, but a combination of many different components and systems. Further, previous evidence suggested that a TSP-1/TNFa axis could be controlling skeletal muscle capillarity rarefaction in chronic systemic inflammation. In chapter 5 we examined the role overexpression of TNFa has on skeletal muscle capillary regression in a mouse model of chronic lung disease. Despite showing a 16% decrease in capillarity of the soleus, we found no change in TSP-1 expression. What factors are at play in this specific disease model remains unknown; however our data suggests that TSP-2 could be central to pathological capillary regression seen with this model. Finally, in chapter 4 we also suggest that TSP-1 may be playing a role in the regulation of mitochondrial electron transport enzyme activity, and hence perhaps mitochondrial function. This could provide a new and exciting role for TSP-1. This will require further investigation. Together, the studies in this document build upon data showing that skeletal muscle angiogenesis is a dynamic process controlled by positive and negative angiogenic proteins. It provides new and exciting evidence for the importance of negative angiogenic proteins, specifically that of TSP-1 and TSP- 2, and lays the groundwork for investigation into potential medical therapies targeting aberrant angiogenesis in skeletal muscle

Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds

Teratology Primer-2nd Edition (7/9/2010)

Foreword: What is Teratology? “What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism. And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.” Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed. Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought. In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin! Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused. In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens. The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late. As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother. The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought. Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans. The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world. Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter. F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad