Oren Rom

Cigarette smoking and inflammation revisited.

Despite the significant health risks resulting from tobacco use, the prevalence of smokers worldwide remains high. Cigarette smoking is one of the major sources of toxic chemical exposure to humans and is the greatest cause of preventable illnesses and premature death. The adverse consequences of smoking in various pathologies are mediated by its effects on the immune-inflammatory system. In this review, we aim to explore the effects of cigarette smoking on the inflammatory response and molecular mechanisms with emphasis on the nuclear factor kappa B (NF-kB) pathway. The effects of smoking on various inflammatory pathologies will be discussed, focusing on oral diseases, airway inflammation, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD).

Are E‐cigarettes a safe and good alternative to cigarette smoking?

Electronic cigarettes (E‐cigarettes) are devices that can vaporize a nicotine solution combined with liquid flavors instead of burning tobacco leaves. Since their emergence in 2004, E‐cigarettes have become widely available, and their use has increased exponentially worldwide. E‐cigarettes are aggressively advertised as a smoking cessation aid; as healthier, cheaper, and more socially acceptable than conventional cigarettes. In recent years, these claims have been evaluated in numerous studies. This review explores the development of the current E‐cigarette and its market, prevalence of awareness, and use. The review also explores the beneficial and adverse effects of E‐cigarettes in various aspects in accordance with recent research. The discussed aspects include smoking cessation or reduction and the health risks, social impact, and environmental consequences of E‐cigarettes.

Lifestyle and Sarcopenia—Etiology, Prevention, and Treatment

The term sarcopenia describes the loss of skeletal muscle mass, strength, and function in old age. As the world population continues to grow older, more attention is given to the phenomena of sarcopenia and the search for strategies of prevention and treatment. The progression of sarcopenia is affected by age-related physiological and systemic changes in the body, including alterations in skeletal muscle tissue, hormonal changes, increased inflammatory activities, and oxidative stress. Sarcopenia progression is also affected by lifestyle factors which are far more controllable. These factors include various aspects of nutrition, physical activity, exercise, alcohol intake, and tobacco use. Raising the public awareness regarding the impact of these factors, as causes of sarcopenia and potential strategies of prevention and treatment, is of great importance. In this review we aim to describe various lifestyle factors that affect the etiology, prevention, and treatment of sarcopenia.

Sarcopenia and smoking: a possible cellular model of cigarette smoke effects on muscle protein breakdown

Sarcopenia, the age‐related loss of muscle mass and strength, is a multifactorial impaired state of health. Lifestyle habits such as physical activity and nutrition have a major impact on sarcopenia progression. Several epidemiological studies have also shown an association between cigarette smoking and increased levels of sarcopenia in elderly long‐time smokers. Clinical, in vivo, and in vitro studies have tried to investigate the mechanism behind exposure to cigarette smoke (CS) and the subsequent effects on skeletal muscles. The aim of this review is to present a cellular model of CS‐induced skeletal muscle protein breakdown based on recent studies dealing with this issue and to propose new potential research directions that may explain the effects of exposure to CS on skeletal muscle integrity.

The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass

The ubiquitin-proteasome system (UPS) is the main regulatory mechanism of protein degradation in skeletal muscle. The ubiquitin-ligase enzymes (E3s) have a central role in determining the selectivity and specificity of the UPS. Since their identification in 2001, the muscle specific E3s, muscle RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx), have been shown to be implicated in the regulation of skeletal muscle atrophy in various pathological and physiological conditions. This review aims to explore the involvement of MuRF-1 and MAFbx in catabolism of skeletal muscle during various pathologies, such as cancer cachexia, sarcopenia of aging, chronic kidney disease (CKD), diabetes, and chronic obstructive pulmonary disease (COPD). In addition, the effects of various lifestyle and modifiable factors (e.g. nutrition, exercise, cigarette smoking, and alcohol) on MuRF-1 and MAFbx regulation will be discussed. Finally, evidence of potential strategies to protect against skeletal muscle wasting through inhibition of MuRF-1 and MAFbx expression will be explored.

Cigarette smoke and muscle catabolism in C2 myotubes.

Previous studies have revealed evidence of muscular damage and up-regulation of genes associated with impaired muscle maintenance in smokers. Cigarette smoking has also been associated with sarcopenia, the age-related loss of muscle mass and strength. In order to investigate the cellular mechanisms by which cigarette smoke (CS) promotes muscle catabolism, C2 myotubes from an in vitro skeletal muscle cell line, were exposed to different levels of whole vapor phase CS using a controlled CS exposure apparatus. Exposure of C2 myotubes to CS caused a reduction in diameter of myotubes and a time- and dose-dependent degradation of myosin heavy chain. Also, CS exposure resulted in increased intracellular oxidative stress and p38 MAPK phosphorylation, which led to up-regulation of the muscle specific E3 ubiquitin ligases: MAFbx/atrogin-1 and MuRF1. Pretreatment with the antioxidant N-acetylcysteine and inhibition of p38 MAPK by SB203580 prevented CS induced catabolism. In conclusion, our results demonstrate that exposure of skeletal myotubes to CS leads to increased oxidative stress and activation of the p38 MAPK pathway resulting in muscle cell atrophy and breakdown of muscle protein mediated by muscle specific E3 ubiquitin ligases. Our findings provide a possible molecular mechanism for the catabolic effects of CS in skeletal muscle.

The effects of acetaldehyde and acrolein on muscle catabolism in C2 myotubes.

The toxic aldehydes acetaldehyde and acrolein were previously suggested to damage skeletal muscle. Several conditions in which exposure to acetaldehyde and acrolein is increased were associated with muscle wasting and dysfunction. These include alcoholic myopathy, renal failure, oxidative stress, and inflammation. A main exogenous source of both acetaldehyde and acrolein is cigarette smoking, which was previously associated with increased muscle catabolism. Recently, we have shown that exposure of skeletal myotubes to cigarette smoke stimulated muscle catabolism via increased oxidative stress, activation of p38 MAPK, and upregulation of muscle-specific E3 ubiquitin ligases. In this study, we aimed to investigate the effects of acetaldehyde and acrolein on catabolism of skeletal muscle. Skeletal myotubes differentiated from the C2 myoblast cell line were exposed to acetaldehyde or acrolein and their effects on signaling pathways related to muscle catabolism were studied. Exposure of myotubes to acetaldehyde did not promote muscle catabolism. However, exposure to acrolein caused increased generation of free radicals, activation of p38 MAPK, upregulation of the muscle-specific E3 ligases atrogin-1 and MuRF1, degradation of myosin heavy chain, and atrophy of myotubes. Inhibition of p38 MAPK by SB203580 abolished acrolein-induced muscle catabolism. Our findings demonstrate that acrolein but not acetaldehyde activates a signaling cascade resulting in muscle catabolism in skeletal myotubes. Although within the limitations of an in vitro study, these findings indicate that acrolein may promote muscle wasting in conditions of increased exposure to this aldehyde.

Smoking cessation-related weight gain—beneficial effects on muscle mass, strength and bone health

AIMS To examine the effects of smoking cessation on body composition and muscle strength in comparison with continued smoking. DESIGN AND SETTING Twelve-month longitudinal study of adult smokers conducted in Haifa, Israel. PARTICIPANTS Eighty-one smokers recruited from a smoking cessation programme combining group counselling and varenicline treatment. MEASUREMENTS Measurements were taken at the beginning of the programme and after 12 months. Body composition was assessed by dual-energy X-ray absorptiometry. Muscle strength was measured by handgrip dynamometry and predicted one-repetition maximum tests. Dietary intake and physical activity levels were estimated using questionnaires. Smoking status was determined by urine cotinine. The effect of smoking cessation was assessed using univariate and multivariable linear regression analyses. FINDINGS Forty-one participants (age 44 ± 12 years) completed all baseline and follow-up measurements (76% continued smokers; 24% quitters). All measures of body composition and muscle strength were increased among quitters when compared with continued smokers. Adjusted differences [95% confidence interval (CI)] between quitters and smokers were: body weight 4.43 kg (1.56-7.31 kg); lean mass 1.26 kg (0.24-2.28 kg); fat mass 3.15 kg (0.91-5.39 kg); bone mineral content 48.76 g (12.06-85.54 g); bone mineral density 0.024 g/cm(2) (0.004-0.043 g/cm(2) ); handgrip strength 3.6 kg (1.12-6.08 kg); predicted one-repetition maximum of chest press 7.85 kg (1.93-13.76 kg); and predicted one-repetition maximum of leg press 17.02 kg (7.29-26.75 kg). CONCLUSIONS Smoking cessation is associated with weight gain mainly through accumulating extra fat, but is also associated with increased muscle mass, muscle strength and bone density.

Peroxynitrite Induces Degradation of Myosin Heavy Chain via p38 MAPK and Muscle-Specific E3 Ubiquitin Ligases in C2 Skeletal Myotubes

Oxidative stress and inflammation play an important role in the catabolism of skeletal muscles. Recently, cigarette smoke (CS) was shown to stimulate muscle catabolism by activation of p38 MAPK and up-regulation of the muscle-specific E3 ubiquitin ligases (E3s) atrogin-1 and MuRF1 which are over-expressed during muscle atrophy. Peroxynitrite (ONOO-), an oxidative ingredient of CS, also produced during oxidative stress and inflammation, was previously shown to induce ubiquitination and degradation of muscle proteins. To investigate the involvement of p38 MAPK and the muscle-specific E3s in ONOO--induced muscle catabolism, C2 myotubes, differentiated from a myoblast cell line, were exposed to ONOO- (25 μM) in a time-dependent manner. Following exposure, degradation of myosin heavy chain (MyHC) and actin, activation of p38 MAPK, and levels of atrogin-1 and MuRF1 were studied by Western blotting. Peak phosphorylation of p38 MAPK was observed at 1 h of ONOO- exposure. ONOO- caused a significant increase in the levels of atrogin-1 and MuRF1. In accordance, a significant decrease in MyHC levels was observed in a time-dependent manner. These findings support previous studies in which the catabolic effects of ONOO- were shown. In addition, ONOO- was demonstrated to induce degradation of muscle proteins by activation of p38 MAPK and up-regulation of the muscle-specific E3s atrogin-1 and MuRF1.

Pomegranate Juice Polyphenols Induce Macrophage Death via Apoptosis as Opposed to Necrosis Induced by Free Radical Generation: A Central Role for Oxidative Stress.

Abstract: At high concentrations, polyphenols induce cell death, and the polyphenols-rich pomegranate juice (PJ), known for its antioxidative/antiatherogenic properties, can possibly affect cell death, including macrophage death involved in atherogenesis. In the present study, apoptotic/necrotic macrophage death was analyzed in J774A.1 macrophages and in peritoneal macrophages isolated from atherosclerotic apoE−/− mice treated with PJ. The effects of PJ were compared with those of the free radical generator 2, 2′-azobis (2-amidinopropane) dihydrochloride (AAPH). Both PJ and AAPH significantly increased J774A.1 macrophage death; however, flow cytometric and microscopic analyses using annexin V/propidium iodide revealed that PJ increased the early apoptosis of the macrophage dose dependently (up to 2.5-fold, P < 0.01), whereas AAPH caused dose-dependent increases in late apoptosis/necrosis (up to 12-fold, P < 0.001). Unlike PJ, AAPH-induced macrophage death was associated with increased intracellular oxidative stress (up to 7-fold, P < 0.001) and with lipid stress demonstrated by triglyceride accumulation (up to 3-fold, P < 0.01) and greater chromatic vesicle response to culture medium (up to 5-fold, P < 0.001). Accordingly, recombinant paraoxonase 1, which hydrolyzes oxidized lipids, attenuated macrophage death induced by AAPH, but not by PJ. Similar apoptotic and oxidative effects were found in macrophages from apoE−/− mice treated with PJ or AAPH. As macrophage apoptotic/necrotic death has considerable impact on atherosclerosis progression, these findings may provide novel mechanisms for the antiatherogenicity of PJ.