Stress-induced Mechanisms Research Articles

Mechanisms of Hop Inhibition Include the Transmembrane Redox Reaction

In this work, a novel mechanistic model of hop inhibition beyond the proton ionophore action toward (beer spoiling) bacteria was developed. Investigations were performed with model systems using cyclic voltammetry for the determination of redox processes/conditions in connection with growth challenges with hop-sensitive and -resistant Lactobacillus brevis strains in the presence of oxidants. Cyclic voltammetry identified a transmembrane redox reaction of hop compounds at low pH (common in beer) and in the presence of manganese (present in millimolar levels in lactic acid bacteria). The antibacterial action of hop compounds could be extended from the described proton ionophore activity, lowering the intracellular pH, to pronounced redox reactivity, causing cellular oxidative damage. Accordingly, a correlation between the resistance of L. brevis strains to a sole oxidant to their resistance to hop could not be expected and was not detected. However, in connection with our recent study concerning hop ionophore properties and the resistance of hop-sensitive and -tolerant L. brevis strains toward proton ionophores (J. Behr and R. F. Vogel, J. Agric. Food Chem. 57:6074-6081, 2009), we suggest that both ionophore and oxidant resistance are required for survival under hop stress conditions and confirmed this correlation according to the novel mechanistic model. In consequence, the expression of several published hop resistance mechanisms involved in manganese binding/transport and intracellular redox balance, as well as that of proteins involved in oxidative stress under "highly reducing" conditions (cf. anaerobic cultivation and "antioxidative" hop compounds in the growth medium), is now comprehensible. Accordingly, hop resistance as a multifactorial dynamic property at least implies distinct resistance levels against two different mechanisms of hop inhibition, namely, proton ionophore-induced and oxidative stress-induced mechanisms. Beyond this specific model of hop inhibition, these investigations provide general insight on the role of electrophysiology and ion homeostasis in bacterial stress responses to membrane-active drugs.

An SOS-Regulated Type 2 Toxin-Antitoxin System

The Escherichia coli chromosome encodes seven demonstrated type 2 toxin-antitoxin (TA) systems: cassettes of two or three cotranscribed genes, one encoding a stable toxin protein that can cause cell stasis or death, another encoding a labile antitoxin protein, and sometimes a third regulatory protein. We demonstrate that the yafNO genes constitute an additional chromosomal type 2 TA system that is upregulated during the SOS DNA damage response. The yafNOP genes are part of the dinB operon, of which dinB underlies stress-induced mutagenesis mechanisms. yafN was identified as a putative antitoxin by homology to known antitoxins, implicating yafO (and/or yafP) as a putative toxin. Using phage-mediated cotransduction assays for linkage disruption, we show first that yafN is an essential gene and second that it is essential only when yafO is present. Third, yafP is not a necessary part of either the toxin or the antitoxin. Fourth, although DinB is required, the yafNOP genes are not required for stress-induced mutagenesis in the Escherichia coli Lac assay. These results imply that yafN encodes an antitoxin that protects cells against a yafO-encoded toxin and show a protein-based TA system upregulated by the SOS response.

Stress-induced nanoislands nucleation during growth of Ge/Si heterostructures under low-energy ion irradiation

Stress-induced nucleation of nanoislands under pulsed low-energy ion-beam assisted growth of Si/Ge heterostructures is studied by molecular dynamics and Monte-Carlo calculations. It is shown that cluster of interstitials is produced in Si bulk by an ion impact. Stresses induced at the surface by clusters of interstitials affect migration ability, stimulating nucleation and growth of Ge nanoislands. The main effects of ion-beam action observed in experiments, e.g. increase in islands density, decrease in islands average size and nonmonotonous dependence of islands density upon degree of molecular beam ionization, are interpreted in terms of stress-induced mechanism.

Testosterone treatment diminishes sickness behavior in male songbirds

Males of many vertebrate species are typically more prone to disease and infection than female conspecifics, and this sexual difference is partially influenced by the immunosuppressive properties of testosterone (T) in males. T-induced immunosuppression has traditionally been viewed as a pleiotropic handicap, rather than an adaptation. Recently, it has been hypothesized that suppression of sickness behavior, or the symptoms of infection, may have adaptive value if sickness interferes with the expression of T-mediated behaviors important for male reproductive success. We conduct a classic hormone replacement experiment to examine if T suppresses sickness behavior in a seasonally-breeding songbird, Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii). Triggered experimentally by bacterial lipopolysaccharide (LPS), sickness behavior includes decreased activity, anorexia, and weight loss. Gonadectomized (GDX) males that were treated with silastic implants filled with T exhibited suppression of behavioral and physiological responses to LPS compared to GDX and sham-GDX controls given empty implants. Sickness responses of control groups were statistically indistinguishable. T-implanted birds had significantly higher plasma T than control groups and levels were within the range associated with aggressive interactions during male-to-male contests. These findings imply that suppression of sickness behavior could occur when T is elevated to socially-modulated levels. Alternatively, it is possible that this suppressive effect is mediated through a stress-induced mechanism, as corticosterone levels were elevated in T-implanted subjects compared to controls. We propose that males wounded and infected during contests may gain a brief selective advantage by suppressing sickness responses that would otherwise impair competitive performance. The cost of immunosuppression would be manifested in males through an increased susceptibility to disease, which is presumably offset by capitalizing upon limited reproductive opportunities.

Management of Pitfalls for the Successful Clinical Use of Hypothermia Treatment

Therapeutic hypothermia is a promising method for controlling intracranial pressure (ICP) in severely brain-injured patients. However, clinical data regarding the effect of brain hypothermia on overall outcome of these patients is limited. This may be because there are specific pitfalls associated with the clinical management of induced hypothermia in patients with severe traumatic brain injury (TBI). These pitfalls may be avoided by preventing specific risk factors when cooling is induced and with rewarming. However, these risk factors have not been well systematically discussed in the literature. In this paper, three categories of clinical issues regarding the management of brain hypothermia are discussed: (1) stress-induced secondary brain injury mechanisms; (2) technical aspects of intensive care unit (ICU) cooling management; and (3) rewarming rates and methods. For patients with a Glasgow Coma Scale (GCS) score of less than 8, management of stress-induced insulin-resistant hyperglycemia, and unstable systemic circulation due to impaired cardiac contractility are especially important. For example, in our experience, posttraumatic hyperglycemia, exacerbated by cooling, may be ameliorated by the administration of a ketone body with mannitol. Prevention of selective free radical damage to neurons is also an important target for successful brain hypothermia treatment. Taken together, it is clear that several orchestrated steps should be initiated to enhance the protective effects of hypothermia therapy and prevent these possible pitfalls.

Third body effects in the wear of polyamide: Micro-mechanisms and wear particles analysis

The wear micro-mechanisms at a frictional interface between a polyamide 4,6 (PA 46) substrate and a spherical sapphire counterface have been investigated using in situ contact observation. Experiments were carried out under reciprocating sliding conditions with varying values of the overlap ratio, Δ, defined as the ratio of the displacement amplitude to the contact diameter. Using this procedure, it was found possible to vary the extent of wear particles accumulation within coherent third body agglomerates. For low overlap ratios ( Δ < 0.2), particles detached from the PA 46 substrate were extensively agglomerated within distinct third body corrugations. In this regime, the rate limiting process regarding the wear degradation was found to be the extrusion of fibril-like wear particles from the extremities of sheared third body agglomerates. On the other hand, no substantial debris accumulation was found to occur when the overlap ratio was greater than 0.2. Additional infrared thermal contact imaging showed that these wear mechanisms were induced under essentially isothermal conditions. From differential scanning calorimetry (DSC) and size exclusion chromatography (SEC) analysis, micro-structural changes within wear particles were found to be associated with a strong reduction in the molecular weight of the PA 46 molecules by virtue of stress-induced chain scission mechanisms.

Formation of Na0.44MnO2 nanowires via stress-induced splitting of birnessite nanosheets

High aspect ratio Na0.44MnO2 nanowires with a complex one-dimensional (1-D) tunnel structure have been synthesized. We found that the reaction went through layered birnessite nanosheet intermediates, and that their conversion to the final product involved splitting of the nanosheets into nanowires. Based on our observations, a stress-induced splitting mechanism for conversion of birnessite nanosheets to Na0.44MnO2 nanowires is proposed. The final and intermediate phases show topotaxy with 〈001〉f // 〈020〉b or 〈110〉b where f represents the final Na0.44MnO2 phase and b the intermediate birnessite phase. As a result of their high surface areas, the nanowires are efficient catalysts for the oxidation of pinacyanol chloride dye.

Mutability and importance of a hypermutable cell subpopulation that produces stress-induced mutants in Escherichia coli.

In bacterial, yeast, and human cells, stress-induced mutation mechanisms are induced in growth-limiting environments and produce non-adaptive and adaptive mutations. These mechanisms may accelerate evolution specifically when cells are maladapted to their environments, i.e., when they are are stressed. One mechanism of stress-induced mutagenesis in Escherichia coli occurs by error-prone DNA double-strand break (DSB) repair. This mechanism was linked previously to a differentiated subpopulation of cells with a transiently elevated mutation rate, a hypermutable cell subpopulation (HMS). The HMS could be important, producing essentially all stress-induced mutants. Alternatively, the HMS was proposed to produce only a minority of stress-induced mutants, i.e., it was proposed to be peripheral. We characterize three aspects of the HMS. First, using improved mutation-detection methods, we estimate the number of mutations per genome of HMS-derived cells and find that it is compatible with fitness after the HMS state. This implies that these mutants are not necessarily an evolutionary dead end, and could contribute to adaptive evolution. Second, we show that stress-induced Lac+ mutants, with and without evidence of descent from the HMS, have similar Lac+ mutation sequences. This provides evidence that HMS-descended and most stress-induced mutants form via a common mechanism. Third, mutation-stimulating DSBs introduced via I-SceI endonuclease in vivo do not promote Lac+ mutation independently of the HMS. This and the previous finding support the hypothesis that the HMS underlies most stress-induced mutants, not just a minority of them, i.e., it is important. We consider a model in which HMS differentiation is controlled by stress responses. Differentiation of an HMS potentially limits the risks of mutagenesis in cell clones.

Extended liver resection after preoperative chemotherapy: influence on regeneration and endoplasmic reticulum stress response

The increasing interest in preoperative chemotherapy (CH) of liver metastasis after colorectal carcinoma has focused surgical concerns on the influence of CH on hepatic tolerance during intraoperative ischemia. In this context, CH was described to lead to massive parenchyma harm but also to induce protective cascades initiated by stressed endoplasmic reticulum (ER). The aim of this study was to investigate whether ischemic resection after systemic CH affects liver regeneration and induces antiapoptotic mechanisms on the ER. Rats were randomized into two groups and treated either by intraperitoneally injected CH (n = 12) or saline (PL, n = 12); 24 h later, 2/3 of the liver was resected paired +/- Pringle's maneuver (PM) under general anesthesia. Tissue samples were taken from resected left-lateral lobe immediately and 24 h/7 days after the operation from the remaining proliferated right lobe. PCNA (Western blotting) and Ki67 (immunohistochemistry) were analyzed as proliferating markers. ER stress (elF2alpha, GRP78, cleaved caspase 3) was analyzed by Western blotting after 24 h. Only the PL group without PM showed an increase in protein reactivity for PCNA and Ki67. During 7 days of observation, the livers regained weight steadily in both groups. An upregulation of cleaved caspase 3 as indicator for cellular apoptosis was detected in PL animals with PM compared to CH with PM; by contrast, elF2alpha and GRP78, as markers of ER stress-inducing protective mechanisms, were significantly augmented in CH with PM. It is concluded that CH leads to a delay in liver regeneration but is no contraindication for ischemia. On the contrary, CH seems to cause a preconditioning of livers leading to the induction of antiapoptotic chaperones in our short-term model.

Molecular dynamics simulation of polycrystalline molybdenum nanowires under uniaxial tensile strain: Size effects

The effects of grain size and length-to-diameter ratio (LDR) on deformation behaviors of polycrystalline molybdenum nanowires are studied with molecular dynamics simulations at room temperature under uniaxial tensile strain. The results show that the nanowires display the ductile characteristic through the formation of the neck and atom-thick contact before failure. We find the deformation behaviors and fractures of the nanowires that depend heavily on the grain size and LDR, and that the size-dependent deformation behavior of polycrystalline nanowires is originated from rearrangement of atomic positions with grain size and surface effect with LDR. The nanowires with smaller grain size or LDR may exhibit superplasticity behaviors due to an amorphous rearrangement of atomic positions. However, the nanowires with larger grain size and LDR rupture at the strain of 39–76% and keep most crystalline structures. For the moderate grain size nanowires, the stress–strain relation displays a distinct zigzag curve. During the plastic deformation, Mo atom with “bcc” configurations near neck can transform into other configurations due to stress-induced mechanism.

Inflammation as an intermediate pathway in the association between psychosocial stress and obesity

Psychosocial stress is associated with risk of obesity although little is known about stress-induced biological mechanisms of obesity. We examined the potential mediating role of inflammatory processes. Data were collected from a nationally representative sample of 7540 individuals (54% women, mean age 46.8 ± 15.4 years), from the Scottish Health Surveys. We calculated risk estimates of obesity for increasing numbers of psychosocial stressors (based on social position, education, psychological distress and marital/partner discord) using logistic regression analyses. Obesity was assessed using body mass index and central obesity using waist circumference. Potential mediators included inflammatory markers (C-reactive protein and fibrinogen) and health behaviours (physical activity, smoking, alcohol, and dietary intake). The unadjusted odds ratio of obesity for three or more psychosocial stressors was 1.81 (95% CI, 1.39–2.36, p < 0.001). In multivariate analyses that adjusted for age, gender, health behaviours and inflammatory markers the association between psychosocial stress and obesity was attenuated but remained significant (1.49, 1.11–2.00, p < 0.001). Inflammatory markers independently accounted for ~ 25% of the association between stress and obesity. We found similar associations in separate analyses of psychosocial stress and central obesity, although results were confounded by overall obesity. In summary, inflammatory processes appear to be an important intermediate pathway in the association between psychosocial stress and obesity.

Earth's core formation aided by flow channelling instabilities induced by iron diapirs

The core formation mechanism remains poorly known. An unstable gravitational configuration of a dense molten metallic layer overlying a cold chondritic protocore is predicted by most studies, which leads to the formation of a Rayleigh–Taylor (RT) instability. Recent results [Dahl, T.W., 2005. Turbulent mixing during planet accretion and core formation: Interpretation of the Hf/W chronometer and implications for the age of the Moon. M. Sc. Thesis, University of Copenhagen.] indicate that additionally, iron cores of predifferentiated planetesimals are also able to plunge mostly intact into the cold protocore and create large iron diapirs. For both scenarios we propose the application of the stress-induced melt channelling mechanism [Stevenson, D.J., 1989. Spontaneous small-scale melt segregation in partial melts undergoing deformation. Geophys. Res. Lett. 16, 1,067–1,070] in the region surrounding an incipient iron diapir. We therefore perform numerical experiments solving the two-phase, two composition flow equations within a 2D rectangular box with symmetrical boundary conditions. We apply the Compaction Boussinesq Approximation (CBA) and include a depth-dependent gravity. For simplicity we use a constant viscosity for the solid phase and a melt fraction dependent rheology for the partially molten region around the diapir. We investigate the physical conditions under which the melt channels can form and whether they are applicable to the early Earth. As a result, for sufficiently small melt retention numbers iron-rich melt channels develop within a region of approximately twice the diapir's size. This could lead to effective draining of the surrounding region and might initiate cascading daughter diapirs. The region of the protocore drained by this cascading mechanism is expected to significantly increase with depth, and thus indicates an effective mechanism to also extract iron melt from deeper parts of the initially chondritic protocore. This mechanism could effectively accelerate the process of core formation.

Mechanical properties of bimetallic crystalline and nanostructured nanowires

Nanowires are basic components of interconnects at the nanoscale level in electronic as well as in electromechanical devices. Presently, there is a fast growing interest in their synthesis as well as in their mechanical testing. Focused ion beams now allow machining pillars with diameters as small as a few tens of nanometres and nanoindenter systems allow measuring strains at the atomic scale and compressive stresses up to the 10 GPa range. Such pillars typically contain less than millions of atoms, which makes their modelling and the modelling of their mechanical properties at the atomic scale realistic. A few Molecular Dynamics studies are presently available, discussing deformation mechanisms in thin narrow crystalline nanowires, but the literature about nanoalloy wires and nanostructured wires, as they can be synthesized from clusters, is almost non-existent. In the latter, the dislocation activity may be inhibited, leading to specific mechanical properties. By means of large scale computations, we use Ni3A1 to discuss the mechanical properties of crystalline and nanostructured nanowires. We also compare wires to their bulk counterparts. Both isothermal and isoenergetic whereby mechanical work converts into heat in the system-deformation mechanisms are considered. The comparison between pair correlation functions, stress distributions, configuration analysis and strain stress relations capture most of the stress-induced evolution mechanisms of nanowires with different diameters and structures, including elastic properties, dislocation activity, grain rotation and boundary motion, local melting, superplasticity and fracture. A structural transition which may be martensitic is predicted for the first time at the nanoscale level, suggesting possible shape memory properties of nanoalloy nanowires.

Os riscos e danos nas intoxicações por paraquat em animais domésticos

O paraquat é um herbicida de contato não-seletivo. É amplamente utilizado na agricultura em mais de 100 países, pois apresenta baixo custo, grande eficácia e não possui efeitos poluentes cumulativos para o solo. Porém, ele é um produto muito tóxico para humanos e animais, podendo causar intoxicações fatais, principalmente pela falta de um antídoto eficaz na reversão do quadro clínico. O paraquat atua mediante mecanismos de indução do estresse oxidativo, produção aumentada de radicais livres associada à depleção dos sistemas antioxidantes do organismo. Sua toxicidade acomete rins, fígado, músculos, cérebro, dentre outros. Os pulmões são considerados os órgãos-alvo deste herbicida, levando a severas injúrias como edema, hemorragia, inflamação intersticial e fibrose pulmonar. A falência respiratória grave é a causa comum de morte. O tratamento da intoxicação, atualmente, é baseado em medidas que diminuam a absorção e aumentem a excreção. Entretanto, o uso de agentes antioxidantes e antifibróticos vem sendo estudado, pois há interesse crescente no estudo de substâncias que possam servir como antídoto nas intoxicações, uma vez que o paraquat aumenta os índices de morbidade e mortalidade.

Inducible and constitutive mechanisms of salt stress resistance in Geum urbanum L.

The avens (Geum urbanum L.) seedlings were grown for 6 weeks until the expansion of five to six leaves and then exposed to salinity shock (300 mM NaCl in the nutrient medium) or to a gradual (within 4 days) increase in NaCl concentration from 100 to 400 mM. The dynamics of stress-dependent accumulation of Na+, Cl−, proline, and polyamines in leaves and roots was measured, together with activities of antioxidant enzymes, namely, superoxide dismutase (SOD) and guaiacol-dependent peroxidase occurring in soluble, ionically bound, and covalently bound forms. It is shown that avens plants can adapt to gradual salinization by mobilizing stressinducible protective mechanisms (accumulation of proline and spermine) and by activating constitutive enzyme systems (SOD and peroxidase).

Effects of heat stress on filamentous actin and prestin of outer hair cells in mice

When the ear is exposed to traumatic loud noise, outer hair cells (OHCs) are damaged and thus permanent hearing loss occurs. Recently, prior conditioning with heat stress has been reported to protect OHCs from traumatic noise exposure by increasing the stiffness of the OHC soma and has also been reported to enhance distortion product otoacoustic emissions [DPOAEs; Murakoshi, M., Yoshida, N., Kitsunai, Y., Iida, K., Kumano, S., Suzuki, T., Kobayashi, T., Wada, H., 2006. Effects of heat stress on Young's modulus of outer hair cells in mice. Brain Res. 1107, 121–130]. In the present study, to further investigate the heat stress-induced protective mechanism of hearing and such stress-induced DPOAE enhancement mechanism, the amount of filamentous actin (F-actin), which is concerned with cell stiffness, and the amount of prestin, which is concerned with the generation of DPOAEs, were examined in OHCs, with and without heat stress. Heat stress was found to increase the amount of F-actin 6–24 h after heat stress. The greatest increase in the amount of F-actin was observed at the cuticular plate where F-actin anchors the roots of the stereocilia to the cell body. Based on this result, the part of the stereocilia most reinforced and protected by heat stress was concluded to be the roots of the stereocilia. In contrast with F-actin, heat stress did not affect the amount of prestin.

Irreversible Translation Arrest in the Reperfused Brain

Irreversible translation arrest occurs in reperfused neurons that will die by delayed neuronal death. It is now recognized that suppression of protein synthesis is a general response of eukaryotic cells to exogenous stressors. Indeed, stress-induced translation arrest can be viewed as a component of cell stress responses, and consists of initiation, maintenance, and termination phases that work in concert with stress-induced transcriptional mechanisms. Within this framework, we review translation arrest in reperfused neurons. This framework provides a basis to recognize that phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is the initiator of translation arrest, and a key marker indicating activation of neuronal stress responses. However, eIF2 alpha phosphorylation is reversible. Other phases of stress-induced translation arrest appear to contribute to irreversible translation arrest specifically in ischemic vulnerable neuron populations. We detail two lines of evidence supporting this view. First, ischemia, as a stress stimulus, induces irreversible co-translational protein misfolding and aggregation after 4 to 6 h of reperfusion, trapping protein synthesis machinery into functionally inactive protein aggregates. Second, ischemia and reperfusion leads to modifications of stress granules (SGs) that sequester functionally inactive 48S preinitiation complexes to maintain translation arrest. At later reperfusion durations, these mechanisms may converge such that SGs become sequestered in protein aggregates. These mechanisms result in elimination of functionally active ribosomes and preclude recovery of protein synthesis in selectively vulnerable neurons. Thus, recognizing translation arrest as a component of endogenous cellular stress response pathways will aid in making sense of the complexities of postischemic translation arrest.

Thermomechanical effects on phase transformations in single-crystal Cu–Al–Ni shape-memory alloy

Single-crystal rods of Cu–Al–Ni shape-memory alloy fabricated from a molten pool of 82 wt% Cu, 14 wt% Al, and 4 wt% Ni by the Czochralski method were first heated to ∼870 °C and then quenched to obtain austenitic microstructures. Various microanalysis techniques were used to determine the chemical composition, microstructure, and phase-transformation temperatures of the produced alloy. Cyclic tensile tests with in situ temperature control demonstrated the occurrence of pseudoelastic deformation at elevated and close to phase-transformation temperatures and provided insight into the temperature dependence of the phase-transformation stress, damping characteristics, and cyclic straining of single-crystal Cu–Al–Ni alloy. The stress hysteresis observed in the pseudoelastic deformation cycles decreased at elevated temperatures. The stress response at different temperatures is associated with the formation, growth, and coalescence of martensite variants. Stress-induced phase-transformation mechanisms, coalescence of twin variants, and energy dissipation by pseudoelastic deformation are discussed in the context of experimental findings. The results illustrate the potential of single-crystal Cu–Al–Ni as a structural material for dynamic microsystems and temperature sensors.

Domestic violence is associated with adult and childhood asthma prevalence in India

Little is known on the influence of stressful psychosocial circumstances in predicting asthma. We examine the link between asthma prevalence and domestic violence (DV) in a nationally representative sample of adults and children in India. Analyses were based on the 1998-99 cross-sectional nationally representative Indian National Family Health Survey administered in 92 486 households. Individual-level prevalence of asthma was the primary outcome for this study. Exposure to DV was based on women's self-report of DV. In adjusted models, women who experienced DV either recently or in the past were at greater risk of being asthmatic [odds ratio (OR) range 1.26-1.37], compared with those who did not report any abuse. In households where women reported to have experienced DV, asthma risk was higher for all individuals in those households (OR range 1.15-1.19). The association between household DV and individual risk for asthma was also observed in gender-stratified analysis, and also in age-stratified analysis, with strong association observed in age groups of under-five, 5-14, 15-24 and 25-44 years. We find a consistent association between being exposed to, and having experienced, DV and asthma prevalence. Stress-induced mechanisms, partially captured through violence and social circumstances, may be a critical explanatory link in furthering our understanding of the social disparities in asthma.

Signaling mechanisms in alcoholic liver injury: Role of transcription factors, kinases and heat shock proteins

Alcoholic liver injury comprises of interactions of various intracellular signaling events in the liver. Innate immune responses in the resident Kupffer cells of the liver, oxidative stress-induced activation of hepatocytes, fibrotic events in liver stellate cells and activation of liver sinusoidal endothelial cells all contribute to alcoholic liver injury. The signaling mechanisms associated with alcoholic liver injury vary based on the cell type involved and the extent of alcohol consumption. In this review we will elucidate the oxidative stress and signaling pathways affected by alcohol in hepatocytes and Kupffer cells in the liver by alcohol. The toll-like receptors and their down-stream signaling events that play an important role in alcohol-induced inflammation will be discussed. Alcohol-induced alterations of various intracellular transcription factors such as NFkappaB, PPARs and AP-1, as well as MAPK kinases in hepatocytes and macrophages leading to induction of target genes that contribute to liver injury will be reviewed. Finally, we will discuss the significance of heat shock proteins as chaperones and their functional regulation in the liver that could provide new mechanistic insights into the contributions of stress-induced signaling mechanisms in alcoholic liver injury.