Antibacterial mechanism of Pseudomonas aeruginosa UKMP14T rhamnolipids against multidrug resistant Acinetobacter baumannii.

Rhamnolipids, a major category of glycolipid biosurfactant, have recently gained enormous attention in medical field because of their relevance as effective antibacterial agents against a wide variety of pathogenic bacteria. Our previous studies have shown that rhamnolipids from an environmental isolate of Pseudomonas aeruginosa UKMP14T possess antibacterial, anti-adhesive and anti-biofilm activity against multidrug-resistant ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp.) pathogens. However, the mechanism of their antibacterial action remains unclear. Thus, this study aimed to elucidate the mechanism of the antibacterial action of P. aeruginosa UKMP14T rhamnolipids by studying the changes in cells of one of the ESKAPE pathogens, Acinetobacter baumannii, which is the most difficult strain to kill. Results revealed that rhamnolipid treatment rendered A. baumannii cells more hydrophobic as evaluated through contact angle measurements. It also induced the release of cellular proteins measuring 510 µg/mL at a rhamnolipid concentration of 1000 µg/mL. In addition, rhamnolipids were found to be bactericidal in their action as they could permeate the inner membranes, leading to a leak-out of nucleotides. More than 50 % of the cells were found to be killed upon 1000 µg/mL rhamnolipid treatment as observed through fluorescence microscopy. Other cellular changes such as irregular shape and size, membrane perturbations, clumping, shrinkage and physical damage were clearly visible in SEM, FESEM and laser micrographs. Furthermore, rhamnolipid treatment inhibited the levels of acyl-homoserine lactones (AHLs) in A. baumannii, which are vital for their biofilm formation and virulence. The obtained results indicate that P. aeruginosa UKMP14T rhamnolipids target outer and inner bacterial membranes through permeation, including physical damage to the cells, leading to cell leakage. Furthermore, AHL inhibition appears to be the mechanism behind their anti-biofilm action. All these observations can be correlated to rhamnolipids' antibacterial effect against A. baumannii.

Mitochondrial DNA Mutations and Ageing.

Mitochondria are subcellular organelles present in most eukaryotic cells which play a significant role in numerous aspects of cell biology. These include carbohydrate and fatty acid metabolism to generate cellular energy through oxidative phosphorylation, apoptosis, cell signalling, haem biosynthesis and reactive oxygen species production. Mitochondrial dysfunction is a feature of many human ageing tissues, and since the discovery that mitochondrial DNA mutations were a major underlying cause of changes in oxidative phosphorylation capacity, it has been proposed that they have a role in human ageing. However, there is still much debate on whether mitochondrial DNA mutations play a causal role in ageing or are simply a consequence of the ageing process. This chapter describes the structure of mammalian mitochondria, and the unique features of mitochondrial genetics, and reviews the current evidence surrounding the role of mitochondrial DNA mutations in the ageing process. It then focusses on more recent discoveries regarding the role of mitochondrial dysfunction in stem cell ageing and age-related inflammation.

Bioactive role of vitamins as a key modulator of oxidative stress, cellular damage and comorbidities associated with spinal cord injury (SCI).

Introduction: Spinal cord injury (SCI) cause significant disability and impact the quality of life of those affected by it. The nutritional status and diet are fundamental to diminish the progression of complications; vitamins modulate the inflammatory response and oxidative stress, promote blood-spinal cord barrier preservation and the prompt recovery of homeostasis. A deep knowledge of the benefits achieved from vitamins in patients with SCI are summarized. Information of dosage, time, and effects of vitamins in these patients are also displayed. Vitamins have been extensively investigated; however, more clinical trials are needed to clarify the scope of vitamin supplementation.Objective: The objective of this review was to offer relevant therapeutic information based on vitamins supplementation for SCI patients.Methods: Basic and clinical studies that have implemented the use of vitamins in SCI were considered. They were selected from the year 2000-2022 from three databases: PubMed, Science Direct and Google Scholar.Results: Consistent benefits in clinical trials were shown in those who were supplemented with vitamin D (prevents osteoporosis and improves physical performance variables), B3 (improves lipid profile) and B12 (neurological prophylaxis of chronic SCI damage) mainly. On the other hand, improvement related to neuroprotection, damage modulation (vitamin A) and its prophylaxis were associated to B complex vitamins supplementation; the studies who reported positive results are displayed in this review.Discussion: Physicians should become familiar with relevant information that can support conventional treatment in patients with SCI, such as the use of vitamins, a viable option that can improve outcomes in patients with this condition.

Pulsed Electromagnetic Fields Induce Skeletal Muscle Cell Repair by Sustaining the Expression of Proteins Involved in the Response to Cellular Damage and Oxidative Stress.

Pulsed electromagnetic fields (PEMF) are employed as a non-invasive medicinal therapy, especially in the orthopedic field to stimulate bone regeneration. However, the effect of PEMF on skeletal muscle cells (SkMC) has been understudied. Here, we studied the potentiality of 1.5 mT PEMF to stimulate early regeneration of human SkMC. We showed that human SkMC stimulated with 1.5 mT PEMF for four hours repeated for two days can stimulate cell proliferation without inducing cell apoptosis or significant impairment of the metabolic activity. Interestingly, when we simulated physical damage of the muscle tissue by a scratch, we found that the same PEMF treatment can speed up the regenerative process, inducing a more complete cell migration to close the scratch and wound healing. Moreover, we investigated the molecular pattern induced by PEMF among 26 stress-related cell proteins. We found that the expression of 10 proteins increased after two consecutive days of PEMF stimulation for 4 h, and most of them were involved in response processes to oxidative stress. Among these proteins, we found that heat shock protein 70 (HSP70), which can promote muscle recovery, inhibits apoptosis and decreases inflammation in skeletal muscle, together with thioredoxin, paraoxonase, and superoxide dismutase (SOD2), which can also promote skeletal muscle regeneration following injury. Altogether, these data support the possibility of using PEMF to increase SkMC regeneration and, for the first time, suggest a possible molecular mechanism, which consists of sustaining the expression of antioxidant enzymes to control the important inflammatory and oxidative process occurring following muscle damage.

Effects of melatonin ingestion on physical performance and biochemical responses following exhaustive running exercise in soccer players.

Antioxidant supplementation has become a common practice among athletes to boost sport achievement. Likewise, melatonin (MEL) has been ingested as an ergogenic aid to improve physical performance. To date, no study has checked whether the multiple beneficial effects of MEL have an outcome during a maximum running exercise until exhaustion. Therefore, the present study aimed to evaluate the effect of MEL ingestion on physical performance and biochemical responses (i.e., oxidative stress) during exhaustive exercise. In a double blind randomized study, thirteen professional soccer players [age: 17.5 ± 0.8 years, body mass: 70.3 ± 3.9 kg, body height: 1.80 ± 0.08 m; maximal aerobic speed (MAS): 16.85 ± 0.63 km/h; mean ± standard deviation], members of a first league squad, performed a running exercise until exhaustion at 100% of MAS, after either MEL or placebo ingestion. Physical performance was assessed, and blood samples were obtained at rest and following the exercise. Compared to placebo, MEL intake prevented the increase in oxidative stress markers (i.e., malondialdehyde), alleviated the alteration of antioxidant status (i.e., glutathione peroxidase, uric acid and total bilirubin) and decreased post-exercise biomarkers of muscle damage (i.e., creatine kinase and lactate dehydrogenase) (p < 0.05). However, physical performance was not affected by MEL ingestion (p > 0.05). In conclusion, acute MEL intake before a maximal running exercise protected athletes from oxidative stress and cellular damage but without an effect on physical performance.

Tissue remodelling and increased DNA damage in patients with incompetent valves in chronic venous insufficiency.

Chronic venous insufficiency (CVI), in which blood return to the heart is impaired, is a prevalent condition worldwide. Valve incompetence is a complication of CVI that results in blood reflux, thereby aggravating venous hypertension. While CVI has a complex course and is known to produce alterations in the vein wall, the underlying pathological mechanisms remain unclear. This study examined the presence of DNA damage, pro-inflammatory cytokines and extracellular matrix remodelling in CVI-related valve incompetence. One hundred and ten patients with CVI were reviewed and divided into four groups according to age (<50 and ≥50 years) and a clinical diagnosis of venous reflux indicating venous system valve incompetence (R) (n = 81) or no reflux (NR) (n = 29). In vein specimens (greater saphenous vein) from each group, PARP, IL-17, COL-I, COL-III, MMP-2 and TIMP-2 expression levels were determined by RT-qPCR and immunohistochemistry. The younger patients with valve incompetence showed significantly higher PARP, IL-17, COL-I, COL-III, MMP-2 and reduced TIMP-2 expression levels and a higher COL-I/III ratio. Young CVI patients with venous reflux suffer chronic DNA damage, with consequences at both the local tissue and systemic levels, possibly associated with ageing.

Melatonin is an effective protector of gingival cells damaged by the cytotoxic effect of glutamate and DL-buthionine sulfoximine.

BACKGROUND AND OBJECTIVE: Cellular damage related to oxidative stress (OS) is implicated in periodontal diseases (PD). Melatonin (MEL) has multiple functions, and it has been described as a potential treatment for PD. We aim at evaluating the protective effects of MEL on an in vitro model of cellular damage triggered by glutamate (GLUT) and DL-buthionine sulfoximine (BSO), on gingival cells (GCs) in culture. MATERIAL AND METHODS: A primary culture of GCs from Wistar rats was developed in order to test the protective property of MEL; BSO and GLUT were administered alone as well as in combination with MEL. The viability and apoptosis were measured with MTT assay and TUNEL, respectively, and the concentration of superoxide anion ( O 2 - ) was measured with the NBT method. RESULTS: The combination of BSO and GLUT treatment resulted in a decreased viability of GCs. This was evidenced by the increase in both the production of superoxide anion and apoptosis. After MEL administration, the oxidant and pro-apoptotic effects of BSO and GLUT were totally counteracted. CONCLUSIONS: These findings demonstrated that MEL has an effective protective role on GCs subjected to cellular damage in a model of OS and cytotoxicity triggered by BSO and GLUT. Consequently, MEL could be used as a therapeutic agent in PD which begin with a significative loss of GCs.

Warming enhances lanthanum accumulation and toxicity promoting cellular damage in glass eels (Anguilla anguilla).

Cumulative and continuing human emissions of greenhouse gases to the atmosphere are causing ocean warming. Rising temperature is a major threat to aquatic organisms and may affect physiological responses, such as acid-base balance, often compromising species fitness and survival. It is also expected that warming may influence the availability and toxicological effects of pollutants, including Rare Earth Elements. These are contaminants of environmental emerging concern with great economic interest. This group comprises yttrium, scandium and lanthanides, being Lanthanum (La) one of the most common. The European eel (Anguilla anguilla) is critically endangered and constitutes a delicacy in South East Asia and Europe, being subject to an increasing demand on a global scale. Considering the vulnerability of early life stages to contaminants, we exposed glass eels to 1.5 µg L-1 of La for five days, plus five days of depuration, under a present-day temperature and warming scenarios (△T = +4 °C). The aim of this study was to assess the bioaccumulation, elimination and specific biochemical enzymatic endpoints in glass eels (Anguilla anguilla) tissues, under warming and La. Overall, our results showed that the accumulation and toxicity of La were enhanced with increasing temperature. The accumulation was higher in the viscera, followed by the head, and ultimately the body. Elimination was less effective under warming. Exposure to La did not impact acetylcholinesterase activity. Moreover, lipid peroxidation peaked after five days under the combined exposure of La and warming. The expression of heat shock proteins was majorly suppressed in glass eels exposed to La, at both tested temperatures. This result suggests that, when exposed to La, glass eels were unable to efficiently prevent cellular damage, with a particularly dramatic setup in a near-future scenario. Further studies are needed towards a better understanding of the effects of lanthanum in a changing world.

Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation.

BACKGROUND: Artificial Mitochondrial Transfer or Transplant (AMT/T) can be used to reduce the stress and loss of viability of damaged cells. In MitoCeption, a type of AMT/T, the isolated mitochondria and recipient cells are centrifuged together at 4 °C and then co-incubated at 37 °C in normal culture conditions, inducing the transfer. Ultraviolet radiation (UVR) can affect mitochondria and other cell structures, resulting in tissue stress, aging, and immunosuppression. AMT/T could be used to repair UVR cellular and mitochondrial damage. We studied if a mitochondrial mix from different donors (Primary Allogeneic Mitochondrial Mix, PAMM) can repair UVR damage and promote cell survival. RESULTS: Using a simplified adaption of the MitoCeption protocol, we used peripheral blood mononuclear cells (PBMCs) as the recipient cell model of the PAMM in order to determine if this protocol could repair UVR damage. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage. CONCLUSION: Our results represent an advancement in the applications of MitoCeption and other AMT/T. We showed that PBMCs could be used as a PAMM source of mitochondria. We also showed that these mitochondria can be transferred in a mix from different donors (PAMM) to UVR-damaged, non-adherent primary cells. Additionally, we decreased the duration of the MitoCeption protocol.

Glucose-restriction increases Trichomonas vaginalis cellular damage towards HeLa cells and proteolytic activity of cysteine proteinases (CPs), such as TvCP2.

Trichomonas vaginalis induces cellular damage to the host cells (cytotoxicity) through the proteolytic activity of multiple proteinases of the cysteine type (CPs). Some CPs are modulated by environmental factors such as iron, zinc, polyamines, etc. Thus, the goal of this study was to assess the effect of glucose on T. vaginalis cytotoxicity, proteolytic activity and the particular role of TvCP2 (TVAG_057000) during cellular damage. Cytotoxicity assays showed that glucose-restriction (GR) promotes the highest HeLa cell monolayers destruction (~95%) by trichomonads compared to those grown under high glucose (~44%) condition. Zymography and Western blot using different primary antibodies showed that GR increased the proteolytic activity, amount and secretion of certain CPs, including TvCP2. We further characterized the effect of glucose on TvCP2. TvCP2 increases in GR, localized in vesicles close to the plasma membrane and on the surface of T. vaginalis. Furthermore, pretreatment of GR-trichomonads with an anti-TvCP2r polyclonal antibody specifically reduced the levels of cytotoxicity and apoptosis induction to HeLa cells in a concentration-dependent manner. In conclusion, our data show that GR, as a nutritional stress condition, promotes trichomonal cytotoxicity to the host cells, increases trichomonad proteolytic activity and amount of CPs, such as TvCP2 involved in cellular damage.

Guanidine-based disinfectants, polyhexamethylene guanidine-phosphate (PHMG-P), polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) induced epithelial-mesenchymal transition in A549 alveolar epithelial cells.

Abstracts Objective: The major active ingredient of humidifier disinfectant, polyhexamethylene guanidine-phosphate (PHMG-P), caused hundreds of deaths with pulmonary fibrosis. However, structurally similar guanidine-based disinfectants are still in use in various fields. Moreover, as they are precursors of excellent antimicrobial compounds, new chemicals with guanidine-based structures have been synthesized and introduced. In this study, we evaluated pulmonary fibrotic responses induced by PHMG-P, polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) and their toxicity mechanisms in type II alveolar epithelial A549 cells. Materials and methods: Cellular damage was compared by using the cytotoxicity test (WST-1 assay) and plasma membrane toxicity tests (Lactate dehydrogenase leakage detection assay and plasma membrane staining). As a measure of fibrotic response, induction of the epithelial-mesenchymal transition (EMT) was evaluated by measuring E-cadherin and α-smooth muscle actin (α-SMA) protein expression (epithelial and mesenchymal marker, respectively). Results: All tested compounds showed membrane damage; PHMG-P and PGH induced the highest and lowest damage, respectively. Moreover, they induced EMT when the test chemicals were treated with similar cytotoxic concentrations. Conclusions: Our study indicates that three guanidine-based disinfectants are potential fibrosis-inducing chemicals that induce EMT through cellular damage. Therefore, use of guanidine-based polymers should be strictly regulated by considering their potential adverse effects on the lungs.

Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3ß in MPP⁺-Induced Cell Damage.

Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3ß (GSK-3ß) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP⁺-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3ß enzyme inhibition against MPP⁺. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3ß enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3ß along with PPARγ activation may be responsible for neuroprotection.

Fungicide tolerant Bradyrhizobium japonicum mitigate toxicity and enhance greengram production under hexaconazole stress.

Bacterial strain RV9 recovered from greengram nodules tolerated 2400µg/mL of hexaconazole and was identified by 16S rDNA sequence analysis as Bradyrhizobium japonicum (KY940048). Strain RV9 produced IAA (61.6µg/mL), ACC deaminase (51.7mg/(protein·hr)), solubilized TCP (105µg/mL), secreted 337.6µg/mL EPS, and produced SA (52.2µg/mL) and 2,3-DHBA (28.3µg/mL). Exopolysaccharides produced by strain RV9 was quantified and characterized by SEM, AFM, EDX and FTIR. Beyond tolerance limit, hexaconazole caused cellular impairment and reduced the viability of strain RV9 revealed by SEM and CLSM. Hexaconazole distorted the root tips and altered nodule structure leading thereby to reduction in the performance of greengram. Also, the level of antioxidant enzymes, proline, TBARS, ROS and cell death was increased in hexaconazole treated plants. CLSM images revealed a concentration dependent increase in the characteristic green and blue fluorescence of hexaconazole treated roots. The application of B. japonicum strain RV9 alleviated the fungicide toxicity and improved the measured plant characteristics. Also, rhizobial cells were localized inside tissues as revealed by CLSM. Colonization of B. japonicum strain RV9 decreased the levels of CAT, POD, APX, GPX and TBARS by 80%, 5%, 13%, 13% and 19%, respectively over plants grown at 80µg/(hexaconazole·kg) soil. The ability to detoxify hexaconazole, colonize plant tissues, secrete PGP bioactive molecules even under fungicide pressure and its unique ability to diminish oxidative stress make B. japonicum an attractive choice for remediation of fungicide polluted soils and to concurrently enhance greengram production under stressed environment.

Patients with HBV-related acute-on-chronic liver failure have increased concentrations of extracellular histones aggravating cellular damage and systemic inflammation.

Acute-on-chronic liver failure (ACLF) is the most common type of liver failure and associated with grave consequences. Systemic inflammation has been linked to its pathogenesis and outcome, but the identifiable triggers are absent. Recently, extracellular histones, especially H4, have been recognized as important mediators of cell damage in various inflammatory conditions. This study aimed to investigate whether extracellular histones have clinical implications in patients with hepatitis B virus (HBV)-related ACLF. One hundred and twelve patients with HBV-related ACLF, 90 patients with chronic hepatitis B, 88 patients with HBV-related liver cirrhosis and 40 healthy volunteers were entered into this study. Plasma histone H4 levels, cytokine profile and clinical data were obtained. Besides, patient's sera were incubated overnight with human L02 hepatocytes or monocytic U937 cells in the presence or absence of antihistone H4 antibody, and cellular damage and cytokine production were evaluated. We found that plasma histone H4 levels were greatly increased in patients with ACLF as compared with chronic hepatitis B, liver cirrhosis and healthy control subjects and were significantly associated with disease severity, systemic inflammation and outcome. Notably, ACLF patients' sera incubation decreased cultured L02 cell integrity and induced profound cytokine production in the supernatant of U937 cells. Antihistone H4 antibody treatment abrogated these adverse effects, thus confirming a cause-effect relationship between extracellular histones and organ injury/dysfunction. The data support the hypothesis that the increased extracellular histone levels in ACLF patients may aggravate disease severity by inducing cellular injury and systemic inflammation. Histone-targeted therapies may have potentially interventional value in clinical practice.

Occurrence of oxidative stress in dairy cows seropositives for Brucella abortus.

Bovine brucellosis is an important zoonotic disease caused by the bacterium Brucella abortus that leads to economic losses due to animal discard and commercial restrictions. Since positive animals for brucellosis are culled, little is known about the pathogenesis of this disease. Therefore, the aims of this study were to evaluate possible changes in the activity of deaminase adenosine (ADA) and the oxidative stress in cows seropositives for brucellosis (Experiment I), and to evaluate the seroprevalence of B. abortus in dairy cows from the Western state of Santa Catarina, Southern Brazil (Experiment II). The Experiment I evaluated 20 pregnant cows: ten seropositives for B. abortus and ten seronegatives that were used as controls. The ADA activity and markers of oxidative stress (TBARS, catalase (CAT) and superoxide dismutase (SOD)) were evaluated in these animals. A reduction in the activity of ADA and catalase enzymes in seropositive animals was observed (p < 0.001). Conversely, there was an increase in TBARS levels and superoxide dismutase activity in cows infected by B. abortus (p < 0.001). The presence of oxidative stress and a reduction of ADA might be related to the modulation of the inflammatory response. The experiment II was performed due to a high number of herds with restrictions imposed by cases of brucellosis in the state of Santa Catarina in the last two years, and thus, the seroprevalence for B. abortus was evaluated in 1242 serum samples of cows of 69 herds. The serodiagnosis was performed using two tests: buffered acidified antigen and 2-mercaptoethanol. However, none of the serum samples were positive for B. abortus. Although we did not find seropositive animals for brucellosis in our study, the disease still requires continued surveillance, due to its economic impact, and to the oxidative stress caused by it, which may have contributed to cases of abortion in three seropositive cows (Experiment I) in the final third of the gestation.

Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field.

IMPORTANCE: Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes. OBJECTIVE: We conducted a systematic review and meta-analysis to determine the association between self-reported, perceived psychological stress (PS) and telomere length (TL). DATA SOURCES: We searched 3 databases (PubMed, PsycInfo, and Scopus), completed manual searches of published and unpublished studies, and contacted all study authors to obtain potentially relevant data. STUDY SELECTION: Two independent reviewers assessed studies for original research measuring (but not necessarily reporting the correlation between) PS and TL in human subjects. 23 studies met inclusion criteria; 22 (totaling 8948 subjects) could be meta-analyzed. DATA EXTRACTION AND SYNTHESIS: We assessed study quality using modified MINORS criteria. Since not all included studies reported PS-TL correlations, we obtained them via direct calculation from author-provided data (7 studies), contact with authors (14 studies), or extraction from the published article (1 study). MAIN OUTCOMES AND MEASURES: We conducted random-effects meta-analysis on our primary outcome, the age-adjusted PS-TL correlation. We investigated potential confounders and moderators (sex, life stress exposure, and PS measure validation) via post hoc subset analyses and meta-regression. RESULTS: Increased PS was associated with a very small decrease in TL (n=8724 total; r=-0.06; 95% CI: -0.10, -0.008; p=0.01; α=0.025), adjusting for age. This relationship was similar between sexes and within studies using validated measures of PS, and marginally (nonsignificantly) stronger among samples recruited for stress exposure (r=-0.13; vs. general samples: b=-0.11; 95% CI: -0.27, 0.01; p=0.05; α=0.013). Publication bias may exist; correcting for its effects attenuated the relationship. CONCLUSIONS AND RELEVANCE: Our analysis finds a very small, statistically significant relationship between increased PS (as measured over the past month) and decreased TL that may reflect publication bias, although fully parsing the effects of publication bias from other sample-size correlates is challenging, as discussed. The association may be stronger with known major stressors and is similar in magnitude to that noted between obesity and TL. All included studies used single measures of short-term stress; the literature suggests long-term chronic stress may have a larger cumulative effect. Future research should assess for potential confounders and use longitudinal, multidimensional models of stress.

Feedbacks and tipping points in organismal response to oxidative stress.

Biological feedbacks play a crucial role in determining effects of toxicants, radiation, and other environmental stressors on organisms. Focusing on reactive oxygen species (ROS) that are increasingly recognized as a crucial mediator of many stressor effects, we investigate how feedback strength affects the ability of organisms to control negative effects of exposure. We do this by developing a general theoretical framework for describing effects of a wide range of stressors and species. The framework accounts for positive and negative feedbacks representing cellular processes: (i) production of ROS due to metabolism and the stressor, (ii) ROS reactions with cellular compounds that cause damage, and (iii) cellular control of both ROS and damage. We suggest functional forms that capture generic properties of cellular control mechanisms constituting the feedbacks, assess stability of equilibrium states in the resulting models, and investigate tipping points at which cellular control breaks down causing unregulated increase of ROS and damage. Depending on the chosen functional forms, the models can have zero, one, or two positive steady states; except in one singular case, the steady state with lowest values of ROS and damage is locally stable. We found two types of tipping points: those induced by changes in the parameters (including the stressor intensity), and those induced by the history of exposure, i.e. ROS and damage levels. The relatively simple models effectively describe several patterns of cellular responses to stress, such as the covariation of ROS and damage, the break-down of cellular control leading to explosion of ROS and/or damage, increase in damage even when ROS is (near)-constant, and the effects of exposure history on the ability of the cell to handle additional stress. The models quantify dynamics of cellular control, and could therefore be used to estimate the metabolic costs of stress and help integrate them into models that use energetic considerations to model organism's response to the environment. Although developed with unicellular organisms in mind, our models can be applied to all multicellular organisms that utilize similar feedbacks when dealing with stress.

Vitamin E supplementation inhibits muscle damage and inflammation after moderate exercise in hypoxia.

BACKGROUND: Exercise under hypoxic conditions represents an additional stress in relation to exercise in normoxia. Hypoxia induces oxidative stress and inflammation as mediated through tumour necrosis factor (TNF)-α release that might be exacerbated through exercise. In addition, vitamin E supplementation might attenuate oxidative stress and inflammation resulting from hypoxia during exercise. The present study aimed to evaluate the effects of vitamin E supplementation (250 mg) on inflammatory parameters and cellular damage after exercise under hypoxia simulating an altitude of 4200 m. METHODS: Nine volunteers performed three sessions of 60 min of exercise (70% maximal oxygen uptake) interspersed for 1 week under normoxia, hypoxia and hypoxia after vitamin E supplementation 1 h before exercise. Blood was collected before, immediately after and at 1 h after exercise to measure inflammatory parameters and cell damage. RESULTS: Percentage oxygen saturation of haemoglobin decreased after exercise and recovered 1 h later in the hypoxia + vitamin condition (P < 0.05). Supplementation decreased creatine kinase (CK)-TOTAL, CK-MB and lactate dehydrogenase 1 h after exercise (P < 0.05). The exercise in hypoxia increased interleukin (IL)-6, TNF-α, IL-1ra and IL-10 immediately after exercise (P < 0.05). Supplementation reversed the changes observed after exercise in hypoxia without supplementation (P < 0.05). CONCLUSIONS: We conclude that 250 mg of vitamin E supplementation at 1 h before exercise reduces cell damage markers after exercise in hypoxia and changes the concentration of cytokines, suggesting a possible protective effect against inflammation induced by hypoxia during exercise.

Unraveling the non-senescence phenomenon in Hydra.

Unlike other metazoans, Hydra does not experience the distinctive rise in mortality with age known as senescence, which results from an increasing imbalance between cell damage and cell repair. We propose that the Hydra controls damage accumulation mainly through damage-dependent cell selection and cell sloughing. We examine our hypothesis with a model that combines cellular damage with stem cell renewal, differentiation, and elimination. The Hydra individual can be seen as a large single pool of three types of stem cells with some features of differentiated cells. This large stem cell community prevents "cellular damage drift," which is inevitable in complex conglomerate (differentiated) metazoans with numerous and generally isolated pools of stem cells. The process of cellular damage drift is based on changes in the distribution of damage among cells due to random events, and is thus similar to Muller's ratchet in asexual populations. Events in the model that are sources of randomness include budding, cellular death, and cellular damage and repair. Our results suggest that non-senescence is possible only in simple Hydra-like organisms which have a high proportion and number of stem cells, continuous cell divisions, an effective cell selection mechanism, and stem cells with the ability to undertake some roles of differentiated cells.

Photosynthetic and antioxidative alterations in coffee leaves caused by epoxiconazole and pyraclostrobin sprays and Hemileia vastatrix infection.

Coffee leaf rust (CLR), caused by Hemileia vastatrix, is a major disease affecting coffee production worldwide. In this study, an in-depth analysis of the photosynthetic performance of coffee leaves challenged or not with H. vastatrix and sprayed with either epoxiconazole (EPO) or pyraclostrobin (PYR) was performed by combining chlorophyll a fluorescence images, photosynthetic pigment pools and the activities of chitinase (CHI), ß-1,3-glucanase (GLU), peroxidase (POX) and catalase (CAT). The CLR severity was higher in the control plants, but reduced in plants sprayed with both PYR and EPO. Also, the CLR severity was reduced in plants sprayed with PYR compared with plants sprayed with EPO. Plants sprayed with either EPO or PYR showed maximal photosystem II quantum efficiency (Fv/Fm) values ranging from 0.78 to 0.80, which were quite similar to those obtained with inoculated plants (values ranging from 0.74 to 0.77). The decreases in the Fv/Fm ratio values and parallel increases in the F0 values in the inoculated plants, which were not observed in the control plants (sprayed with water) and were confirmed by images of the initial fluorescence (F0) and Fv/Fm parameters in the regions of the leaf tissue containing pustules and in the asymptomatic leaf tissue, indicated that photosynthesis was negatively impacted. When effective photosystem II quantum yield (Y(II)) values approached zero with a high photosynthetic photon flux density, high values of quantum yield of regulated energy dissipation (Y(NPQ)) in association with a high carotenoid concentration were noted in the inoculated plants sprayed either with PYR or EPO. The increased CLR severity in inoculated plants in contrast to inoculated plants sprayed with either PYR or EPO was associated with greater POX activity and a reduced photosynthetic pigment concentration. POX and CAT activities were increased in inoculated plants sprayed with either EPO or PYR when compared with control plants. CHI and GLU activities were maintained at high levels in the leaves of inoculated plants, regardless of the fungicide sprayed, indicating that CHI and GLU are less important for coffee resistance against CLR. The results of the present study clearly demonstrated that plants sprayed with either EPO or PYR showed milder CLR symptoms with adequate photosynthetic performance and optimal conditioning of their antioxidant systems.