Identification of global transcriptional variations in human peripheral blood mononuclear cells two months postheat injury helps categorization heat-tolerant or heat-intolerant phenotypes.

Thermal intolerance may limit activity in hostile environments. After heat illness, two physiologically distinct phenotypes evolve: heat tolerant (HT) and heat intolerant (HI). The recognition that heat illness alters gene expression justified revisiting the established physiological concept of HI. We used a DNA microarray to examine the global transcriptional response in peripheral blood mononuclear cells (PMBCs) from HI and HT phenotypes, categorized 2-mo postheat injury using a functional physiological heat-tolerance test (HTT, 40°C)-Recovery (R, 24°C) protocol. The impact of recurrent heat stress was studied in vitro using peripheral blood mononuclear cells (PBMCs) from controls (participants with no history of heat injury), HI, and HT (categorized by functional HTT) with a customized NanoString array. There were significant differences under basal conditions between the HI and HT. HI were more immunological alerted. Almost no shared genes were found between end-HTT and recovery phases, suggesting vast cellular plasticity. In HI, mitochondrial function was dysregulated, canonical pathways associated with exercise endurance-NRF2 and insulin were downregulated, whereas AMPK and peroxisome proliferator-activated receptor (PPAR) were upregulated. HT exhibited reciprocal responses, suggesting that energy dysregulation found in HI interfered with performance in the heat. The endoplasmic-reticulum stress response was also suppressed in HI. In vitro HTT (43°C) abolished differences between HI and HT PBMCs including the HSPs genes, whereas controls showed profound HSPs upregulation.

Epigenetic responses to heat: From adaptation to maladaptation.

NEW FINDINGS: What is the topic of this review? This review outlines the history of research on epigenetic adaptations to heat exposure. The perspective taken is that adaptations reflect properties of hormesis, whereby low, repeated doses of heat induce adaptation (acclimation/acclimatization); whereas brief, life-threatening exposures can induce maladaptive responses. What advances does it highlight? The epigenetic mechanisms underlying acclimation/acclimatization comprise specific molecular programmes on histones that regulate heat shock proteins transcriptionally and protect the organism from subsequent heat exposures, even after long delays. The epigenetic signalling underlying maladaptive responses might rely, in part, on extensive changes in DNA methylation that are sustained over time and might contribute to later health challenges. ABSTRACT: Epigenetics plays a strong role in molecular adaptations to heat by producing a molecular memory of past environmental exposures. Moderate heat, over long periods of time, induces an 'adaptive' epigenetic memory, resulting in a condition of 'resilience' to future heat exposures or cross-tolerance to other forms of toxic stress. In contrast, intense, life-threatening heat exposures, such as severe heat stroke, can result in a 'maladaptive' epigenetic memory that can place an organism at risk of later health complications. These cellular memories are coded by post-translational modifications of histones on the nucleosomes and/or by changes in DNA methylation. They operate by inducing changes in the level of gene transcription and therefore phenotype. The adaptive response to heat acclimation functions, in part, by facilitating transcription of essential heat shock proteins and exhibits a biphasic short programme (maintaining DNA integrity, followed by a long-term consolidation). The latter accelerates acclimation responses after de-acclimation. Although less studied, the maladaptive responses to heat stroke appear to be coded in long-lasting changes in DNA methylation near the promoter region of genes involved with basic cell function. Whether these memories are also encoded in histone modifications is not yet known. There is considerable evidence that both adaptive and maladaptive epigenetic responses to heat can be inherited, although most evidence comes from lower organisms. Future challenges include understanding the signalling mechanisms responsible and discovering new ways to promote adaptive responses while suppressing maladaptive responses to heat, as all life forms adapt to life on a warming planet.

Heat-Stress Preconditioning Attenuates Behavioral Responses to Psychological Stress: The Role of HSP-70 in Modulating Stress Responses.

Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40-41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS exposure before predator-scent stress (PSS) exposure (i.e., HS preconditioning) was examined. Finally, a possible mechanism of HS-preconditioning to PSS was investigated. Immunohistochemical analyses of chosen cellular markers were performed in the hippocampus and in the hypothalamic paraventricular nucleus (PVN). Plasma corticosterone levels were evaluated, and the behavioral assessment included the elevated plus-maze (EPM) and the acoustic startle response (ASR) paradigms. Endogenous levels of heat shock protein (HSP)-70 were manipulated using an amino acid (L-glutamine) and a pharmacological agent (Doxazosin). A single exposure to an acute HS resulted in decreased body mass (BM), increased body temperature and increased corticosterone levels. Additionally, extensive cellular, but not behavioral changes were noted. HS-preconditioning provided behavioral resiliency to anxiety-like behavior associated with PSS, possibly through the induction of HSP-70. Targeting of HSP-70 is an attractive strategy for stress-related psychopathology treatment.

Long-term HIF-1α transcriptional activation is essential for heat-acclimation-mediated cross tolerance: mitochondrial target genes.

An important adaptive feature of heat acclimation (HA) is the induction of cross tolerance against novel stressors (HACT) Reprogramming of gene expression leading to enhanced innate cytoprotective features by attenuating damage and/or enhancing the response of "help" signals plays a pivotal role. Hypoxia-inducible factor-1α (HIF-1α), constitutively upregulated by HA (1 mo, 34°C), is a crucial transcription factor in this program, although its specific role is as yet unknown. By using a rat HA model, we studied the impact of disrupting HIF-1α transcriptional activation [HIF-1α:HIF-1ß dimerization blockade by intraperitoneal acriflavine (4 mg/kg)] on its mitochondrial gene targets [phosphoinositide-dependent kinase-1 (PDK1), LON, and cyclooxygenase 4 (COX4) isoforms] in the HA rat heart. Physiological measures of cardiac HACT were infarct size after ischemia-reperfusion and time to rigor contracture during hypoxia in cardiomyocytes. We show that HACT requires transcriptional activation of HIF-1α throughout the course of HA and that this activation is accompanied by two metabolic switches: 1) profound upregulation of PDK1, which reduces pyruvate entry into the mitochondria, consequently increasing glycolytic lactate production; 2) remodeling of the COX4 isoform ratio, inducing hypoxic-tolerant COX4.2 dominance, and optimizing electron transfer and possibly ATP production during the ischemic and hypoxic insults. LON and COX4.2 transcript upregulation accompanied this shift. Loss of HACT despite elevated expression of the cytoprotective protein heat shock protein-72 concomitantly with disrupted HIF-1α dimerization suggests that HIF-1α is essential for HACT. The role of a PDK1 metabolic switch is well known in hypoxia acclimation but not in the HA model and its ischemic setting. Remodeling of COX4 isoforms by environmental acclimation is a novel finding.

AdE-1, a new inotropic Na(+) channel toxin from Aiptasia diaphana, is similar to, yet distinct from, known anemone Na(+) channel toxins.

Heart failure is one of the most prevalent causes of death in the western world. Sea anemone contains a myriad of short peptide neurotoxins affecting many pharmacological targets, several of which possess cardiotonic activity. In the present study we describe the isolation and characterization of AdE-1 (ion channel modifier), a novel cardiotonic peptide from the sea anemone Aiptasia diaphana, which differs from other cnidarian toxins. Although AdE-1 has the same cysteine residue arrangement as sea anemone type 1 and 2 Na(+) channel toxins, its sequence contains many substitutions in conserved and essential sites and its overall homology to other toxins identified to date is low (<36%). Physiologically, AdE-1 increases the amplitude of cardiomyocyte contraction and slows the late phase of the twitch relaxation velocity with no induction of spontaneous twitching. It increases action potential duration of cardiomyocytes with no effect on its threshold and on the cell's resting potential. Similar to other sea anemone Na(+) channel toxins such as Av2 (Anemonia viridis toxin II), AdE-1 markedly inhibits Na(+) current inactivation with no significant effect on current activation, suggesting a similar mechanism of action. However, its effects on twitch relaxation velocity, action potential amplitude and on the time to peak suggest that this novel toxin affects cardiomyocyte function via a more complex mechanism. Additionally, Av2's characteristic delayed and early after-depolarizations were not observed. Despite its structural differences, AdE-1 physiologic effectiveness is comparable with Av2 with a similar ED(50) value to blowfly larvae. This finding raises questions regarding the extent of the universality of structure-function in sea anemone Na(+) channel toxins.

Vascular compliance and left ventricular compliance cross talk: Implications for using long-term heat acclimation in cardiac care.

1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2) There is a cross-talk between vascular and cardiac compliance. Vascular compliance per se is defined by central venous pressure-Blood volume relationship-Global Vascular Compliance (GVC). It is determined by the sum of the vascular compliance of the vessels in every organ in any physiological state, varies with LTHA and thus influences cardiac performance. LTHA improves endothelial function, increases NO (nitric oxide) production, in-turn stimulating alterations in ECM (extracellular matrix) via the TGF ß1-SMAD pathway. 3) LTHA is associated with transformation from fast to slow myosin, heat acclimation ischemic/hypoxic cross-tolerance and alterations in the extracellular matrix. 4) A human translational study demonstrated improved LV compliance following bypass surgery in LTHA subjects compared to controls. 5) Diastolic dysfunction and the impact of comorbidities with vascular and non- vascular origins are major contributors to the syndrome of heart failure with preserved ejection function (HFPEF). Unfortunately, there is a paucity of treatment modalities that improve diastolic dysfunction. 6) In the current mini-review we suggest that LTHA may be beneficial to HFPEF patients by remodeling cardiac compliance and vascular response.

Mitochondrial performance in heat acclimation--a lesson from ischemia/reperfusion and calcium overload insults in the heart.

Long-term heat acclimation (LTHA; 30 days, 34°C) causes phenotypic adaptations that render protection against ischemic/reperfusion insult (I/R, 30 min global ischemia and 40 min reperfusion) via heat acclimation-mediated cross-tolerance (HACT) mechanisms. Short-term acclimation (STHA, 2 days, 34 °C), in contrast, is characterized by cellular perturbations, leading to increased susceptibility to insults. Here, we tested the hypothesis that enhanced mitochondrial respiratory function is part of the acclimatory repertoire and that the 30-day regimen is required for protection via HACT. We subjected isolated hearts and mitochondria from controls (C), STHA, or LTHA rats to I/R, hypoxia/reoxygenation, or Ca2+ overload insults. Mitochondrial function was assessed by measuring O2 consumption, membrane potential (ΔΨm), mitochondrial Ca2+ ([Ca2+]m), ATP production, respiratory chain complex activities, and molecular markers of mitochondrial biogenesis. Our results, combining physiological and biochemical parameters, confirmed that mitochondria from LTHA rats subjected to insults, in contrast to C, preserve respiratory functions (e.g., upon I/R, C mitochondria fueled by glutamate-malate, demonstrated decreases of 81%, 13%, 25%, and 50% in O2/P ratio, ATP production, ΔΨm, and complex I activity, respectively, whereas the corresponding LTHA parameters remained unchanged). STHA mitochondria maintained ΔΨm but did not preserve ATP production. LTHA [Ca2+]m was significantly higher than that of C and STHA and was not affected by the hypoxia/reoxygenation protocol compared with C. Enhanced mitochondrial biogenesis markers, switched-on during STHA coincidentally with enhanced membrane integrity (ΔΨm), were insufficient to confer intact respiratory function upon insult. LTHA was required for respiratory complex I adaptation and HACT. Stabilized higher basal [Ca2+]m and attenuated Ca2+ overload are likely connected to this adaptation.

Intermittent aerobic-resistance interval training versus continues aerobic training: Improvement in cardiac electrophysiologic and anthropometric measures in male patients post myocadiac infarction, a randomized control trial.

PURPOSE: Exercise is a valuable intervention modality for patients post-myocardial infarction (MI). Aerobic and resistance training are both commonly used separately in cardiac rehabilitation. However, the effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac electrophysiologic and anthropometric measures had not been thoroughly investigated. AIM: The primary objective of this study was to compare the effectiveness of moderate-intensity continuous-aerobic training (CAT) vs. SCT on cardiac electrical measures (resting electrocardiographic, ECG; a nd heart rate variability, HRV) in patients' post-MI presenting reduced left ventricular function. Second, to examine its effect on anthropometric measures. MATERIAL AND METHODS: Twenty-nine men post-MI with reduced left ventricular function were assigned randomly to either 12 weeks of CAT (n = 15) or SCT (n = 14). CAT group performed moderate-intensity activity. SCT group performed high-intensity exercise, alternating between resistance and aerobic training. Differences between CAT and SCT groups were done using independent t-tests, paired t-tests and effect size (ES). RESULTS: Participants in both groups improved their HRV measures (increase in HFnu; p < 0.05; ES > 0.51) and ECG (reduction in QT-dispersion; p < 0.05; ES > 0.51). Only the SCT group had significant improvements in waist circumference (p < 0.05). CONCLUSION: Exercise improves cardiac electrical measures post-MI. However, in comparison to CAT, SCT may yield greater anthropometric changes. In order to have improvements in cardiac electrical stability, clinicians working with post-MI patients may use both CAT and SCT. However, SCT might result in greater improvements.

ß-Alanine Supplementation Attenuates the Neurophysiological Response in Animals Exposed to an Acute Heat Stress.

The effect of 30 days of ß-alanine supplementation on neurophysiological responses of animals exposed to an acute heat stress (HS) was examined. Animals were randomized to one of three groups; exposed to HS (120 min at 40-41 °C) and fed a normal diet (EXP; n = 12); EXP and supplemented with ß-alanine (EXP + BA; n = 10); or not exposed (CTL; n = 10). Hippocampal (CA1, CA3 and DG) and hypothalamic (PVN) immunoreactive (ir) cell numbers of COX2, IBA-1, BDNF, NPY and HSP70 were analyzed. Three animals in EXP and one in EXP-BA did not survive the HS, however no significant difference (p = 0.146) was noted in survival rate in EXP + BA. The % change in rectal temperature was significantly lower (p = 0.04) in EXP + BA than EXP. Elevations (p's < 0.05) in COX-2, IBA-1 and HSP70 ir-cell numbers were noted in animals exposed to HS in all subregions. COX-2 ir-cell numbers were attenuated for EXP + BA in CA1 (p = 0.02) and PVN (p = 0.015) compared to EXP. No difference in COX-2 ir-cell numbers was noted between CTL and EXP + BA at CA1. BDNF-ir cell numbers in CA1, DG and PVN were reduced (p's < 0.05) during HS compared to CTL. No difference in BDNF-ir cell numbers was noted between EXP + BA and CTL in CA3 and PVN. NPY-ir density was reduced in exposed animals in all subregions, but NPY-ir density for EXP-BA was greater than EXP in CA3 (p < 0.001) and PVN (p = 0.04). ß-Alanine supplementation attenuated the thermoregulatory and inflammatory responses and maintained neurotrophin and neuropeptide levels during acute HS. Further research is necessary to determine whether ß-alanine supplementation can increase survival rate during a heat stress.

Heat acclimation and exercise training interact when combined in an overriding and trade-off manner: physiologic-genomic linkage.

Combined heat acclimation (AC) and exercise training (EX) enhance exercise performance in the heat while meeting thermoregulatory demands. We tested the hypothesis that different stress-specific adaptations evoked by each stressor individually trigger similar cardiac alterations, but when combined, overriding/trade-off interactions take place. We used echocardiography, isolated cardiomyocyte imaging and cDNA microarray techniques to assay in situ cardiac performance, excitation-contraction (EC) coupling features, and transcriptional programs associated with cardiac contractility. Rat groups studied were controls (sedentary 24°C); AC (sedentary, 34°C, 1 mo); normothermic EX (treadmill at 24°C, 1 mo); and heat-acclimated, exercise-trained (EXAC; treadmill at 34°C, 1 mo). Prolonged heat exposure decreased heart rate and contractile velocity and increased end ventricular diastolic diameter. Compared with controls, AC/EXAC cardiomyocytes demonstrated lower l-type Ca(2+) current (I(CaL)) amplitude, higher Ca(2+) transient (Ca(2+)T), and a greater Ca(2+)T-to-I(CaL) ratio; EX alone enhanced I(CaL) and Ca(2+)T, whereas aerobic training in general induced cardiac hypertrophy and action potential elongation in EX/EXAC animals. At the genomic level, the transcriptome profile indicated that the interaction between AC and EX yields an EXAC-specific molecular program. Genes affected by chronic heat were linked with the EC coupling cascade, whereas aerobic training upregulated genes involved with Ca(2+) turnover via an adrenergic/metabolic-driven positive inotropic response. In the EXAC cardiac phenotype, the impact of chronic heat overrides that of EX on EC coupling components and heart rate, whereas EX regulates cardiac morphometry. We suggest that concerted adjustments induced by AC and EX lead to enhanced metabolic and mechanical performance of the EXAC heart.

Back to Amido Black: Uncovering touch DNA in blood-contaminated fingermarks.

Blood-contaminated fingermarks (FMs) found in violent crime scenes may directly connect the suspect to the crime by linking the FM to the suspect and the DNA from the blood to the victim. However, marks that are incomparable are considered "dead-evidence" as the link to the suspect is lost. In this study, a novel approach was attempted to uncover the trace amount of touch DNA of the suspect in such marks. We examined the effect of two enhancement methods, ninhydrin (NIN) and amido black (AB), on DNA recovery from blood-contaminated FMs. A total of 108 fingerprints were deposited in three sets of depleted blood prints, blood-contaminated FMs, and latent FMs. All FMs were developed by either NIN or AB, or left undeveloped as reference followed by the quantification of the total DNA amount. This work shows that while AB had a detrimental effect on the quantity of blood-derived DNA specifically, reducing it by half, no similar effect was observed for touch DNA in latent FMs. This reduction led to the alteration of the major-to-minor DNA profile ratio to 70:30, thus enabling to obtain two distinct DNA profiles of the suspect from the touch DNA as well as the victim's profile from the blood. From an operational perspective, the use of AB in crime scenes may have an added value to retrieve the crucial DNA profile of the suspect, thus resurrecting a "dead-evidence."

Cognitive Effects of Astaxanthin Pretreatment on Recovery From Traumatic Brain Injury.

Traumatic brain injury (TBI), caused by mechanical impact to the brain, is a leading cause of death and disability among young adults, with slow and often incomplete recovery. Preemptive treatment strategies may increase the injury resilience of high-risk populations such as soldiers and athletes. In this work, the xanthophyll carotenoid Astaxanthin was examined as a potential nutritional preconditioning method in mice (sabra strain) to increase their resilience prior to TBI in a closed head injury (CHI) model. The effect of Astaxanthin pretreatment on heat shock protein (HSP) dynamics and functional outcome after CHI was explored by gavage or free eating (in pellet form) for 2 weeks before CHI. Assessment of neuromotor function by the neurological severity score (NSS) revealed significant improvement in the Astaxanthin gavage-treated group (100 mg/kg, ATX) during recovery compared to the gavage-treated olive oil group (OIL), beginning at 24 h post-CHI and lasting throughout 28 days (p < 0.007). Astaxanthin pretreatment in pellet form produced a smaller improvement in NSS vs. posttreatment at 7 days post-CHI (p < 0.05). Cognitive and behavioral evaluation using the novel object recognition test (ORT) and the Y Maze test revealed an advantage for Astaxanthin administration via free eating vs. standard chow during recovery post-CHI (ORT at 3 days, p < 0.035; improvement in Y Maze score from 2 to 29 days, p < 0.02). HSP profile and anxiety (open field test) were not significantly affected by Astaxanthin. In conclusion, astaxanthin pretreatment may contribute to improved recovery post-TBI in mice and is influenced by the form of administration.

Correction to: Astaxanthin supplementation impacts the cellular HSP expression profile during passive heating.

Due to an unfortunate misunderstanding, the top part of Figures 2 and 3 are not correctly displayed. The original article has been corrected and the proper version of Figures 2 and 3 is also published here.

Astaxanthin supplementation impacts the cellular HSP expression profile during passive heating.

Astaxanthin is a powerful carotenoid antioxidant prevalent in marine organisms and approved as a food supplement. Recent studies have demonstrated Astaxanthin's beneficial attributes in various health states. Following initial reports of potential heat protective properties in Astaxanthin supplemented rats, we present here results of a novel study examining the effect of Astaxanthin supplementation on the heat shock response in rats in relation to core temperature (Tc) and the ensuing physiological strain. Two hours of heat stress at 41 °C during which rats developed their thermoregulatory hyperthermic plateau resulted in progressive increases in HSP72 and HSP27 in the Astaxanthin (Oleoresin)-treated group but not in the control (Olive oil) group. Enhanced elevation in HSPs suggests that Astaxanthin supplementation may augment the cellular stress protective response to heat stress.

Asthaxanthin Improves Aerobic Exercise Recovery Without Affecting Heat Tolerance in Humans.

Objectives: To examine the supplementation effects of the xanthophyll carotenoid Astaxanthin on physical performance and exertional heat strain in humans. Design: A randomized double blind placebo controlled trial. Methods: Twenty two male participants (Age: 23.14 ± 3.5 y, height: 175 ± 6 cm, body mass: 69.6 ± 8.7 kg, % body fat: 16.8 ± 3.8) received placebo (PLA, n = 10) or Astaxanthin (ATX, n = 12) 12 mg/day Per os (P.O), for 30 days, and were tested pre and post-supplementation with a maximal oxygen uptake (VO2 Max) test and the heat tolerance test (HTT) (2 h walk at 40°C, 40% relative humidity (RH), 5 kph, 2% incline). NIH database registration no. NCT02088242. Gas exchange, Heart rate (HR), Relative perceived exertion (RPE), and blood lactate were measured during the VO2 Max test. Heart rate (HR), rectal (Trec), and skin (Tskin) temperatures, RPE, and sweat rate (SR) were monitored in the HTT. Serum heat shock protein 72 (HSP72), Creatine phospho-kinase (CPK), C-reactive protein (CRP), and lipid profile were measured before and after the test. Results: The rise in blood lactate caused by the VO2 Max test was significantly diminished in the ATX group (9.4 ± 3.1 and 13.0 ± 3.1 mmole*l-1 in the ATX and PLA groups, respectively P < 0.02), as was the change in oxygen uptake during recovery (-2.02 ± 0.64 and 0.83 ± 0.79% of VO2 Max in the ATX and PLA group, respectively, p = 0.001). No significant differences were observed in the anaerobic threshold or VO2 Max. In the HTT, no significant physiological or biochemical differences were observed (HR <120 bpm, Trec rose by ~1°C to <38°C, no difference in SR). Conclusions: Astaxanthin supplementation improved exercise recovery. No benefit was observed for ATX over PLA in response to heat stress. Further examination of Astaxanthin in higher exertional heat strain is required.

Impacts of previous heatstroke history on physiological parameters eHSP72 and biomarkers of oxidative stress in military working dogs.

Heatstroke (HS) is an acute, progressive life-threatening emergency. Animals, including military working dogs (IDFMWD), rapidly activate cytoprotective processes, e.g., heat shock proteins (HSPs) and antioxidative molecules, in response to heat stress. We hypothesized that serum HSPs (eHSP72) and oxidative stress markers would differ in IDFMWD with a history of HS compared with controls and thus could be used to detect susceptibility to recurrent HS. eHSPs concentration, oxidative stress markers, and systemic physiological parameters were studied in dogs with and without histories of HS, undergoing indoor or outdoor training. Treadmill physical performance tests (PPTs) were conducted indoors at 22 °C (groups C-I and HS-I) or outdoors under heat stress conditions of 36 °C; 60% humidity (groups C-O and HS-O). Pre-, immediately post-, and 45 min post-PPT heart rate (HR), respiratory rate, and rectal temperature (Tre) were recorded in all dogs. Likewise, blood samples were collected and eHSP72, venous blood gas analysis, and lactate and creatine kinase activity (CK) were assayed. Serum uric acid (sUA) and total serum redox potential (TRP) were measured only in the indoor group. Immediately post-PPT under both environmental conditions, Tre, HR, eHSP, sUA, and TRP (only measured in indoor PPT) significantly (P < 0.05) increased, whereas venous blood pH and bicarbonate decreased significantly (P < 0.05). Between groups comparisons demonstrated significant differences in basal HR and post-PPT Tre immediately after outdoor PPT. eHSP72 induction, CK, sUA, and serum TRP remained significantly higher in the HS group during post-PPT recovery. Taken together, animals with a history of HS have different results, and this signature of previous HS may predict altered heat sensitivity.

Physiological and molecular evidence of heat acclimation memory: a lesson from thermal responses and ischemic cross-tolerance in the heart.

Sporadic findings in humans suggest that reinduction of heat acclimation (AC) after its loss occurs markedly faster than that during the initial AC session. Animal studies substantiated that the underlying acclimatory processes are molecular. Here we test the hypothesis that faster reinduction of AC (ReAC) implicates "molecular memory." In vivo measurements of colonic temperature profiles during heat stress and ex vivo assessment of cross-tolerance to ischemia-reperfusion or anoxia insults in the heart demonstrated that ReAC only needs 2 days vs. the 30 days required for the initial development of AC. Stress gene profiling in the experimental groups highlighted clusters of transcriptionally activated genes (37%), which included heat shock protein (HSP) genes, antiapoptotic genes, and chromatin remodeling genes. Despite a return of the physiological phenotype to its preacclimation state, after a 1 mo deacclimation (DeAC) period, the gene transcripts did not resume their preacclimation levels, suggesting a dichotomy between genotype and phenotype in this system. Individual detection of hsp70 and hsf1 transcripts agreed with these findings. HSP72, HSF1/P-HSF1, and Bcl-xL protein profiles followed the observed dichotomized genomic response. In contrast, HSP90, an essential cytoprotective component mismatched transcriptional activation upon DeAC. The uniform activation of the similarly responding gene clusters upon De-/ReAC implies that reacclimatory phenotypic plasticity is associated with upstream denominators. During AC, DeAC, and ReAC, the maintenance of elevated/phosphorylated HSF1 protein levels and transcriptionally active chromatin remodeling genes implies that chromatin remodeling plays a pivotal role in the transcriptome profile and in preconditioning to rapid cytoprotective acclimatory memory.

Differential neuroprotective properties of endogenous and exogenous erythropoietin in a mouse model of traumatic brain injury.

Both heat acclimation (HA) and post-injury treatment with recombinant human erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced cerebral edema formation. Additionally, in earlier Western-blot analyses, we found that HA mice display increased expression of the specific erythropoietin receptor (EpoR) and of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the inducible subunit of the transcription factor, which regulates Epo gene expression, but not of Epo itself. In light of this, the aim of the current study was threefold: (1) to assess Epo expression in the trauma area and hippocampus following HA, rhEpo administration, or combined HA-rhEpo treatment, using immunohistochemical methods that offer enhanced anatomical resolution; (2) to examine the effects of endogenous and exogenous Epo on edema formation in normothermic (NT) mice; and (3) to evaluate the effects of exogenous Epo administration on neuroprotective outcome measures in HA animals. HA induced enhanced expression of endogenous Epo in the trauma area and the hippocampus. Treatment with anti-Epo antibody given to NT mice increased edema formation, whereas rhEpo induced no beneficial effect. Cognitive performance testing and immunohistochemical findings reinforced HA and rhEpo as separate protective interventions but showed no advantage to combining the two strategies. We therefore suggest that HA-induced neuroprotection is shaped by pre-existing mediators but cannot be modified by post-injury treatment aimed at increasing the levels of neuroprotective agents.

Correction: Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial.

[This corrects the article DOI: 10.1371/journal.pone.0188551.].