Reduction In Metabolic Rate Research Articles

Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H215O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals.These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.

Long-term microplastic retention causes reduced body condition in the langoustine, Nephrops norvegicus

Microplastic represents a rising proportion of marine litter and is widely distributed throughout a range of marine habitats. Correspondingly, the number of reports of species containing microplastics increases annually. Nephrops norvegicus in the Firth of Clyde have previously been shown to retain large aggregations of microplastic fibres. The potential for N. norvegicus to retain plastic over an extended time period increases the likelihood of any associated negative impacts to the individual. This study represents the longest observation of the impacts of microplastic retention in invertebrates. We exposed N. norvegicus to plastic over eight months to determine the impacts of extended exposure. Over this period we compared the feeding rate, body mass, and nutritional state of plastic-fed N. norvegicus to that of fed and starved control groups. Following the experimental period, the plastic-fed langoustine contained microplastic aggregations comparable to those of small individuals from the Clyde Sea Area. Comparisons between fed, unfed and plastic-fed individuals indicated a reduction in feeding rate, body mass, and metabolic rate as well as catabolism of stored lipids in plastic contaminated animals. We conclude that N. norvegicus exposed to high levels of environmental microplastic pollution may experience reduced nutrient availability. This can result in reduced population stability and may affect the viability of local fisheries.

Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity

ObjectiveA major challenge for obesity treatment is the maintenance of reduced body weight. Diet-induced obese mice are resistant to achieving normoweight once the obesogenic conditions are reversed, in part because lowered circulating leptin leads to a reduction in metabolic rate and a rebound of hyperphagia that defend the previously elevated body weight set point. Because hypothalamic POMC is a central leptin target, we investigated whether changes in circulating leptin modify Pomc expression to maintain normal energy balance in genetically predisposed obese mice. MethodsMice with reversible Pomc silencing in the arcuate nucleus (ArcPomc−/−) become morbidly obese eating low-fat chow. We measured body composition, food intake, plasma leptin, and leptin sensitivity in ArcPomc−/− mice weight-matched to littermate controls by calorie restriction, either from weaning or after developing obesity. Pomc was reactivated by tamoxifen-dependent Cre recombinase transgenes. Long acting PASylated leptin was administered to weight-reduced ArcPomc−/− mice to mimic the super-elevated leptin levels of obese mice. ResultsArcPomc−/− mice had increased adiposity and leptin levels shortly after weaning. Despite chronic calorie restriction to achieve normoweight, ArcPomc−/− mice remained moderately hyperleptinemic and resistant to exogenous leptin's effects to reduce weight and food intake. However, subsequent Pomc reactivation in weight-matched ArcPomc−/− mice normalized plasma leptin, leptin sensitivity, adiposity, and food intake. In contrast, extreme hyperleptinemia induced by PASylated leptin blocked the full restoration of hypothalamic Pomc expression in calorie restricted ArcPomc−/− mice, which consequently regained 30% of their lost body weight and attained a metabolic steady state similar to that of tamoxifen treated obese ArcPomc−/− mice. ConclusionsPomc reactivation in previously obese, calorie-restricted ArcPomc−/− mice normalized energy homeostasis, suggesting that their body weight set point was restored to control levels. In contrast, massively obese and hyperleptinemic ArcPomc−/− mice or those weight-matched and treated with PASylated leptin to maintain extreme hyperleptinemia prior to Pomc reactivation converged to an intermediate set point relative to lean control and obese ArcPomc−/− mice. We conclude that restoration of hypothalamic leptin sensitivity and Pomc expression is necessary for obese ArcPomc−/− mice to achieve and sustain normal metabolic homeostasis; whereas deficits in either parameter set a maladaptive allostatic balance that defends increased adiposity and body weight.

Thermal physiology of a reproductive female marsupial, Antechinus flavipes

Reproduction is an energetically costly, but necessary, process for animals. Small mammals in particular are at a disadvantage as they experience high heat losses to their environment, substantially increasing their energetic costs. However, many small mammals save energy by using torpor, a reduction in metabolic rate and body temperature (Tb). Antechinus flavipes is a small dasyurid marsupial endemic to Australia that uses torpor during adverse conditions. Females usually produce only one litter in their life. In our study, we aimed to quantify the thermal physiology of reproductive female A. flavipes held under natural ambient conditions in an outdoor aviary, and also under stable conditions indoors, during gestation, parturition and lactation. Throughout gestation, A. flavipes displayed similar variations in torpor use and Tb to reproductively unsuccessful females (did not produce young). Torpor use increased with decreasing ambient temperature in the outdoor aviary and ceased when held under stable ambient conditions indoors. Interestingly, during parturition/early lactation, Tb was tightly controlled and daily Tb variation decreased by ≥2.3 °C in comparison to all other reproductive states. Additionally, daily Tb variations during lactation were slightly smaller than those of gestating and reproductively unsuccessful females; however, this conclusion is only preliminary. Our results reveal that the flexibility of the thermal physiology of female A. flavipes is important throughout the reproductive period, except during parturition/early lactation when a stable Tb is likely beneficial to the early stages of development.

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment

Amnestic mild cognitive impairment represents an early stage of Alzheimer’s disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O2/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction (p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% (p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO2-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.

Variation in winter metabolic reduction between sympatric amphibians

Distribution and abundance of temperate ectotherms is determined, in part, by the depletion of their limited caloric reserves during wintering. The magnitude of winter energy drain depends on the species-specific capacity to seasonally modify the minimal maintenance costs. We examined seasonal variation of minimum oxygen consumption between two newt species, Ichthyosaura alpestris and Lissotriton vulgaris. Oxygen consumption was measured in both species during their active season (daily temperature range=12–22°C) and wintering period (4°C) at 4°C and 8°C. The seasonal reduction in metabolic rates differed between species and experimental temperatures. Wintering newts reduced their metabolic rates at 4°C and 8°C in I. alpestris, but only at 8°C in L. vulgaris. Both species reduced the thermal sensitivity of oxygen consumption during wintering. Theoretical calculations of winter depletion of caloric reserves under various thermal conditions revealed that seasonal metabolic reduction is more effective in I. alpestris than in L. vulgaris, and its effectiveness will increase with the proportion of warmer days during wintering period. The variation in winter metabolic reduction between sympatric newt species potentially contributes to their distribution patterns and population dynamics under climate change.

Connectivity in the cold: the comparative population genetics of vent-endemic fauna in the Scotia Sea, Southern Ocean.

We report the first comparative population genetics study for vent fauna in the Southern Ocean using cytochrome C oxidase I and microsatellite markers. Three species are examined: the kiwaid squat lobster, Kiwa tyleri, the peltospirid gastropod, Gigantopelta chessoia, and a lepetodrilid limpet, Lepetodrilus sp., collected from vent fields 440km apart on the East Scotia Ridge (ESR) and from the Kemp Caldera on the South Sandwich Island Arc, ~95km eastwards. We report no differentiation for all species across the ESR, consistent with panmixia or recent range expansions. A lack of differentiation is notable for Kiwa tyleri, which exhibits extremely abbreviated lecithotrophic larval development, suggestive of a very limited dispersal range. Larval lifespans may, however, be extended by low temperature-induced metabolic rate reduction in the Southern Ocean, muting the impact of dispersal strategy on patterns of population structure. COI diversity patterns suggest all species experienced demographic bottlenecks or selective sweeps in the past million years and possibly at different times. ESR and Kemp limpets are divergent, although with evidence of very recent ESR-Kemp immigration. Their divergence, possibility indicative of incipient speciation, along with the absence of the other two species at Kemp, may be the consequence of differing dispersal capabilities across a ~1000m depth range and/or different selective regimes between the two areas. Estimates of historic and recent limpet gene flow between the ESR and Kemp are consistent with predominantly easterly currents and potentially therefore, cross-axis currents on the ESR, with biogeographic implications for the region.

Life in the cold: links between mammalian hibernation and longevity.

The biological process of aging is the primary determinant of lifespan, but the factors that influence the rate of aging are not yet clearly understood and remain a challenging question. Mammals are characterized by >100-fold differences in maximal lifespan, influenced by relative variances in body mass and metabolic rate. Recent discoveries have identified long-lived mammalian species that deviate from the expected longevity quotient. A commonality among many long-lived species is the capacity to undergo metabolic rate depression, effectively re-programming normal metabolism in response to extreme environmental stress and enter states of torpor or hibernation. This stress tolerant phenotype often involves a reduction in overall metabolic rate to just 1-5% of the normal basal rate as well as activation of cytoprotective responses. At the cellular level, major energy savings are achieved via coordinated suppression of many ATP-expensive cell functions; e.g. global rates of protein synthesis are strongly reduced via inhibition of the insulin signaling axis. At the same time, various studies have shown activation of stress survival signaling during hibernation including up-regulation of protein chaperones, increased antioxidant defenses, and transcriptional activation of pro-survival signaling such as the FOXO and p53 pathways. Many similarities and parallels exist between hibernation phenotypes and different long-lived models, e.g. signal transduction pathways found to be commonly regulated during hibernation are also known to induce lifespan extension in animals such as Drosophila melanogaster and Caenorhabditis elegans. In this review, we highlight some of the molecular mechanisms that promote longevity in classic aging models C. elegans, Drosophila, and mice, while providing a comparative analysis to how they are regulated during mammalian hibernation.

A study of the employment of melatonin supplementation and darkness regime on reducing the negative effects of acute heat stress and mortality in broiler chickens

Background: Heat stress is one of the most important environmental stressors challenging poultry production worldwide. Understanding and controlling environmental stressors is crucial for successful poultry production. OBJECTIVES: The aim of the present study was to investigate the effects of melatonin supplementation and darkness regime on reducing the negative effects of heat stress in broiler chickens. METHODS: A total of 400 broiler chickens (Arian) were obtained and subjected to four different groups. The control chickens were grown in normal conditions without receiving any treatment. The positive control birds were grown similar to the control but exposed to an acute heat stress for 6 h/d from days 35 to 40. The dark group chickens were reared under a dark schedule and exposed to heat stress. The birds of the fourth group were reared similar to the positive control but received 40 ppm melatonin in the diet from days 30 to 40 of age. Dead birds were autopsied. The weekly growth performance of chickens was determined and blood samples were taken for hormonal analysis. RESULTS: The number of dead birds due to heat stress was significantly decreased in chickens subjected to the dark program and/or those which received melatonin in the diet compared with those of positive control chickens. Such differences were accompanied with the significantly lower levels of plasma T3, T3/T4 and corticosterone in these groups of chickens. Additionally, plasma thiobarbituric acid reacting substances level was significantly higher in positive control broilers compared to their counterparts. CONCLUSIONS: Our findings indicate a reduction of metabolic rate and heat production in dark regime and melatonin supplementation that can reduce the side effects of heat stress and, therefore, reduce the mortality rate.

Exploring principles of hibernation for organ preservation.

Interest in mimicking hibernating states has led investigators to explore the biological mechanisms that permit hibernating mammals to survive for months at extremely low ambient temperatures, with no food or water, and awaken from their hibernation without apparent organ injury. Hibernators have evolved mechanisms to adapt to dramatic reductions in core body temperature and metabolic rate, accompanied by prolonged periods without nutritional intake and at the same time tolerate the metabolic demands of arousal. This review discusses the inherent resilience of hibernators to kidney injury and provides a potential framework for new therapies targeting ex vivo preservation of kidneys for transplantation.

THERAPEUTIC MILD HYPOTHERMIA TOWARDS BLOOD LACTATE LEVELS AND GLASGOW COMA SCORE IN SEVERE TRAUMATIC BRAIN INJURY

Background: Raised body temperature is a common occurrence after severe traumatic brain injury (TBI). TBI is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. This metabolic disturbance reflected by increase and accumulation of the brain lactate levels. The study aimed to evaluate the effect of therapeutic mild hypotermia (TMH) on lactate levels and GCS (Glasgow Coma Score) of severe TBI. Methods: Fourthy patients with TBI were randomly divided into normothermia (n=20) and mild hypothermia (n=20) group. Body temperature of hypothermia group was maintained at 35°C for 72 hours. Blood lactate level and GCS were determined before and after hypothermia therapy ( on 3th and 7th day). Results: The mean lactate {5.370 vs 4.025 mmol/L, p<0.001 (on 3th day); 5.070 vs 2.775 mmol/L, p<0.001(on 7th day)}. TMH group was lower than in the normothermia group after TMH. The mean GCS was higher in TMH group than in the normothermia group {8.45 vs 7.80, p < 0.002 (on 3th day); 9.85 vs 8.25, p<0.005 (on 7th day)}. Conclusion: There was a significant correlation between blood lactate level and GCS according to TMH. Mild hypothermia therapy improves neurologic outcomes in patients with severe TBI, and reduction in blood lactate level may be partially responsible for the improved outcomes.

180 Comprehensive Study of Posttraumatic Cerebral Energy Metabolism

INTRODUCTION: Previous studies have documented dysfunctional cerebral metabolism following traumatic brain injury (TBI), characterized by reduction in cerebral metabolic rates (CMRs) of glucose and oxygen. In our largest series to date, here, we provide further evidence and time courses of these metabolic changes. METHODS: CMRs for oxygen, glucose, and lactate were determined in 74 TBI subjects over 6 postinjury days by a modified Kety-Schmidt method and in 35 normal subjects. Comparison to normal, and time courses, utilized a mixed-effects model, accounting for repeated measurements in the trauma group. Time courses are represented as a restricted cubic spline with 3 interior knots placed at the quartiles of postinjury hours. A random intercept for subject was used as the random-effects structure. RESULTS: Post-TBI CMRO2 (0.599 vs 1.391; P CONCLUSION: In our largest series of patients to date, we have demonstrated that posttraumatic cerebral metabolism is characterized by depressed glucose and oxygen metabolism that is persistent for at least 6 days postinjury. There is mismatch between glucose and oxygen utilization, indicated by diminished metabolic ratio, and frequent lactate uptake. Further study is required to fully characterize the dysfunctional metabolism, which may be a source of further secondary injury in the early postinjury period. Language: en

BUILD MUSCLE, IMPROVE HEALTH

LEARNING OBJECTIVES To realize that age-related muscle loss is associated with bone loss, metabolic rate reduction, fat gain, diabetes, metabolic syndrome, heart disease, and various problems associated with physical degeneration/dysfunction. To recognize the beneficial effects of resistance exercise for increasing muscle mass, bone density, metabolic rate, insulin sensitivity, high-density lipoprotein cholesterol, cognitive ability, and self-esteem, as well as for decreasing body fat, resting blood pressure, low-density lipoprotein cholesterol, low-back pain, arthritic discomfort, and depression. To use programs of resistance exercise that provide safe, progressive, and effective strength training experiences in accordance with the 2014 ACSM strength training recommendations.

Changes to Metabolism and Cell Physiology that Enable Mammalian Hibernation

Heterothermy is a widespread, adaptive strategy used by many species of bird and mammal to conserve energy during periods of energetic deficit, the expression of which varies greatly depending on the species and environment. A temporary, reversible reduction in metabolic rate and body temperature (i.e., torpor) is an adaptive response used by many species of birds and mammals to conserve energy during periods of resource scarcity. Long-term employment of torpor (i.e., hibernation) is a seasonally expressed phenotype, the genetic and regulated pathways of which can be found throughout all mammal lineages, including hibernators and nonhibernators alike. In mammals, adaptations that allow for hibernation can be classified as those involved in preparation for hibernation, metabolic reduction, continued cellular function and protection, and arousal. Key physiological changes involve seasonal regulation of metabolic hormones, a shift to largely using endogenous fuel sources (i.e., increased lipolysis), global down regulation of protein transcription by posttranslational modification and microRNA save for the increased production of a small number of protective proteins, shifts in membrane composition, and thermogenesis by brown adipose tissue. There is some evidence of cold acclimations in nonhibernators, such as during fetal development, but responses are limited and cursory, and eventually cellular damage occurs. Therefore, it appears that a complete suite of adaptations to metabolism, vital physiological functions, and thermogenic mechanisms is required for the successful expression of the hibernation phenotype.

Pregnancy limits lung function during exercise and depresses metabolic rate in the skink Tiliqua nigrolutea.

High gestational loads have been associated with a range of ecological costs, such as decreased locomotor ability; however, the physiological mechanisms that underpin these changes are poorly understood. In this study, breathing patterns, metabolic rates, lung volume and lung diffusing capacity were measured at rest and during exercise in the pregnant skink Tiliqua nigrolutea. Breathing patterns were largely unaffected by gestation; however, decreases in metabolic rate (rate of oxygen consumption) in the late stages of pregnancy induced a relative hyperventilation. The reductions in metabolic rate during late pregnancy prevent the calculation of the maintenance cost of pregnancy based on post-partum and neonatal metabolic rates. Despite the high relative litter mass of 38.9±5.3%, lung diffusing capacity was maintained during all stages of pregnancy, suggesting that alterations in diffusion at the alveolar capillary membrane were not responsible for the relative hyperventilation. Lung volume was increased during pregnancy compared with non-pregnant females, but lung volume was significantly lower during pregnancy compared with post-partum lung volume. Pregnant females were unable to produce the same metabolic and ventilatory changes induced by exercise in non-pregnant females. This lack of ability to respond to increased respiratory drive during exercise may underpin the locomotor impairment measured during gestation in previous studies.

Convergent evolution of alternative developmental trajectories associated with diapause in African and South American killifish.

Annual killifish adapted to life in seasonally ephemeral water-bodies exhibit desiccation resistant eggs that can undergo diapause, a period of developmental arrest, enabling them to traverse the otherwise inhospitable dry season. Environmental cues that potentially indicate the season can govern whether eggs enter a stage of diapause mid-way through development or skip this diapause and instead undergo direct development. We report, based on construction of a supermatrix phylogenetic tree of the order Cyprinodontiformes and a battery of comparative analyses, that the ability to produce diapause eggs evolved independently at least six times within African and South American killifish. We then show in species representative of these lineages that embryos entering diapause display significant reduction in development of the cranial region and circulatory system relative to direct-developing embryos. This divergence along alternative developmental pathways begins mid-way through development, well before diapause is entered, during a period of purported maximum developmental constraint (the phylotypic period). Finally, we show that entering diapause is accompanied by a dramatic reduction in metabolic rate and concomitant increase in long-term embryo survival. Morphological divergence during the phylotypic period thus allows embryos undergoing diapause to conserve energy by shunting resources away from energetically costly organs thereby increasing survival chances in an environment that necessitates remaining dormant, buried in the soil and surrounded by an eggshell for much of the year. Our results indicate that adaptation to seasonal aquatic environments in annual killifish imposes strong selection during the embryo stage leading to marked diversification during this otherwise conserved period of vertebrate development.

The influence of push-off timing in a robotic ankle-foot prosthesis on the energetics and mechanics of walking.

BackgroundRobotic ankle-foot prostheses that provide net positive push-off work can reduce the metabolic rate of walking for individuals with amputation, but benefits might be sensitive to push-off timing. Simple walking models suggest that preemptive push-off reduces center-of-mass work, possibly reducing metabolic rate. Studies with bilateral exoskeletons have found that push-off beginning before leading leg contact minimizes metabolic rate, but timing was not varied independently from push-off work, and the effects of push-off timing on biomechanics were not measured. Most lower-limb amputations are unilateral, which could also affect optimal timing. The goal of this study was to vary the timing of positive prosthesis push-off work in isolation and measure the effects on energetics, mechanics and muscle activity.MethodsWe tested 10 able-bodied participants walking on a treadmill at 1.25 m · s−1. Participants wore a tethered ankle-foot prosthesis emulator on one leg using a rigid boot adapter. We programmed the prosthesis to apply torque bursts that began between 46% and 56% of stride in different conditions. We iteratively adjusted torque magnitude to maintain constant net positive push-off work.ResultsWhen push-off began at or after leading leg contact, metabolic rate was about 10% lower than in a condition with Spring-like prosthesis behavior. When push-off began before leading leg contact, metabolic rate was not different from the Spring-like condition. Early push-off led to increased prosthesis-side vastus medialis and biceps femoris activity during push-off and increased variability in step length and prosthesis loading during push-off. Prosthesis push-off timing had no influence on intact-side leg center-of-mass collision work.ConclusionsProsthesis push-off timing, isolated from push-off work, strongly affected metabolic rate, with optimal timing at or after intact-side heel contact. Increased thigh muscle activation and increased human variability appear to have caused the lack of reduction in metabolic rate when push-off was provided too early. Optimal timing with respect to opposite heel contact was not different from normal walking, but the trends in metabolic rate and center-of-mass mechanics were not consistent with simple model predictions. Optimal push-off timing should also be characterized for individuals with amputation, since meaningful benefits might be realized with improved timing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12984-015-0014-8) contains supplementary material, which is available to authorized users.

Eukaryotic elongation factor 2 kinase regulates the cold stress response by slowing translation elongation.

Cells respond to external stress conditions by controlling gene expression, a process which occurs rapidly via post-transcriptional regulation at the level of protein synthesis. Global control of translation is mediated by modification of translation factors to allow reprogramming of the translatome and synthesis of specific proteins that are required for stress protection or initiation of apoptosis. In the present study, we have investigated how global protein synthesis rates are regulated upon mild cooling. We demonstrate that although there are changes to the factors that control initiation, including phosphorylation of eukaryotic translation initiation factor 2 (eIF2) on the α-subunit, the reduction in the global translation rate is mediated by regulation of elongation via phosphorylation of eukaryotic elongation factor 2 (eEF2) by its specific kinase, eEF2K (eukaryotic elongation factor 2 kinase). The AMP/ATP ratio increases following cooling, consistent with a reduction in metabolic rates, giving rise to activation of AMPK (5'-AMP-activated protein kinase), which is upstream of eEF2K. However, our data show that the major trigger for activation of eEF2K upon mild cooling is the release of Ca2+ ions from the endoplasmic reticulum (ER) and, importantly, that it is possible to restore protein synthesis rates in cooled cells by inhibition of this pathway at multiple points. As cooling has both therapeutic and industrial applications, our data provide important new insights into how the cellular responses to this stress are regulated, opening up new possibilities to modulate these responses for medical or industrial use at physiological or cooler temperatures.

Medicinal Chemistry: Insights into the Development of Novel H2S Donors.

Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.