急性低温暴露对大鼠肝脏的损伤及机制研究
|
摘要
研究背景
寒冷地区的冬季,人们在户外活动时会暴露于低温环境中。从事低温环境作业的人员和参加特殊环境军事活动的官兵也经常暴露于低温环境中。低温环境对机体的影响和如何预防低温暴露相关疾病一直是人们研究的热点,具有重要意义。
低温环境对人体造成损伤的机制以其特殊的军事地位和作用,很少有相关内容的公开报道。目前,人们对于低温环境对机体损伤机制的研究多限于长期的慢性暴露模型,而急性的低温暴露模型尚未见到相关的报道。在北方高寒地区冬季,部队执行野外巡逻和站岗任务的士兵需要暴露在寒冷环境中,如果防护措施不当则很容易造成急性冻伤。目前,对于急性寒冷损伤的研究多集中在体表皮肤及肌肉组织的冻伤,而体内脏器在急性低温暴露时受到的影响及其发挥的作用尚未见到相关报道。人体暴露于低温环境后,需要动员产热以维持体温。虽然在此时肌肉的寒颤产热占主导作用,但肝脏作为体内最大的糖原储存器官和静息状态的主要产热器官,也可能参与到急性低温暴露下机体的应激过程中。在大鼠和人的正常生长过程中,肝脏可以形成一定数量的双核细胞,双核细胞的形成可能与肝脏损伤和增殖能力相关。在能量缺乏或其他损伤效应作用下,肝细胞有丝分裂失败而形成双核细胞。PI3K-Akt-mTOR通路是重要的生存信号通路,参与细胞的能量代谢,增殖分化,生长繁殖等重要过程。其在低温暴露过程中起到的作用已在慢性模型中进行相关研究,但在急性低温暴露模型中及在肝脏中的相关作用尚未阐明。
本研究试图通过建立急性低温暴露模型,探讨急性低温暴露是否可以引起肝脏病理生理学改变,并探讨PI3K-Akt-mTOR通路是否参与了急性低温暴露过程中的应答过程及其调控机制,为探索更多的低温暴露效应标志物及预防靶点提供理论依据。
研究目的
1.在大鼠急性低温暴露模型中,研究急性低温暴露引起大鼠肝脏的病理生理学改变,观察肝脏有丝分裂细胞及双核细胞在低温暴露过程中数量的变化及细胞能量水平的变化。同时观察PI3K-Akt-mTOR通路的变化情况及其与肝脏病理生理改变的关系。
2.通过使用通路抑制剂,观察PI3K-Akt-mTOR通路与肝细胞能量水平变化的关系及其是否参与了肝细胞有丝分裂增加及双核细胞形成的过程。
研究方法
1.利用低温实验舱,建立大鼠急性低温暴露模型:暴露温度为﹣15℃,暴露时间为0.5 h、1 h、2 h和4 h。
2.利用组化方法,通过HE染色观察急性低温暴露后大鼠肝脏的损伤情况及双核细胞的形成。
3.利用电镜,观察急性低温暴露对大鼠肝脏超微结构的影响。
4.利用western blot方法,观察PI3K-Akt-mTOR通路在急性低温暴露中的变化情况。
研究结果
1.从HE染色结果可以发现,随暴露时间延长,大鼠肝脏的损伤程度逐渐加深。在低温暴露0.5 h即发生轻度肝细胞水肿,在低温暴露4 h后,可发现细胞出现变性、水肿,肝细胞有丝分裂增加并且出现大量双核细胞和少数凋亡细胞。从电镜结果可以发现,低温暴露0.5 h可导致肝细胞糖原减少,线粒体轻度肿胀;低温暴露4 h可致肝细胞内糖原耗竭,线粒体明显肿胀,内质网被压缩,包绕于线粒体周围。
2.通过对肝细胞ATP含量的测定,发现在低温暴露0.5 h,肝细胞ATP含量明显增加,并随暴露时间延长而逐渐降低(p<0.05)。
3. western blot的检测结果发现,PI3K-Akt-mTOR通路相关蛋白出现先升高后降低的一过性激活, Akt蛋白的Ser-473位点、Thr-308位点;mTOR蛋白的Ser-2448位点、Ser-2481位点和p70 S6K蛋白的Thr-389位点在低温暴露0.5 h的磷酸化程度明显升高,随暴露时间延长而逐渐降低。在对线粒体蛋白的测定发现,Akt蛋白和mTOR蛋白在线粒体内的表达与其在胞质中的表达趋势一致。另外,与能量相关的AMPK蛋白的Thr-172位点随暴露时间延长而磷酸化程度逐渐增加。
4.为进一步证实急性低温暴露可以诱导大鼠肝脏有丝分裂增加及双核细胞形成增加,利用免疫组织化学方法对大鼠肝脏双核细胞进行计数,结果发现在低温暴露4 h后,大鼠肝脏有丝分裂期细胞数量明显增加,并且双核细胞数量明显增加(p<0.05)。
5.通过腹腔注射抑制剂渥曼青霉素(wortmannin),可以发现低温暴露4 h大鼠的肝脏细胞ATP水平与非抑制剂处理组相比明显降低,与室温对照组相比明显升高(p<0.05)。大鼠肝脏有丝分裂期细胞所占比例无明显改变,双核细胞的数量明显增加(p<0.05)。
研究结论
1.急性低温暴露4 h可以引起大鼠肝脏损伤,引起肝细胞ATP水平的异常增加,诱导静息期肝细胞进入有丝分裂期并伴随大量双核细胞形成。
2. PI3K-Akt-mTOR通路参与了急性低温暴露对大鼠肝脏的损伤作用,参与了低温暴露过程中ATP的生成调节并促进肝细胞有丝分裂及双核细胞的形成。
Background:
People usually expose to cold environment in out-door activities in the cold winter. And workers who engage in the low temperature environment work and soldiers who execute special environment military missions will commonly expose to harsh weather. The mechanism of healthy effects caused by cold exposure and the method of preventing cold exposure relative diseases is of great interest to scientist and is of great importance.
Being at the important military status, the mechanism of cold relative injuries is hardly to be seen in the open press. Up to now, the experimental models used by the study on mechanisms of cold exposure induced healthy effects are mostly the long lasting chronic ones, while the acute cold exposure models are rarely adopted. Soldiers who execute border patrolling or sentry duty will expose to the low tempareture environment in cold winter, and when they were insufficiently prevented, they will easily get acute cold injuries. The studies on acute cold injury are mainly focusing on the frostbite of skin and superficial structures, while the cold effects on the internal organs and the potential functions of the internal organs during cold exposure is rarely studied or reported. When exposed to the cold environment, adult mammals will sponsor the thermogenic activities to maintain body temperature. Although liver is less efficient on calorification than muscle, as one of the largest clycogen storage organ and the dominant thermogenic organ in the resting status, liver may participate in the response to acute cold stressing. Human and rat liver can form a number of binuclear hepatocytes during development. Under some pathological situations, the formation of binuclear hepatocyte may be relative with the liver injury and generative ability changing. The hepatocyte mitosis will be failure under energy stressing or other injurious status and then the binuclear hepatocyte formed. The PI3K-Akt-mTOR signaling is an important pathway that participates in the regulative progression of metabolism, differentiation, development and survival. The potential functions of the pathway in cold exposure have been studied in the chronic cold exposure model, while its role in the acute cold exposure circumstances is still to be illustrating.
As expected, using the acute cold exposure animal model, we attempt to explain whether liver could get any physiological or pathological changes during acute cold exposure, and to explain whether and what role the PI3K-Akt-mTOR pathway participates in the responsive reactivities. This will be of great importance to find more effective biomarkers and targets of prevention in acute cold exposure situations.
Aims:
1. To observe the physiological and pathological changes of liver during acute cold exposure: The changes of number of mitotic hepatocytes and binuclear hepatocytes and the changes of energy level in the hepatocytes during cold exposure as well as the activity changing of the PI3K-Akt-mTOR pathway and its relative potential functions.
2. By the utility of inhibitor, explores whether the PI3K-Akt-mTOR pathway participates in the regulation of liver ATP level during acute cold exposure. And whether this change can affect the process of promoting hepatocyte enter into the mitosis phase and the formation of binuclear hepatocyte.
Methods:
1. Adult male rats weighing 220-230 g are exposed to the cold environment at﹣15℃for 0.5, 1, 2 and 4 hours.
2. To observe the pathological changes of liver during acute cold exposure by HE staining and immuno-histochemistry detecting.
3. To observe the ultramicrostructure changes of the hepatocytes during acute cold exposure.
4. To observe the changes of activities of the PI3K-Akt-mTOR pathway by western blot method.
Results:
1. Acute cold exposure could injure the liver by a time dependent manner. After 4 hours exposure, the rat hepatocytes were vacuolate degeneration and there were an increasing number of mitosis hepatocytes and binuclear hepatocytes, as well as some apoptosis hepatocytes. 4 hours exposure also caused the microstructure injuries such as the swollen of mitochondria and the depletion of clycogen.
2. The ATP level elevated rapidly and peaked at the 0.5 hours during cold exposure and then declined as the exposure time prolonged.
3. The activity of the PI3K-Akt-mTOR pathway paralleled with the changes of ATP level. And the AMPK activated in a time dependent manner.
4. After injecting of inhibitor wortmannin intraperitoneally, the ATP level declined magnificently and the binuclear hepatocyte increased.
Conclution:
1. 4 hours acute cold exposure causes rat liver injury and an abnormally transiently increasing in the ATP level, and promotes the liver entering into the mitosis phase as well as forming an increasing number of binuclear hepatocytes.
2. PI3K-Akt-mTOR pathway participates in the progression of liver injury during acute cold exposure that regulates the ATP genesis and promotes the hepatocyte getting into the M phase and forming the binuclear hepatocyte.
寒冷地区的冬季,人们在户外活动时会暴露于低温环境中。从事低温环境作业的人员和参加特殊环境军事活动的官兵也经常暴露于低温环境中。低温环境对机体的影响和如何预防低温暴露相关疾病一直是人们研究的热点,具有重要意义。
低温环境对人体造成损伤的机制以其特殊的军事地位和作用,很少有相关内容的公开报道。目前,人们对于低温环境对机体损伤机制的研究多限于长期的慢性暴露模型,而急性的低温暴露模型尚未见到相关的报道。在北方高寒地区冬季,部队执行野外巡逻和站岗任务的士兵需要暴露在寒冷环境中,如果防护措施不当则很容易造成急性冻伤。目前,对于急性寒冷损伤的研究多集中在体表皮肤及肌肉组织的冻伤,而体内脏器在急性低温暴露时受到的影响及其发挥的作用尚未见到相关报道。人体暴露于低温环境后,需要动员产热以维持体温。虽然在此时肌肉的寒颤产热占主导作用,但肝脏作为体内最大的糖原储存器官和静息状态的主要产热器官,也可能参与到急性低温暴露下机体的应激过程中。在大鼠和人的正常生长过程中,肝脏可以形成一定数量的双核细胞,双核细胞的形成可能与肝脏损伤和增殖能力相关。在能量缺乏或其他损伤效应作用下,肝细胞有丝分裂失败而形成双核细胞。PI3K-Akt-mTOR通路是重要的生存信号通路,参与细胞的能量代谢,增殖分化,生长繁殖等重要过程。其在低温暴露过程中起到的作用已在慢性模型中进行相关研究,但在急性低温暴露模型中及在肝脏中的相关作用尚未阐明。
本研究试图通过建立急性低温暴露模型,探讨急性低温暴露是否可以引起肝脏病理生理学改变,并探讨PI3K-Akt-mTOR通路是否参与了急性低温暴露过程中的应答过程及其调控机制,为探索更多的低温暴露效应标志物及预防靶点提供理论依据。
研究目的
1.在大鼠急性低温暴露模型中,研究急性低温暴露引起大鼠肝脏的病理生理学改变,观察肝脏有丝分裂细胞及双核细胞在低温暴露过程中数量的变化及细胞能量水平的变化。同时观察PI3K-Akt-mTOR通路的变化情况及其与肝脏病理生理改变的关系。
2.通过使用通路抑制剂,观察PI3K-Akt-mTOR通路与肝细胞能量水平变化的关系及其是否参与了肝细胞有丝分裂增加及双核细胞形成的过程。
研究方法
1.利用低温实验舱,建立大鼠急性低温暴露模型:暴露温度为﹣15℃,暴露时间为0.5 h、1 h、2 h和4 h。
2.利用组化方法,通过HE染色观察急性低温暴露后大鼠肝脏的损伤情况及双核细胞的形成。
3.利用电镜,观察急性低温暴露对大鼠肝脏超微结构的影响。
4.利用western blot方法,观察PI3K-Akt-mTOR通路在急性低温暴露中的变化情况。
研究结果
1.从HE染色结果可以发现,随暴露时间延长,大鼠肝脏的损伤程度逐渐加深。在低温暴露0.5 h即发生轻度肝细胞水肿,在低温暴露4 h后,可发现细胞出现变性、水肿,肝细胞有丝分裂增加并且出现大量双核细胞和少数凋亡细胞。从电镜结果可以发现,低温暴露0.5 h可导致肝细胞糖原减少,线粒体轻度肿胀;低温暴露4 h可致肝细胞内糖原耗竭,线粒体明显肿胀,内质网被压缩,包绕于线粒体周围。
2.通过对肝细胞ATP含量的测定,发现在低温暴露0.5 h,肝细胞ATP含量明显增加,并随暴露时间延长而逐渐降低(p<0.05)。
3. western blot的检测结果发现,PI3K-Akt-mTOR通路相关蛋白出现先升高后降低的一过性激活, Akt蛋白的Ser-473位点、Thr-308位点;mTOR蛋白的Ser-2448位点、Ser-2481位点和p70 S6K蛋白的Thr-389位点在低温暴露0.5 h的磷酸化程度明显升高,随暴露时间延长而逐渐降低。在对线粒体蛋白的测定发现,Akt蛋白和mTOR蛋白在线粒体内的表达与其在胞质中的表达趋势一致。另外,与能量相关的AMPK蛋白的Thr-172位点随暴露时间延长而磷酸化程度逐渐增加。
4.为进一步证实急性低温暴露可以诱导大鼠肝脏有丝分裂增加及双核细胞形成增加,利用免疫组织化学方法对大鼠肝脏双核细胞进行计数,结果发现在低温暴露4 h后,大鼠肝脏有丝分裂期细胞数量明显增加,并且双核细胞数量明显增加(p<0.05)。
5.通过腹腔注射抑制剂渥曼青霉素(wortmannin),可以发现低温暴露4 h大鼠的肝脏细胞ATP水平与非抑制剂处理组相比明显降低,与室温对照组相比明显升高(p<0.05)。大鼠肝脏有丝分裂期细胞所占比例无明显改变,双核细胞的数量明显增加(p<0.05)。
研究结论
1.急性低温暴露4 h可以引起大鼠肝脏损伤,引起肝细胞ATP水平的异常增加,诱导静息期肝细胞进入有丝分裂期并伴随大量双核细胞形成。
2. PI3K-Akt-mTOR通路参与了急性低温暴露对大鼠肝脏的损伤作用,参与了低温暴露过程中ATP的生成调节并促进肝细胞有丝分裂及双核细胞的形成。
Background:
People usually expose to cold environment in out-door activities in the cold winter. And workers who engage in the low temperature environment work and soldiers who execute special environment military missions will commonly expose to harsh weather. The mechanism of healthy effects caused by cold exposure and the method of preventing cold exposure relative diseases is of great interest to scientist and is of great importance.
Being at the important military status, the mechanism of cold relative injuries is hardly to be seen in the open press. Up to now, the experimental models used by the study on mechanisms of cold exposure induced healthy effects are mostly the long lasting chronic ones, while the acute cold exposure models are rarely adopted. Soldiers who execute border patrolling or sentry duty will expose to the low tempareture environment in cold winter, and when they were insufficiently prevented, they will easily get acute cold injuries. The studies on acute cold injury are mainly focusing on the frostbite of skin and superficial structures, while the cold effects on the internal organs and the potential functions of the internal organs during cold exposure is rarely studied or reported. When exposed to the cold environment, adult mammals will sponsor the thermogenic activities to maintain body temperature. Although liver is less efficient on calorification than muscle, as one of the largest clycogen storage organ and the dominant thermogenic organ in the resting status, liver may participate in the response to acute cold stressing. Human and rat liver can form a number of binuclear hepatocytes during development. Under some pathological situations, the formation of binuclear hepatocyte may be relative with the liver injury and generative ability changing. The hepatocyte mitosis will be failure under energy stressing or other injurious status and then the binuclear hepatocyte formed. The PI3K-Akt-mTOR signaling is an important pathway that participates in the regulative progression of metabolism, differentiation, development and survival. The potential functions of the pathway in cold exposure have been studied in the chronic cold exposure model, while its role in the acute cold exposure circumstances is still to be illustrating.
As expected, using the acute cold exposure animal model, we attempt to explain whether liver could get any physiological or pathological changes during acute cold exposure, and to explain whether and what role the PI3K-Akt-mTOR pathway participates in the responsive reactivities. This will be of great importance to find more effective biomarkers and targets of prevention in acute cold exposure situations.
Aims:
1. To observe the physiological and pathological changes of liver during acute cold exposure: The changes of number of mitotic hepatocytes and binuclear hepatocytes and the changes of energy level in the hepatocytes during cold exposure as well as the activity changing of the PI3K-Akt-mTOR pathway and its relative potential functions.
2. By the utility of inhibitor, explores whether the PI3K-Akt-mTOR pathway participates in the regulation of liver ATP level during acute cold exposure. And whether this change can affect the process of promoting hepatocyte enter into the mitosis phase and the formation of binuclear hepatocyte.
Methods:
1. Adult male rats weighing 220-230 g are exposed to the cold environment at﹣15℃for 0.5, 1, 2 and 4 hours.
2. To observe the pathological changes of liver during acute cold exposure by HE staining and immuno-histochemistry detecting.
3. To observe the ultramicrostructure changes of the hepatocytes during acute cold exposure.
4. To observe the changes of activities of the PI3K-Akt-mTOR pathway by western blot method.
Results:
1. Acute cold exposure could injure the liver by a time dependent manner. After 4 hours exposure, the rat hepatocytes were vacuolate degeneration and there were an increasing number of mitosis hepatocytes and binuclear hepatocytes, as well as some apoptosis hepatocytes. 4 hours exposure also caused the microstructure injuries such as the swollen of mitochondria and the depletion of clycogen.
2. The ATP level elevated rapidly and peaked at the 0.5 hours during cold exposure and then declined as the exposure time prolonged.
3. The activity of the PI3K-Akt-mTOR pathway paralleled with the changes of ATP level. And the AMPK activated in a time dependent manner.
4. After injecting of inhibitor wortmannin intraperitoneally, the ATP level declined magnificently and the binuclear hepatocyte increased.
Conclution:
1. 4 hours acute cold exposure causes rat liver injury and an abnormally transiently increasing in the ATP level, and promotes the liver entering into the mitosis phase as well as forming an increasing number of binuclear hepatocytes.
2. PI3K-Akt-mTOR pathway participates in the progression of liver injury during acute cold exposure that regulates the ATP genesis and promotes the hepatocyte getting into the M phase and forming the binuclear hepatocyte.
引文
[1] Goglia F, Liverini G, De Leo T, Barletta A. Thyroid state and mitochondrial population during cold exposure. Pflugers Arch. 1983;396(1):49–53.
[2] Foster, D. O., M. L. Frydman. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood ?ow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmacol. 1979;57:257–270.
[3] Iossa, S., Barletta, A., Liverini, G. Effect of thyroidstate and cold exposure on rat liver mitochondrial protein mass and function. J Endocrinol. 1991;131:67–73.
[4] Hidenori Toyoda, Takashi Kumada, Olivier Bregerie, Christian Brechot, Chantal Desdouets. Conserved balance of hepatocyte nuclear DNA content in mononuclear and binuclear hepatocyte populations during the course of chronic viral hepatitis. World J Gastroenterol. 2006;12(28): 4546–4548.
[5] Fabio Grizzi, Maurizio Chiriva-Internati. Human binucleate hepatocytes: Are they a defence during chronic liver diseases? Medical Hypotheses. 2007;69:258–261.
[6] Grizzi F, Orbetegli O, Dioguardi N. Retinol-binding protein synthesis in binucleate hepatocytes during chronic viralliver disease. Gastroenterol Int. 1998;4:220–221.
[7] Hess KL, Wilson TE, Sauder CL, Gao Z, Ray CA, Monahan KD. Aging affects the cardiovascular responses to cold stress in humans. J Appl Physiol. 2009;107(4):1076–1082.
[8] Lieberman HR, Castellani JW, Young AJ. Cognitive function and moodduring acute cold stress after extended military training and recovery. Aviat Space Environ Med. 2009;80(7):629–636.
[9] Petersen AM, Gleeson TT. Skeletal muscle substrate utilization is altered by acute and acclimatory temperature in the American bullfrog (Lithobates catesbeiana). J Exp Biol. 2009;212(Pt 15):2378–2385.
[10] Duncko R, Johnson L, Merikangas K, Grillon C. Working memory performance after acute exposure to the cold pressor stress in healthy volunteers. Neurobiol Learn Mem. 2009;91(4):377–381.
[11] Himms-Hagen, J., Melnyk, A., Zingaretti, M. C., Ceresi, E., Barbatelli, G., Cinti, S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. American journal of physiology. Cell physiology. 2000;279:670–681.
[12] Koska J, Ksinantova L, Seb?kováE, Kvetnansky R, Klimes I, Chrousos G, Pacak K. Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans. Ann N Y Acad Sci. 2002;967:500–505.
[13] Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
[14] Mozo, J., Emre, Y., Bouillaud, F., Ricquier, D., Criscuolo, F. Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep. 2005;25:227–249.
[15] Krauss S, Zhang CY, Lowell BB. The mitochondrial uncoupling protein homologues. Nat Rev Mol Cell Biol. 2005;6(3):248–261.
[16] Vallerand AL, Perusse F, Bukowiecki LJ. Stimulatory effects of cold exposure and cold acclimation on glucose uptake in rat peripheral tissues. Am J Physiol Regul Integr Comp Physiol. 1990;259:1043–1049.
[17] Gasparetti AL, de Souza CT, Pereira-da-Silva M, Oliveira RL, Saad MJ,Carneiro EM, Velloso LA. Cold exposure induces tissue-specific modulation of the insulin-signalling pathway in Rattus norvegicus. J Physiol. 2003;552(1):149–162.
[18] Mollica MP, Lionetti L, Crescenzo R, Tasso R, Barletta A, Liverini G, Iossa S.. Cold exposure differently in?uences mitochondrial energy effciency in rat liver and skeletal muscle. FEBS Letters. 2005;579:1978–1982.
[19] Hong JH, Kim HJ, Kim KJ, Suzuki K, Lee IS. Comparison of metabolic substrates between exercise and cold exposure in skaters. J Physiol Anthropol. 2008;27(5):273–281.
[20] Louzao, M.C., Vieytes, M.R., Botana, L.M. Effect of okadaic acid on glucose regulation. Mini Rev Med Chem. 2005;5:207–215.
[21] Vallerand AL, Zamecnik J, Jacobs I. Plasma glucose turnover during cold stress in humans. J Appl Physiol. 1995;78:1296–1302.
[22] Haman F, Peronnet F, Kenny GP, Massicotte D, Lavoie C, Scott C, Weber JM. Effect of cold exposure on fuel utilization in humans: plasma glucose, muscle glycogen, and lipids. J Appl Physiol. 2002;93:77–84.
[23] Venditti P, De Rosa R, Portero-Otin M, Pamplona R, Di Meo S. Cold-induced hyperthyroidism produces oxidative damage in rat tissues and increases susceptibility to oxidants. The International Journal of Biochemistry & Cell Biology. 2004;36:1319–1331.
[24] Heise K, Puntarulo S, Portner HO, Abele D. Production of reactive oxygen species by isolated mitochondria of the Antarctic bivalve Laternula elliptica (King and Broderip) under heat stress. Comp Biochem Physiol. 2003;134:79–90.
[25] Selman C, McLaren JS, Himanka MJ, Speakman JR. Effect of long-term cold exposure on antioxidant enzyme activities in a small mammal. FreeRadic Biol Med. 2000;28:1279–1285.
[26] BRAUER RW, HOLLOWAY RJ, KREBS JS, LEONG GF, CARROLL HW. The liver in hypothermia. Ann N Y Acad Sci. 1959;80:395–423.
[27] Nagano K, Gelman S, Bradley EL Jr, Parks D. Hypothermia, hepatic oxygen supply-demand, and ischemia-reperfusion injury in pigs. Am J Physiol. 1990;258(G):910–918.
[28] E. ?ahin, S. Gümü?lü. Cold-stress-induced modulation of antioxidant defence: role of stressed conditions in tissue injury followed by protein oxidation and lipid peroxidation. Int J Biometeorol. 2004;48:165–171.
[29] Selman C, Grune T, Stolzing A, Jakstadt M, McLaren JS, Speakman JR. The consequences of acute cold exposure on protein oxidation and proteasome activity in short-tailed field voles, microtus agres. Free Radic Biol Med. 2002;33:259–265.
[30] Xiang-Yu Ren, Yan-Ning Li, Jin-Sheng Qi, Tao Niu. Peroxynitrite-induced protein nitration contributes to liver mitochondrial damage in diabetic rats. Journal of Diabetes and Its Complications. 2008;22:357–364.
[31] Iossa, S., Lionetti, L., Mollica, M.P., Crescenzo, R., Barletta, A. Liverini, G. Effect of cold exposure on energy balance and liver respiratory capacity in post-weaning rats fed a high-fat diet. Br J Nutr. 2000;84:1–9.
[32] J. Enrique Silva. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2002;86:435–464.
[33] Mak, I.T., Shrago, E. Elson, C.E. Modification of liver mitochondrial lipids and of adenine nucleotide translocase and oxidative phosphorylation by cold adaptation. Biochim Biophys Acta. 1983;722:302–309.
[34] Bravo, C., Vargas-Suarez, M., Rodriguez-Enriquez, S., Loza-Tavera, H. Moreno-Sanchez, R. Metabolic changes induced by cold stress in rat liver mitochondria. J Bioenerg Biomembr. 2001;33:289–301.
[35] P. Venditti, R. Pamplona, V. Ayala, R. De Rosa, G. Caldarone, S. Di Meo. Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage. The Journal of Experimental Biology. 2006;209:817–825.
[36] Adriano Meneghini, Celso Ferreira, Luiz Carlos de Abreu, Marcelo Ferreira, Celso Ferreira Filho, Vitor Engrácia Valenti, Neif Murad. Cold stress effects on cardiomyocytes nuclear size in rats: light microscopic evaluation. Rev Bras Cir Cardiovasc. 2008;23(4):530–533.
[37] Paisarn Vejchapipat, Sopee Poomsawat, Yong Poovorawan, Edward Proctor, Agostino Pierro. The effects of moderate hypothermia on energy metabolism and serum in?ammatory markers during laparotomy. Pediatr Surg Int. 2006;22:66–71.
[38] Iossa S, Barletta A, Liverini G. Different effects of cold exposure and cold acclimation on rat liver mitochondrial fatty acid oxidation and ketone bodies production. Int J Biochem. 1994;26(3):425–431.
[39] Iossa S, Barletta A, Liverini G. Hepatic selective adjustments in short-term cold exposed rats. Cell Biochem Funct. 1991;9(4):275–280.
[40] Eyolfson DA, Tikuisis P, Xu X, Weseen G, Giesbrecht GG. Measurement and prediction of peak shivering intensity in humans. Eur J Appl Physiol. 2001;84:100–106.
[41] Barja de Quiroga, G., Lopez-Torres, M., Perez-Campo, R., Abelanda, M., Paz Nava, M., Puerta, M. L. Effect of cold acclimation on GSH, antioxidant enzymes and lipid peroxidation in brown adipose tissue. Biochem J. 1991;277:289–292.
[42] Buzad?i?, B., Kora?, B., Petrovi?, V. M. The effect of adaptation to cold and re-adaptation to room temperature on the level of glutathione in rat tissues. J Thermal Biol. 1999;24:373–377.
[43] Kaushik, S., Kaur, J. Chronic cold exposure affects the antioxidant defense in various rat tissues. Clin Chim Acta. 2003;333:69–77.
[44] Danzl DF, Pozos RS. Accidental hypothermia. N Engl J Med. 1994;331:1756–1760.
[45] Drinkwater E. Effects of peripheral cooling on characteristics of local muscle. Med Sport Sci. 2008;53:74–88.
[46] Kalev Kuklane. Protection of feet in cold exposure. Industrial Health. 2009;47:242–253.
[47] Geng Q, Holmér I, Hartog DE, Havenith G, Jay O, Malchaire J, Piette A, Rintam?ki H, Rissanen S. Temperature limit values for touching cold surfaces with the fingertip. Ann Occup Hyg. 2006;50(8):851–862.
[48] Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186–202.
[49] Kunitoshi Uchida, Tetsuya Shiuchi, Hitoshi Inada, Yasuhiko Minokoshi, Makoto Tominaga. Metabolic adaptation of mice in a cool environment. Pflugers Arch. 2010;459(5):765–774.
[50] S. B. Rutkove. Effects of temperature on neuromuscular electrophysiology. Muscle Nerve. 2001;24(7):867–882.
[51] J. Jia, M. Pollock. The pathogenesis of non-freezing cold nerve injury. Observations in the rat. Brain. 1997;120(4):631–646.
[52] J. Jia, M. Pollock. Cold nerve injury is enhanced by intermittent cooling. Muscle and Nerve. 1999;22(12):1644–1652.
[53] S. Ochs, C. Smith. Low temperature slowing and cold block of fast axoplasmic transport in mammalian nerves in vitro. Journal of Neurobiology. 1975;6(1):85–102.
[54] D. S. Forman, A. L. Padjen, G. R. Siggins. Effect of temperature on the rapid retrograde transport of microscopically visible intra-axonal organelles.Brain Research. 1977;136(2):215–226.
[55] C. K. Huang, M. Munakata, J. M. Baraban, H. Menkes. Protein kinase C and tracheal contraction at low temperature. Journal of Pharmacology and Experimental Therapeutics. 1987;243(1)270–280.
[56] Barja de Quiroga, G. Brown fat thermogenesis and exercise: two examples of physiological oxidative stress? Free Radic Biol Med. 1992;13:325–340.
[57] David Hauton, Andrew M. Coney, Stuart Egginton. Both substrate availability and utilisation contribute to the defence of core temperature in response to acute cold. Comparative Biochemistry and Physiology. 2009;154(A) 514–522.
[58] Kolosova, N. G., Kolpakov, A. R., Panin, L. E. Tocopherol level and lipid peroxidation in Wistar rat tissues during adaptation to cold. Int J Circumpolar Health Borodina. 1997;56:49–53.
[59] Venditti P, De Rosa R, Caldarone G, Di Meo S. Arch Biochem Biophys. Effect of prolonged exercise on oxidative damage and susceptibility to oxidants of rat tissues in severe hyperthyroidism. 2005;442(2):229–37.
[60] P. Venditti, R. De Rosa, S. Di Meo, Effect of cold-induced hyperthyroidism on H2O2 production and susceptibility to stress conditions of rat liver mitochondria. Free Radic Biol Med. 2004;36:348–358.
[61] Kehrer, J. P. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol. 1993;23:21–48.
[62] P.Venditti, R. De Rosa, G. Caldarone, S. Di Meo. Functional and biochemical characteristics of mitochondrial fractions from rat liver in cold-induced oxidative stress. Cell Mol Life Sci. 2004;61:3104–3116.
[63] Spasi?, M. B., Sai?i?, Z. S., Buzad?I?, B., Kora?, B., Blagojevi?, D., Petrovi?, V. M. Effect of long-term exposure to cold on the antioxidant defense system in the rat. Free Radical Biology and Medicine. 1993;15:291–299.
[64] Frank, J. W., J. A. Carroll, G. L. Allee, and M. E. Zanelli. The effects of thermal environment and spray-dried plasma on the acute-phase response of pigs challenged with lipopolysaccharide. J Anim Sci. 2003;81:1166– 1176.
[65] Asayama, K., Kato, K. Oxidative muscular injury and its relevance to hyperthyroidism. Free Radic Biol Med. 1990;8:293–303.
[66] Venditti, P., De Rosa, R., Di Meo, S. Effect of thyroid state on H2O2 production by rat liver mitochondria. Mol Cell Endocrinol. 2003;205:185–192.
[67] Venditti, P., Balestrieri, M., Di Meo, S., De Leo, T. Effect of thyroid state on lipid peroxidation, antioxidant defences, and susceptibility to oxidative stress in rat tissues. J Endocrinol. 1997;155:151–157.
[68] Videla, L. A. Energy metabolism, thyroid calorigenesis, and oxidative stress: functional and cytotoxic consequences. Redox Rep. 2000;5:265–275.
[69] Nejad, I. F., Bollinger, J. A., Mitnich, M., Reichlin, S. Importance of T3 (triiodothyronine) secretion in altered states of thyroid function in the rat: cold exposure, subtotal thyroidectomy, and hypophysectomy. Trans Assoc Am Physicians. 1972;85:295–308.
[70] Jay Biem, Niels Koehncke, Dale Classen, James Dosman. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168(3):305–311.
[71] Ayhan Bozkurt , Salah Ghandour , Nesime Okboy , Susanne ?ner , Serap Arbak , Tamer Co?kun , Berrak ?. Ye?en. Inflammatory response to cold injury in remote organs is reduced by corticotropin-releasing factor. Regulatory Peptides. 2001;99:131–139.
[72] Goldenthal, M. J., Marin Garcia, J. Molecular and cellular biochemistry: an international journal for chemical biology in health and disease. Mol CellBiochem. 2004;262:1–16.
[73] Marin-Garcia, J., Goldenthal, M. J. Heart mitochondria signaling pathways: appraisal of an emerging field. J Mol Med. 2004;82:565–578.
[74] David J. Mancuso, Harold F. Sims, Xianlin Han, Christopher M. Jenkins, Shao Ping Guan, Kui Yang, Sung Ho Moon, Terri Pietka, Nada A. Abumrad, Paul H. Schlesinger, RichardW. Gross. Genetic Ablation of Calcium-independent Phospholipase A2γLeads to Alterations in Mitochondrial Lipid Metabolismand Function Resulting in a Deficient Mitochondrial Bioenergetic Phenotype. J Biol Chem. 2007; 282(48):34611–3422.
[75] Solov'eva AG, Zimin YV, Razmakhov AM. Kinetic parameters of liver aldehyde dehydrogenase in rats with cold injury. Bull Exp Biol Med. 2009;148(2):191–2.
[76] Venditti, P., Daniele, M. C., Masullo, P., Di Meo, S. Antioxidant-sensitive triiodothyronine effects on characteristics of rat liver mitochondrial population. Cellular Physiology and Biochemistry. 1999;9:38–52.
[77] Veriaskin VV, Filiushina EE, Shmerling MD. Structural reaction of skeletal muscle mitochondria to deep hypothermia in the experiment. Biull Eksp Biol Med. 1988;106(9):361–363.
[78] Salas M, Tuchweber B, Kourounakis P. Liver ultrastructure during acute stress. Pathol Res Pract. 1980;167(2-4):217–233.
[79] Rutter GA, Da Silva Xavier G, Leclerc I. Roles of 5′-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J. 2003;375:1–16.
[80] Warden SM, Richardson C, O’Donnell J Jr, Stapleton D, Kemp BE, Witters LA. Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellularlocalization. Biochem J. 2001;354:275–283.
[81] D.G. Hardie, D. Carling, M. Carlson, The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem. 1998;67:821–855.
[82] Hardie, D.G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev.Mol Cell Biol. 2007;8:774–785.
[83] Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003;546:113–120.
[84] Inoki, K., Ouyang, H., Li, Y., Guan, K. L. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005;69:79–100.
[85] Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–574.
[86] Erika A. Roman, Maristela Cesquini, Graziela R. Stoppa, JoséB. Carvalheira, Márcio A. Torsoni, Lício A. Velloso, Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals. J Physiol. 2005;568(3)993–1001.
[87] Paulsen SR, Rubink DS, and Winder WW. AMP-activated protein kinase activation prevents denervation-induced decline in gastrocnemius GLUT-4. J Appl Physiol. 2001;91:2102–2108.
[88] Gasparetti AL, De Souza CT, Pereira-Da-Silva M, Oliveira RL, Saad MJ, Carneiro EM, Velloso LA. Cold exposure induces tissue-specific modulation of the insulin-signalling pathway in Rattus norvegicus. J Physiol. 2003;552:149–162.
[89] Vallerand AL, Perusse F, Bukowiecki LJ. Cold exposure potentiates theeffect of insulin on in vivo glucose uptake. Am J Physiol Endocrinol Metab. 1987;253:179–186.
[90] Pereira-Da-Silva M, Torsoni MA, Nourani HV, Augusto VD, Souza CT, Gasparetti AL, Carvalheira JB, Ventrucci G, Marcondes MC, Cruz-Neto AP, Saad MJ, Boschero AC, Carneiro EM, Velloso LA. Hypothalamic melanin-concentrating hormone is induced by cold exposure and participates in the control of energy expenditure in rats. Endocrinology. 2003;144:4831–4840.
[91] Torsoni MA, Carvalheira JB, Pereira-Da-Silva M, De Carvalho-Filho MA, Saad MJ, Velloso LA. Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold. Am J Physiol Endocrinol Metab. 2003;285:216–223.
[92] Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
[93] Rachel L. G. S. Oliveira, Mirian Ueno, Cláudio T. de Souza, Márcio Pereira-da-Silva, Alessandra L. Gasparetti, Rosangela M. N. Bezzera, Luciane C. Alberici,Aníbal E. Vercesi, Mario J. A. Saad, Lício A. Velloso. Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab. 2004;287:686–695.
[94] Yuan T.L. and Cantley L.C.. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–5510.
[95] Scheid, M. P., Woodgett, J. R. PKB/AKT: functional insights from genetic models. Nature Rev Mol Cell Biol. 2001;2:760–768.
[96] Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J,Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science. 1998;279:710–714.
[97] Wullschleger, S., Loewith, R., Hall, M.N. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–484.
[98] Han J, Wang B, Xiao Z, Gao Y, Zhao Y, Zhang J, Chen B, Wang X, Dai J. Mammalian target of rapamycin (mTOR) is involved in the neuronal differentiation of neural progenitors induced by insulin. Mol Cell Neurosci. 2008;39(1):118–24.
[99] Dos D. Sarbassov, Siraj M. Ali, Shomit Sengupta, Joon-Ho Sheen, Peggy P. Hsu, Alex F. Bagley, Andrew L. Markhard, David M. Sabatini. Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB. Molecular Cell. 2006;22:159–168.
[100] Hay, N., Sonenberg, N.. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–1945.
[101] Long, X., Lin, Y.,Ortiz-Vega, S., Yonezawa, K., Avruch. J.. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005;15:702–713.
[102] Inoki, K., Zhu, T., and Guan, K. L.. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590.
[103] Stefan M. Schieke, Darci Phillips, J. Philip McCoy, Jr., Angel M. Aponte, Rong-Fong Shen, Robert S. Balaban, Toren Finkel. The Mammalian Target of Rapamycin (mTOR) Pathway Regulates Mitochondrial Oxygen Consumption and Oxidative Capacity. J Biol Chem. 2006;281(37);27643–27652.
[104] Dos D. Sarbassov, David M. Sabatini. Redox Regulation of the Nutrient-sensitive Raptor-mTOR Pathway and Complex. J Biol Chem. 2005;280(47):39505–39509.
[105] D.H. Kim, D.D. Sarbassov, S.M. Ali, J.E. King, R.R. Latek, H. Erdjument-Bromage, P. Tempst, D.M. Sabatini. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110:163–175.
[106] Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450(7170): 736–740.
[107] Brendan D. Manning, Lewis C. Cantley. AKT/PKB Signaling: Navigating Downstream. Cell. 2007;129(7):1261–1274.
[108] Kathrin Gottlob, Nathan Majewski, Scott Kennedy, Eugene Kandel, R. Brooks Robey, Nissim Hay. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Gene Dev. 2001;15:1406–1418.
[109] Suzanne Floyd, Cedric Favre, Francesco M. Lasorsa, Madeline Leahy, Giuseppe Trigiante, Philipp Stroebel, Alexander Marx, Gary Loughran, Katie O’Callaghan, Carlo M.T. Marobbio, Dirk J. Slotboom, Edmund R.S. Kunji, Ferdinando Palmieri, Rosemary O’Connor. The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth. Molecular Biology of the Cell. 2007;18:3545–3555.
[110] Robey, R.B., and Hay, N.. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006;25: 4683–4696.
[111] Lai H, Liu J, Ting C, Sharma P,Wang PH. Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway. Mol Cell Endocrinology.2003;205:99–106.
[112] Gautam N. Bijur, Richard S. Jope. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003;87(6):1427–1435.
[113] Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008;15:521–529.
[114] Jia-Ying Yang, Hung-Yin Yeh, Kevin Lin, Ping H. Wang. Insulin stimulates Akt translocation to mitochondria: Implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium. Journal of Molecular and Cellular Cardiology. 2009;46:919–926.
[115] Andrew P. Feranchak, Richard M. Roman, R. Brian Doctor, Kelli D. Salter, Alex Toker, J. Gregory Fitz. The Lipid Products of Phosphoinositide 3-Kinase Contribute to Regulation of Cholangiocyte ATP and Chloride Transport. J Biol Chem. 1999;274(43):30979–30986.
[116] P.B. Dennis, A. Jaeschke, M. Saitoh, B. Fowler, S.C. Kozma, G. Thomas. Mammalian TOR: a homeostatic ATP sensor. Science. 2001;294:1102– 1105.
[117] E.A. Dunlop, A.R. Tee. Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms. Cellular Signalling. 2009;21:827–835.
[118] Zabeena P. Shaik, E. Kim Fifer, and Gra?yna Nowak. Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury. Am J Physiol Renal Physiol. 2008;294:F423–F432.
[119] Norman Balcazar, Aruna Sathyamurthy, Lynda Elghazi, Aaron Gould, Aaron Weiss, Ichiro Shiojima, Kenneth Walsh, Ernesto Bernal-Mizrachi.mTORC1 Activition RrgulatesΒ-cell mass and proliferation by modulation of Cyclin D2 synthesis and stability. J Biol Chem. 2009;284(12):7832– 7842.
[120] Jing Ji , Peng-Sheng Zheng. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecologic Oncology. 2010;117:103–108.
[121] R.A. Bachmann, J.-H. Kim, A.-L.Wu, I.-H. Park, J. Chen. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem. 2006;281:7357–7363.
[122] Changxian Shen, Cynthia S. Lancaster, Bin Shi, Hong Guo, Padma Thimmaiah, Mary-Ann Bjornsti. TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol. 2007;27(20): 7007–7017.
[123] Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214–26.
[124] 216+Palmes D, Zibert A, Budny T, Bahde R, Minin E, Kebschull L, H?lzen J, Schmidt H, Spiegel HU. Impact of rapamycin on liver regeneration. Virchows Arch. 2008;452(5):545–557.
[125] Lisa Héron-Milhavet, Celine Franckhauser, Vanessa Rana, Cyril Berthenet, Daniel Fisher, Brian A. Hemmings, Anne Fernandez, Ned J. C. Lamb. Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding. Mol Cell Biol. 2006;(22):8267–8280.
[126] Christoph Oehler-J?nne, AndréO. von Bueren, Van Vuong, Andreas Hollenstein, Michael A. Grotzer, Martin Pruschy. Temperature sensitivity of phospho-Ser473-PKB/AKT. Biochemical and Biophysical Research Communications. 2008;375:399–404.
[127] Heng Zhao, Takayoshi Shimohata, Jade Q.Wang, Guohua Sun, DavidW. Schaal, RobertM. Sapolsky, Gary K. Steinberg. Akt Contributes to Neuroprotection by Hypothermia against Cerebral Ischemia in Rats. The Journal of Neuroscience. 2005;25(42):9794–9806.
[128] Xue-Han Ning, Emil Y. Chi, Norman E. Buroker, Shi-Han Chen, Cheng-Su Xu, Ying-Tzang Tien, Outi M. Hyyti, Ming Ge, Michael A. Portman. Moderate hypothermia (30°C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. Am J Physiol Heart Circ Physiol. 2007;293:H2119–H2128.
[129] Shirly Miniowitz-Shemtov, Adar Teichner, Danielle Sitry-Shevah, Avram Hershko. ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint. PNAS. 2010;107(12):5351–5356.
[130] Séverine Celton-Morizur, Grégory Merlen, Dominique Couton, Germain Margall-Ducos, Chantal Desdouets. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119:1880–1887.
[131] Tetsuji Nagata, Hongjun Ma. Electron microscopic radioautographic study on nucleic acid synthesis in amitotic hepatocytes of the aging mouse. Med Electron Microsc. 2003;36:263–271.
[132] P.O. Seglen. DNA ploidy and autophagic protein degradation as determinants of hepatocellular growth and survival. Cell Biology and Toxicology. 1997;13:301–315.
[133] Jacques-Emmanuel Guidotti, Olivier Brégerie, Aude Robert, Pascale Debey, Christian Brechot, Chantal Desdouets. Liver cell polyploidization: A pivotal role for binuclear hepatocytes. J Biol Chem. 2003;278(21):19095–19101.
[134] K. Kusuzaki, H. Takeshita, H. Murata, S. Hashiguchi, T. Nozaki, K. Emoto,T. Ashihara, Y. Hirasawa. Acridine orange induces binucleation in chondrocytes. Osteoarthritis and Cartilage. 2001;9:147–151.
[135] Aline S De Aguiar, Gilson T Boaventura, Rafael F Abrah?o, Thatiana L Freitas, Christina M Takiya, Porphirio J S Filho, Vilma A Da Silva. Ethanol in low chronic dose level attenuates major organic effects in malnourished rats. Biol Res. 2009;42:31–40.
[136] Nagata T. Electron microscopic radioautographic study on protein synthesis in mitochondria of binucleate hepatocytes of aging mice. Scientific World Journal. 2007;7:1008–1023.
[137] R. Lechowski,W. Bielecki, E. Sawosz, M. Krawiec, W. Klucinski. The effect of lecithin supplementation on the biochemical profile and morphological changes in the liver of rats fed different animal fats. Veterinary Research Communications. 1999;23:1–14.
[138] Gorla GR, Malhi H, Gupta S. Polyploidy associated with oxidative injury attenuates proliferative potential of cells. J Cell Sci. 2001;114:2943–2951.
[139] H Toyoda, O Bregerie, A Vallet, B Nalpas, G Pivert, C Brechot, C Desdouets. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut. 2005;54:297–302.
[140] Fatima Nú?EZ, Michael D. CHIPCHASE, Alan R. CLARKE, David W. MELTON. Nucleotide excision repair gene (ERCC1) deficiency causes G2 arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21. FASEB J. 2000;14:1073–1082.
[141] Gerlyng P, Abyholm A, Grotmol T, Erikstein B, Huitfeldt HS, Stokke T, Seglen PO. Binucleation and polyploidization patterns in developmental and regenerative rat liver growth. Cell Prolif. 1993;26:557–565.
[142] Graham J. Buttrick, Luke M. A. Beaumont, Jessica Leitch, Christopher Yau, Julian R. Hughes, James G. Wakefield. Akt regulates centrosome migrationand spindle orientation in the early Drosophila melanogaster embryo. J C B. 2008;180(3):537–548
[143] Wakefield, J. G., D. J. Stephens, J. M. Tavare. A role for glycogen synthase kinase-3 in mitotic spindle dynamics and chromosome alignment. J Cell Sci. 2003;116: 637–646.
[144] Diane F. Matesic, Kimberly N. Villio, Stacey L. Folse, Erin L. Garcia, Stephen J. Cutlerm Horace G. Cutler. Inhibition of cytokinesis and akt phosphorylation by chaetoglobosin K in ras-transformed epithelial cells. Cancer Chemother Pharmacol. 2006;57:741–754.
[145] Sebastian Wolfrum, Andreas Dendorfer, Yoshiyuki Rikitake, Timothy J. Stalker, Yulan Gong, Rosario Scalia, Peter Dominiak and James K. Liao. 3-Kinase/Protein Kinase Akt and Cardiovascular Protection Inhibition of Rho-Kinase Leads to Rapid Activation of Phosphatidylinositol. Arterioscler Thromb Vasc Biol. 2004;24:1842–1847.
[146] Jing Ji , Peng-Sheng Zheng. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecologic Oncology. 2010;117:103–108.
[147] Sanae Haga, Michitaka Ozaki, Hiroshi Inoue, Yasuo Okamoto, Wataru Ogawa, Kiyoshi Takeda, Shizuo Akira, Satoru Todo. The Survival Pathways Phosphatidylinositol-3 Kinase (PI3-K)/Phosphoinositide Dependent Protein Kinase 1 (PDK1) /Akt Modulate Liver Regeneration Through Hepatocyte Size Rather Than Proliferation. HEPATOLOGY. 2009;49:204–214.
[148] Therese H Hemstr€om, Margareta Sandstr€om, Boris Zhivotovsky. Inhibitors of the PI3-kinase/Akt pathway induce mitotic catastrophe in non-small cell lung cancer cells. Int J Cancer. 2006;119:1028–1038.
[149] Rieder CL, Maiato H. Stuck in division or passing through: what happenswhen cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7:637–651.
[150] Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004;23:2825–2837.
[151] Beatriz Alvarez, Carlos Martínez-A., Boudewijn M. T. Burgering, Ana C. Carrera. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. NATURE. 2001;413:744–747.
[2] Foster, D. O., M. L. Frydman. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood ?ow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmacol. 1979;57:257–270.
[3] Iossa, S., Barletta, A., Liverini, G. Effect of thyroidstate and cold exposure on rat liver mitochondrial protein mass and function. J Endocrinol. 1991;131:67–73.
[4] Hidenori Toyoda, Takashi Kumada, Olivier Bregerie, Christian Brechot, Chantal Desdouets. Conserved balance of hepatocyte nuclear DNA content in mononuclear and binuclear hepatocyte populations during the course of chronic viral hepatitis. World J Gastroenterol. 2006;12(28): 4546–4548.
[5] Fabio Grizzi, Maurizio Chiriva-Internati. Human binucleate hepatocytes: Are they a defence during chronic liver diseases? Medical Hypotheses. 2007;69:258–261.
[6] Grizzi F, Orbetegli O, Dioguardi N. Retinol-binding protein synthesis in binucleate hepatocytes during chronic viralliver disease. Gastroenterol Int. 1998;4:220–221.
[7] Hess KL, Wilson TE, Sauder CL, Gao Z, Ray CA, Monahan KD. Aging affects the cardiovascular responses to cold stress in humans. J Appl Physiol. 2009;107(4):1076–1082.
[8] Lieberman HR, Castellani JW, Young AJ. Cognitive function and moodduring acute cold stress after extended military training and recovery. Aviat Space Environ Med. 2009;80(7):629–636.
[9] Petersen AM, Gleeson TT. Skeletal muscle substrate utilization is altered by acute and acclimatory temperature in the American bullfrog (Lithobates catesbeiana). J Exp Biol. 2009;212(Pt 15):2378–2385.
[10] Duncko R, Johnson L, Merikangas K, Grillon C. Working memory performance after acute exposure to the cold pressor stress in healthy volunteers. Neurobiol Learn Mem. 2009;91(4):377–381.
[11] Himms-Hagen, J., Melnyk, A., Zingaretti, M. C., Ceresi, E., Barbatelli, G., Cinti, S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. American journal of physiology. Cell physiology. 2000;279:670–681.
[12] Koska J, Ksinantova L, Seb?kováE, Kvetnansky R, Klimes I, Chrousos G, Pacak K. Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans. Ann N Y Acad Sci. 2002;967:500–505.
[13] Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
[14] Mozo, J., Emre, Y., Bouillaud, F., Ricquier, D., Criscuolo, F. Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep. 2005;25:227–249.
[15] Krauss S, Zhang CY, Lowell BB. The mitochondrial uncoupling protein homologues. Nat Rev Mol Cell Biol. 2005;6(3):248–261.
[16] Vallerand AL, Perusse F, Bukowiecki LJ. Stimulatory effects of cold exposure and cold acclimation on glucose uptake in rat peripheral tissues. Am J Physiol Regul Integr Comp Physiol. 1990;259:1043–1049.
[17] Gasparetti AL, de Souza CT, Pereira-da-Silva M, Oliveira RL, Saad MJ,Carneiro EM, Velloso LA. Cold exposure induces tissue-specific modulation of the insulin-signalling pathway in Rattus norvegicus. J Physiol. 2003;552(1):149–162.
[18] Mollica MP, Lionetti L, Crescenzo R, Tasso R, Barletta A, Liverini G, Iossa S.. Cold exposure differently in?uences mitochondrial energy effciency in rat liver and skeletal muscle. FEBS Letters. 2005;579:1978–1982.
[19] Hong JH, Kim HJ, Kim KJ, Suzuki K, Lee IS. Comparison of metabolic substrates between exercise and cold exposure in skaters. J Physiol Anthropol. 2008;27(5):273–281.
[20] Louzao, M.C., Vieytes, M.R., Botana, L.M. Effect of okadaic acid on glucose regulation. Mini Rev Med Chem. 2005;5:207–215.
[21] Vallerand AL, Zamecnik J, Jacobs I. Plasma glucose turnover during cold stress in humans. J Appl Physiol. 1995;78:1296–1302.
[22] Haman F, Peronnet F, Kenny GP, Massicotte D, Lavoie C, Scott C, Weber JM. Effect of cold exposure on fuel utilization in humans: plasma glucose, muscle glycogen, and lipids. J Appl Physiol. 2002;93:77–84.
[23] Venditti P, De Rosa R, Portero-Otin M, Pamplona R, Di Meo S. Cold-induced hyperthyroidism produces oxidative damage in rat tissues and increases susceptibility to oxidants. The International Journal of Biochemistry & Cell Biology. 2004;36:1319–1331.
[24] Heise K, Puntarulo S, Portner HO, Abele D. Production of reactive oxygen species by isolated mitochondria of the Antarctic bivalve Laternula elliptica (King and Broderip) under heat stress. Comp Biochem Physiol. 2003;134:79–90.
[25] Selman C, McLaren JS, Himanka MJ, Speakman JR. Effect of long-term cold exposure on antioxidant enzyme activities in a small mammal. FreeRadic Biol Med. 2000;28:1279–1285.
[26] BRAUER RW, HOLLOWAY RJ, KREBS JS, LEONG GF, CARROLL HW. The liver in hypothermia. Ann N Y Acad Sci. 1959;80:395–423.
[27] Nagano K, Gelman S, Bradley EL Jr, Parks D. Hypothermia, hepatic oxygen supply-demand, and ischemia-reperfusion injury in pigs. Am J Physiol. 1990;258(G):910–918.
[28] E. ?ahin, S. Gümü?lü. Cold-stress-induced modulation of antioxidant defence: role of stressed conditions in tissue injury followed by protein oxidation and lipid peroxidation. Int J Biometeorol. 2004;48:165–171.
[29] Selman C, Grune T, Stolzing A, Jakstadt M, McLaren JS, Speakman JR. The consequences of acute cold exposure on protein oxidation and proteasome activity in short-tailed field voles, microtus agres. Free Radic Biol Med. 2002;33:259–265.
[30] Xiang-Yu Ren, Yan-Ning Li, Jin-Sheng Qi, Tao Niu. Peroxynitrite-induced protein nitration contributes to liver mitochondrial damage in diabetic rats. Journal of Diabetes and Its Complications. 2008;22:357–364.
[31] Iossa, S., Lionetti, L., Mollica, M.P., Crescenzo, R., Barletta, A. Liverini, G. Effect of cold exposure on energy balance and liver respiratory capacity in post-weaning rats fed a high-fat diet. Br J Nutr. 2000;84:1–9.
[32] J. Enrique Silva. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2002;86:435–464.
[33] Mak, I.T., Shrago, E. Elson, C.E. Modification of liver mitochondrial lipids and of adenine nucleotide translocase and oxidative phosphorylation by cold adaptation. Biochim Biophys Acta. 1983;722:302–309.
[34] Bravo, C., Vargas-Suarez, M., Rodriguez-Enriquez, S., Loza-Tavera, H. Moreno-Sanchez, R. Metabolic changes induced by cold stress in rat liver mitochondria. J Bioenerg Biomembr. 2001;33:289–301.
[35] P. Venditti, R. Pamplona, V. Ayala, R. De Rosa, G. Caldarone, S. Di Meo. Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage. The Journal of Experimental Biology. 2006;209:817–825.
[36] Adriano Meneghini, Celso Ferreira, Luiz Carlos de Abreu, Marcelo Ferreira, Celso Ferreira Filho, Vitor Engrácia Valenti, Neif Murad. Cold stress effects on cardiomyocytes nuclear size in rats: light microscopic evaluation. Rev Bras Cir Cardiovasc. 2008;23(4):530–533.
[37] Paisarn Vejchapipat, Sopee Poomsawat, Yong Poovorawan, Edward Proctor, Agostino Pierro. The effects of moderate hypothermia on energy metabolism and serum in?ammatory markers during laparotomy. Pediatr Surg Int. 2006;22:66–71.
[38] Iossa S, Barletta A, Liverini G. Different effects of cold exposure and cold acclimation on rat liver mitochondrial fatty acid oxidation and ketone bodies production. Int J Biochem. 1994;26(3):425–431.
[39] Iossa S, Barletta A, Liverini G. Hepatic selective adjustments in short-term cold exposed rats. Cell Biochem Funct. 1991;9(4):275–280.
[40] Eyolfson DA, Tikuisis P, Xu X, Weseen G, Giesbrecht GG. Measurement and prediction of peak shivering intensity in humans. Eur J Appl Physiol. 2001;84:100–106.
[41] Barja de Quiroga, G., Lopez-Torres, M., Perez-Campo, R., Abelanda, M., Paz Nava, M., Puerta, M. L. Effect of cold acclimation on GSH, antioxidant enzymes and lipid peroxidation in brown adipose tissue. Biochem J. 1991;277:289–292.
[42] Buzad?i?, B., Kora?, B., Petrovi?, V. M. The effect of adaptation to cold and re-adaptation to room temperature on the level of glutathione in rat tissues. J Thermal Biol. 1999;24:373–377.
[43] Kaushik, S., Kaur, J. Chronic cold exposure affects the antioxidant defense in various rat tissues. Clin Chim Acta. 2003;333:69–77.
[44] Danzl DF, Pozos RS. Accidental hypothermia. N Engl J Med. 1994;331:1756–1760.
[45] Drinkwater E. Effects of peripheral cooling on characteristics of local muscle. Med Sport Sci. 2008;53:74–88.
[46] Kalev Kuklane. Protection of feet in cold exposure. Industrial Health. 2009;47:242–253.
[47] Geng Q, Holmér I, Hartog DE, Havenith G, Jay O, Malchaire J, Piette A, Rintam?ki H, Rissanen S. Temperature limit values for touching cold surfaces with the fingertip. Ann Occup Hyg. 2006;50(8):851–862.
[48] Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186–202.
[49] Kunitoshi Uchida, Tetsuya Shiuchi, Hitoshi Inada, Yasuhiko Minokoshi, Makoto Tominaga. Metabolic adaptation of mice in a cool environment. Pflugers Arch. 2010;459(5):765–774.
[50] S. B. Rutkove. Effects of temperature on neuromuscular electrophysiology. Muscle Nerve. 2001;24(7):867–882.
[51] J. Jia, M. Pollock. The pathogenesis of non-freezing cold nerve injury. Observations in the rat. Brain. 1997;120(4):631–646.
[52] J. Jia, M. Pollock. Cold nerve injury is enhanced by intermittent cooling. Muscle and Nerve. 1999;22(12):1644–1652.
[53] S. Ochs, C. Smith. Low temperature slowing and cold block of fast axoplasmic transport in mammalian nerves in vitro. Journal of Neurobiology. 1975;6(1):85–102.
[54] D. S. Forman, A. L. Padjen, G. R. Siggins. Effect of temperature on the rapid retrograde transport of microscopically visible intra-axonal organelles.Brain Research. 1977;136(2):215–226.
[55] C. K. Huang, M. Munakata, J. M. Baraban, H. Menkes. Protein kinase C and tracheal contraction at low temperature. Journal of Pharmacology and Experimental Therapeutics. 1987;243(1)270–280.
[56] Barja de Quiroga, G. Brown fat thermogenesis and exercise: two examples of physiological oxidative stress? Free Radic Biol Med. 1992;13:325–340.
[57] David Hauton, Andrew M. Coney, Stuart Egginton. Both substrate availability and utilisation contribute to the defence of core temperature in response to acute cold. Comparative Biochemistry and Physiology. 2009;154(A) 514–522.
[58] Kolosova, N. G., Kolpakov, A. R., Panin, L. E. Tocopherol level and lipid peroxidation in Wistar rat tissues during adaptation to cold. Int J Circumpolar Health Borodina. 1997;56:49–53.
[59] Venditti P, De Rosa R, Caldarone G, Di Meo S. Arch Biochem Biophys. Effect of prolonged exercise on oxidative damage and susceptibility to oxidants of rat tissues in severe hyperthyroidism. 2005;442(2):229–37.
[60] P. Venditti, R. De Rosa, S. Di Meo, Effect of cold-induced hyperthyroidism on H2O2 production and susceptibility to stress conditions of rat liver mitochondria. Free Radic Biol Med. 2004;36:348–358.
[61] Kehrer, J. P. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol. 1993;23:21–48.
[62] P.Venditti, R. De Rosa, G. Caldarone, S. Di Meo. Functional and biochemical characteristics of mitochondrial fractions from rat liver in cold-induced oxidative stress. Cell Mol Life Sci. 2004;61:3104–3116.
[63] Spasi?, M. B., Sai?i?, Z. S., Buzad?I?, B., Kora?, B., Blagojevi?, D., Petrovi?, V. M. Effect of long-term exposure to cold on the antioxidant defense system in the rat. Free Radical Biology and Medicine. 1993;15:291–299.
[64] Frank, J. W., J. A. Carroll, G. L. Allee, and M. E. Zanelli. The effects of thermal environment and spray-dried plasma on the acute-phase response of pigs challenged with lipopolysaccharide. J Anim Sci. 2003;81:1166– 1176.
[65] Asayama, K., Kato, K. Oxidative muscular injury and its relevance to hyperthyroidism. Free Radic Biol Med. 1990;8:293–303.
[66] Venditti, P., De Rosa, R., Di Meo, S. Effect of thyroid state on H2O2 production by rat liver mitochondria. Mol Cell Endocrinol. 2003;205:185–192.
[67] Venditti, P., Balestrieri, M., Di Meo, S., De Leo, T. Effect of thyroid state on lipid peroxidation, antioxidant defences, and susceptibility to oxidative stress in rat tissues. J Endocrinol. 1997;155:151–157.
[68] Videla, L. A. Energy metabolism, thyroid calorigenesis, and oxidative stress: functional and cytotoxic consequences. Redox Rep. 2000;5:265–275.
[69] Nejad, I. F., Bollinger, J. A., Mitnich, M., Reichlin, S. Importance of T3 (triiodothyronine) secretion in altered states of thyroid function in the rat: cold exposure, subtotal thyroidectomy, and hypophysectomy. Trans Assoc Am Physicians. 1972;85:295–308.
[70] Jay Biem, Niels Koehncke, Dale Classen, James Dosman. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168(3):305–311.
[71] Ayhan Bozkurt , Salah Ghandour , Nesime Okboy , Susanne ?ner , Serap Arbak , Tamer Co?kun , Berrak ?. Ye?en. Inflammatory response to cold injury in remote organs is reduced by corticotropin-releasing factor. Regulatory Peptides. 2001;99:131–139.
[72] Goldenthal, M. J., Marin Garcia, J. Molecular and cellular biochemistry: an international journal for chemical biology in health and disease. Mol CellBiochem. 2004;262:1–16.
[73] Marin-Garcia, J., Goldenthal, M. J. Heart mitochondria signaling pathways: appraisal of an emerging field. J Mol Med. 2004;82:565–578.
[74] David J. Mancuso, Harold F. Sims, Xianlin Han, Christopher M. Jenkins, Shao Ping Guan, Kui Yang, Sung Ho Moon, Terri Pietka, Nada A. Abumrad, Paul H. Schlesinger, RichardW. Gross. Genetic Ablation of Calcium-independent Phospholipase A2γLeads to Alterations in Mitochondrial Lipid Metabolismand Function Resulting in a Deficient Mitochondrial Bioenergetic Phenotype. J Biol Chem. 2007; 282(48):34611–3422.
[75] Solov'eva AG, Zimin YV, Razmakhov AM. Kinetic parameters of liver aldehyde dehydrogenase in rats with cold injury. Bull Exp Biol Med. 2009;148(2):191–2.
[76] Venditti, P., Daniele, M. C., Masullo, P., Di Meo, S. Antioxidant-sensitive triiodothyronine effects on characteristics of rat liver mitochondrial population. Cellular Physiology and Biochemistry. 1999;9:38–52.
[77] Veriaskin VV, Filiushina EE, Shmerling MD. Structural reaction of skeletal muscle mitochondria to deep hypothermia in the experiment. Biull Eksp Biol Med. 1988;106(9):361–363.
[78] Salas M, Tuchweber B, Kourounakis P. Liver ultrastructure during acute stress. Pathol Res Pract. 1980;167(2-4):217–233.
[79] Rutter GA, Da Silva Xavier G, Leclerc I. Roles of 5′-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J. 2003;375:1–16.
[80] Warden SM, Richardson C, O’Donnell J Jr, Stapleton D, Kemp BE, Witters LA. Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellularlocalization. Biochem J. 2001;354:275–283.
[81] D.G. Hardie, D. Carling, M. Carlson, The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem. 1998;67:821–855.
[82] Hardie, D.G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev.Mol Cell Biol. 2007;8:774–785.
[83] Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003;546:113–120.
[84] Inoki, K., Ouyang, H., Li, Y., Guan, K. L. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005;69:79–100.
[85] Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–574.
[86] Erika A. Roman, Maristela Cesquini, Graziela R. Stoppa, JoséB. Carvalheira, Márcio A. Torsoni, Lício A. Velloso, Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals. J Physiol. 2005;568(3)993–1001.
[87] Paulsen SR, Rubink DS, and Winder WW. AMP-activated protein kinase activation prevents denervation-induced decline in gastrocnemius GLUT-4. J Appl Physiol. 2001;91:2102–2108.
[88] Gasparetti AL, De Souza CT, Pereira-Da-Silva M, Oliveira RL, Saad MJ, Carneiro EM, Velloso LA. Cold exposure induces tissue-specific modulation of the insulin-signalling pathway in Rattus norvegicus. J Physiol. 2003;552:149–162.
[89] Vallerand AL, Perusse F, Bukowiecki LJ. Cold exposure potentiates theeffect of insulin on in vivo glucose uptake. Am J Physiol Endocrinol Metab. 1987;253:179–186.
[90] Pereira-Da-Silva M, Torsoni MA, Nourani HV, Augusto VD, Souza CT, Gasparetti AL, Carvalheira JB, Ventrucci G, Marcondes MC, Cruz-Neto AP, Saad MJ, Boschero AC, Carneiro EM, Velloso LA. Hypothalamic melanin-concentrating hormone is induced by cold exposure and participates in the control of energy expenditure in rats. Endocrinology. 2003;144:4831–4840.
[91] Torsoni MA, Carvalheira JB, Pereira-Da-Silva M, De Carvalho-Filho MA, Saad MJ, Velloso LA. Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold. Am J Physiol Endocrinol Metab. 2003;285:216–223.
[92] Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
[93] Rachel L. G. S. Oliveira, Mirian Ueno, Cláudio T. de Souza, Márcio Pereira-da-Silva, Alessandra L. Gasparetti, Rosangela M. N. Bezzera, Luciane C. Alberici,Aníbal E. Vercesi, Mario J. A. Saad, Lício A. Velloso. Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab. 2004;287:686–695.
[94] Yuan T.L. and Cantley L.C.. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–5510.
[95] Scheid, M. P., Woodgett, J. R. PKB/AKT: functional insights from genetic models. Nature Rev Mol Cell Biol. 2001;2:760–768.
[96] Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J,Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science. 1998;279:710–714.
[97] Wullschleger, S., Loewith, R., Hall, M.N. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–484.
[98] Han J, Wang B, Xiao Z, Gao Y, Zhao Y, Zhang J, Chen B, Wang X, Dai J. Mammalian target of rapamycin (mTOR) is involved in the neuronal differentiation of neural progenitors induced by insulin. Mol Cell Neurosci. 2008;39(1):118–24.
[99] Dos D. Sarbassov, Siraj M. Ali, Shomit Sengupta, Joon-Ho Sheen, Peggy P. Hsu, Alex F. Bagley, Andrew L. Markhard, David M. Sabatini. Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB. Molecular Cell. 2006;22:159–168.
[100] Hay, N., Sonenberg, N.. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–1945.
[101] Long, X., Lin, Y.,Ortiz-Vega, S., Yonezawa, K., Avruch. J.. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005;15:702–713.
[102] Inoki, K., Zhu, T., and Guan, K. L.. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590.
[103] Stefan M. Schieke, Darci Phillips, J. Philip McCoy, Jr., Angel M. Aponte, Rong-Fong Shen, Robert S. Balaban, Toren Finkel. The Mammalian Target of Rapamycin (mTOR) Pathway Regulates Mitochondrial Oxygen Consumption and Oxidative Capacity. J Biol Chem. 2006;281(37);27643–27652.
[104] Dos D. Sarbassov, David M. Sabatini. Redox Regulation of the Nutrient-sensitive Raptor-mTOR Pathway and Complex. J Biol Chem. 2005;280(47):39505–39509.
[105] D.H. Kim, D.D. Sarbassov, S.M. Ali, J.E. King, R.R. Latek, H. Erdjument-Bromage, P. Tempst, D.M. Sabatini. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110:163–175.
[106] Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450(7170): 736–740.
[107] Brendan D. Manning, Lewis C. Cantley. AKT/PKB Signaling: Navigating Downstream. Cell. 2007;129(7):1261–1274.
[108] Kathrin Gottlob, Nathan Majewski, Scott Kennedy, Eugene Kandel, R. Brooks Robey, Nissim Hay. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Gene Dev. 2001;15:1406–1418.
[109] Suzanne Floyd, Cedric Favre, Francesco M. Lasorsa, Madeline Leahy, Giuseppe Trigiante, Philipp Stroebel, Alexander Marx, Gary Loughran, Katie O’Callaghan, Carlo M.T. Marobbio, Dirk J. Slotboom, Edmund R.S. Kunji, Ferdinando Palmieri, Rosemary O’Connor. The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth. Molecular Biology of the Cell. 2007;18:3545–3555.
[110] Robey, R.B., and Hay, N.. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006;25: 4683–4696.
[111] Lai H, Liu J, Ting C, Sharma P,Wang PH. Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway. Mol Cell Endocrinology.2003;205:99–106.
[112] Gautam N. Bijur, Richard S. Jope. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003;87(6):1427–1435.
[113] Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008;15:521–529.
[114] Jia-Ying Yang, Hung-Yin Yeh, Kevin Lin, Ping H. Wang. Insulin stimulates Akt translocation to mitochondria: Implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium. Journal of Molecular and Cellular Cardiology. 2009;46:919–926.
[115] Andrew P. Feranchak, Richard M. Roman, R. Brian Doctor, Kelli D. Salter, Alex Toker, J. Gregory Fitz. The Lipid Products of Phosphoinositide 3-Kinase Contribute to Regulation of Cholangiocyte ATP and Chloride Transport. J Biol Chem. 1999;274(43):30979–30986.
[116] P.B. Dennis, A. Jaeschke, M. Saitoh, B. Fowler, S.C. Kozma, G. Thomas. Mammalian TOR: a homeostatic ATP sensor. Science. 2001;294:1102– 1105.
[117] E.A. Dunlop, A.R. Tee. Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms. Cellular Signalling. 2009;21:827–835.
[118] Zabeena P. Shaik, E. Kim Fifer, and Gra?yna Nowak. Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury. Am J Physiol Renal Physiol. 2008;294:F423–F432.
[119] Norman Balcazar, Aruna Sathyamurthy, Lynda Elghazi, Aaron Gould, Aaron Weiss, Ichiro Shiojima, Kenneth Walsh, Ernesto Bernal-Mizrachi.mTORC1 Activition RrgulatesΒ-cell mass and proliferation by modulation of Cyclin D2 synthesis and stability. J Biol Chem. 2009;284(12):7832– 7842.
[120] Jing Ji , Peng-Sheng Zheng. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecologic Oncology. 2010;117:103–108.
[121] R.A. Bachmann, J.-H. Kim, A.-L.Wu, I.-H. Park, J. Chen. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem. 2006;281:7357–7363.
[122] Changxian Shen, Cynthia S. Lancaster, Bin Shi, Hong Guo, Padma Thimmaiah, Mary-Ann Bjornsti. TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol. 2007;27(20): 7007–7017.
[123] Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214–26.
[124] 216+Palmes D, Zibert A, Budny T, Bahde R, Minin E, Kebschull L, H?lzen J, Schmidt H, Spiegel HU. Impact of rapamycin on liver regeneration. Virchows Arch. 2008;452(5):545–557.
[125] Lisa Héron-Milhavet, Celine Franckhauser, Vanessa Rana, Cyril Berthenet, Daniel Fisher, Brian A. Hemmings, Anne Fernandez, Ned J. C. Lamb. Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding. Mol Cell Biol. 2006;(22):8267–8280.
[126] Christoph Oehler-J?nne, AndréO. von Bueren, Van Vuong, Andreas Hollenstein, Michael A. Grotzer, Martin Pruschy. Temperature sensitivity of phospho-Ser473-PKB/AKT. Biochemical and Biophysical Research Communications. 2008;375:399–404.
[127] Heng Zhao, Takayoshi Shimohata, Jade Q.Wang, Guohua Sun, DavidW. Schaal, RobertM. Sapolsky, Gary K. Steinberg. Akt Contributes to Neuroprotection by Hypothermia against Cerebral Ischemia in Rats. The Journal of Neuroscience. 2005;25(42):9794–9806.
[128] Xue-Han Ning, Emil Y. Chi, Norman E. Buroker, Shi-Han Chen, Cheng-Su Xu, Ying-Tzang Tien, Outi M. Hyyti, Ming Ge, Michael A. Portman. Moderate hypothermia (30°C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. Am J Physiol Heart Circ Physiol. 2007;293:H2119–H2128.
[129] Shirly Miniowitz-Shemtov, Adar Teichner, Danielle Sitry-Shevah, Avram Hershko. ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint. PNAS. 2010;107(12):5351–5356.
[130] Séverine Celton-Morizur, Grégory Merlen, Dominique Couton, Germain Margall-Ducos, Chantal Desdouets. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119:1880–1887.
[131] Tetsuji Nagata, Hongjun Ma. Electron microscopic radioautographic study on nucleic acid synthesis in amitotic hepatocytes of the aging mouse. Med Electron Microsc. 2003;36:263–271.
[132] P.O. Seglen. DNA ploidy and autophagic protein degradation as determinants of hepatocellular growth and survival. Cell Biology and Toxicology. 1997;13:301–315.
[133] Jacques-Emmanuel Guidotti, Olivier Brégerie, Aude Robert, Pascale Debey, Christian Brechot, Chantal Desdouets. Liver cell polyploidization: A pivotal role for binuclear hepatocytes. J Biol Chem. 2003;278(21):19095–19101.
[134] K. Kusuzaki, H. Takeshita, H. Murata, S. Hashiguchi, T. Nozaki, K. Emoto,T. Ashihara, Y. Hirasawa. Acridine orange induces binucleation in chondrocytes. Osteoarthritis and Cartilage. 2001;9:147–151.
[135] Aline S De Aguiar, Gilson T Boaventura, Rafael F Abrah?o, Thatiana L Freitas, Christina M Takiya, Porphirio J S Filho, Vilma A Da Silva. Ethanol in low chronic dose level attenuates major organic effects in malnourished rats. Biol Res. 2009;42:31–40.
[136] Nagata T. Electron microscopic radioautographic study on protein synthesis in mitochondria of binucleate hepatocytes of aging mice. Scientific World Journal. 2007;7:1008–1023.
[137] R. Lechowski,W. Bielecki, E. Sawosz, M. Krawiec, W. Klucinski. The effect of lecithin supplementation on the biochemical profile and morphological changes in the liver of rats fed different animal fats. Veterinary Research Communications. 1999;23:1–14.
[138] Gorla GR, Malhi H, Gupta S. Polyploidy associated with oxidative injury attenuates proliferative potential of cells. J Cell Sci. 2001;114:2943–2951.
[139] H Toyoda, O Bregerie, A Vallet, B Nalpas, G Pivert, C Brechot, C Desdouets. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut. 2005;54:297–302.
[140] Fatima Nú?EZ, Michael D. CHIPCHASE, Alan R. CLARKE, David W. MELTON. Nucleotide excision repair gene (ERCC1) deficiency causes G2 arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21. FASEB J. 2000;14:1073–1082.
[141] Gerlyng P, Abyholm A, Grotmol T, Erikstein B, Huitfeldt HS, Stokke T, Seglen PO. Binucleation and polyploidization patterns in developmental and regenerative rat liver growth. Cell Prolif. 1993;26:557–565.
[142] Graham J. Buttrick, Luke M. A. Beaumont, Jessica Leitch, Christopher Yau, Julian R. Hughes, James G. Wakefield. Akt regulates centrosome migrationand spindle orientation in the early Drosophila melanogaster embryo. J C B. 2008;180(3):537–548
[143] Wakefield, J. G., D. J. Stephens, J. M. Tavare. A role for glycogen synthase kinase-3 in mitotic spindle dynamics and chromosome alignment. J Cell Sci. 2003;116: 637–646.
[144] Diane F. Matesic, Kimberly N. Villio, Stacey L. Folse, Erin L. Garcia, Stephen J. Cutlerm Horace G. Cutler. Inhibition of cytokinesis and akt phosphorylation by chaetoglobosin K in ras-transformed epithelial cells. Cancer Chemother Pharmacol. 2006;57:741–754.
[145] Sebastian Wolfrum, Andreas Dendorfer, Yoshiyuki Rikitake, Timothy J. Stalker, Yulan Gong, Rosario Scalia, Peter Dominiak and James K. Liao. 3-Kinase/Protein Kinase Akt and Cardiovascular Protection Inhibition of Rho-Kinase Leads to Rapid Activation of Phosphatidylinositol. Arterioscler Thromb Vasc Biol. 2004;24:1842–1847.
[146] Jing Ji , Peng-Sheng Zheng. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecologic Oncology. 2010;117:103–108.
[147] Sanae Haga, Michitaka Ozaki, Hiroshi Inoue, Yasuo Okamoto, Wataru Ogawa, Kiyoshi Takeda, Shizuo Akira, Satoru Todo. The Survival Pathways Phosphatidylinositol-3 Kinase (PI3-K)/Phosphoinositide Dependent Protein Kinase 1 (PDK1) /Akt Modulate Liver Regeneration Through Hepatocyte Size Rather Than Proliferation. HEPATOLOGY. 2009;49:204–214.
[148] Therese H Hemstr€om, Margareta Sandstr€om, Boris Zhivotovsky. Inhibitors of the PI3-kinase/Akt pathway induce mitotic catastrophe in non-small cell lung cancer cells. Int J Cancer. 2006;119:1028–1038.
[149] Rieder CL, Maiato H. Stuck in division or passing through: what happenswhen cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7:637–651.
[150] Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004;23:2825–2837.
[151] Beatriz Alvarez, Carlos Martínez-A., Boudewijn M. T. Burgering, Ana C. Carrera. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. NATURE. 2001;413:744–747.