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Redox and metabolic processes are tightly coupled in both physiological and pathological conditions. In cancer, their integration occurs at multiple levels and is characterized by synchronized reprogramming both in the tumor tissue and its specific but heterogeneous microenvironment. In breast cancer, the principal microenvironment is the cancer‐associated adipose tissue (CAAT). Understanding how the redox‐metabolic reprogramming becomes coordinated in human breast cancer is imperative both for cancer prevention and for the establishment of new therapeutic approaches. This review aims to provide an overview of the current knowledge of the redox profiles and regulation of intermediary metabolism in breast cancer while considering the tumor and CAAT of breast cancer as a unique Warburg's pseudo‐organ. As cancer is now recognized as a systemic metabolic disease, we have paid particular attention to the cell‐specific redox‐metabolic reprogramming and the roles of estrogen receptors and circadian rhythms, as well as their crosstalk in the development, growth, progression, and prognosis of breast cancer. [ABSTRACT FROM AUTHOR]

The beneficial effects of l-arginine supplementation in obesity and type II diabetes involve white adipose tissue (WAT) reduction and increased substrate oxidation. We aimed to test the potential of l-arginine to induce WAT browning. Therefore, the molecular basis of browning was investigated in retroperitoneal WAT (rpWAT) of rats exposed to cold or treated with 2.25% l-arginine for 1, 3, and 7 days. Compared to untreated control, levels of inducible nitric oxide (NO) synthase protein expression and NO signaling increased in both cold-exposed and l-arginine-treated groups. These increases coincided with the appearance of multilocular adipocytes and increased expression levels of uncoupling protein 1 (UCP1), thermogenic and beige adipocyte-specific genes (Cidea, Cd137, and Tmem26), mitochondriogenesis markers (peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α, mitochondrial DNA copy number), nuclear respiratory factor 1, PPARα and their respective downstream lipid oxidation enzymes after l-arginine treatment. Such browning phenotype in the l-arginine-treated group was concordant with end-course decreases in leptinaemia, rpWAT mass, and body weight. In conclusion, l-arginine mimics cold-mediated increases in NO signaling in rpWAT and induces molecular and structural fingerprints of rpWAT browning. The results endorse l-arginine as a pharmaceutical alternative to cold exposure, which could be of great interest in obesity and associated metabolic diseases. [ABSTRACT FROM AUTHOR]

Deciphering lipid metabolism in white adipose tissue (WAT) depots during weight gain is important to understand the heterogeneity of WAT and its roles in obesity. Here, we examined the expression of key enzymes of lipid metabolism and changes in the morphology of representative visceral (epididymal) and subcutaneous (inguinal) WAT (eWAT and iWAT, respectively)-in adult male rats acclimated to cold (4 ± 1 °C) for 45 days and reacclimated to room temperature (RT, 22 ± 1 °C) for 1, 3, 7, 12, 21, or 45 days. The relative mass of both depots decreased to a similar extent after cold acclimation. However, fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), and medium-chain acyl-CoA dehydrogenase (ACADM) protein level increased only in eWAT, whereas adipose triglyceride lipase (ATGL) expression increased only in iWAT. During reacclimation, the relative mass of eWAT reached control values on day 12 and that of iWAT on day 45 of reacclimation. The faster recovery of eWAT mass is associated with higher expression of FAS, acetyl-CoA carboxylase (ACC), G6PDH, and ACADM during reacclimation and a delayed increase in ATGL. The absence of an increase in proliferating cell nuclear antigen suggests that the observed depot-specific mass increase is predominantly due to metabolic adjustments. In summary, this study shows a differential rate of visceral and subcutaneous adipose tissue weight regain during post-cold reacclimation of rats at RT. Faster recovery of the visceral WAT as compared to subcutaneous WAT during reacclimation at RT could be attributed to observed differences in the expression patterns of lipid metabolic enzymes. [ABSTRACT FROM AUTHOR]

Changes in the structural properties of the skin due to collagen alterations are an important factor in diabetic skin complications. Using a combination of photonic methods as an optic diagnostic tool, we investigated the structural alteration in rat dermal collagen I in diabetes, and after short-term l-arginine treatment. The multiplex approach shows that in the early phase of diabetes, collagen fibers are partially damaged, resulting in the heterogeneity of fibers, e.g., "patchy patterns" of highly ordered/disordered fibers, while l-arginine treatment counteracts to some extent the conformational changes in collagen-induced by diabetes and mitigates the damage. Raman spectroscopy shows intense collagen conformational changes via amides I and II in diabetes, suggesting that diabetes-induced structural changes in collagen originate predominantly from individual collagen molecules rather than supramolecular structures. There is a clear increase in the amounts of newly synthesized proline and hydroxyproline after treatment with l-arginine, reflecting the changed collagen content. This suggests that it might be useful for treating and stopping collagen damage early on in diabetic skin. Our results demonstrate that l-arginine attenuates the early collagen I alteration caused by diabetes and that it could be used to treat and prevent collagen damage in diabetic skin at a very early stage. [ABSTRACT FROM AUTHOR]

Significance: The ultimate manifestations of life, birth, survival under various environmental pressures and death are based on bioenergetics. Hibernation is a unique survival strategy for many small mammals that is characterised by severe metabolic depression and transition from euthermia to hypothermia (torpor) at body temperatures close to 0°C. These manifestations of life were made possible by the remarkable "social" behavior of biomolecules during billions of years of evolution: the evolution of life with oxygen. Oxygen was necessary for energy production and the evolutionary explosion of aerobic organisms. Recent Advances: Nevertheless, reactive oxygen species, formed through oxidative metabolism, are dangerous—they can kill a cell and, on the other hand, play a plethora of fundamentally valuable roles. Therefore, the evolution of life depended on energy metabolism and redox-metabolic adaptations. The more extreme the conditions for survival are, the more sophisticated the adaptive responses of organisms become. Hibernation is a beautiful illustration of this principle. Hibernating animals use evolutionarily conserved molecular mechanisms to survive adverse environmental conditions, including reducing body temperature to ambient levels (often to ∼0°C) and severe metabolic depression. This long-built secret of life lies at the intersection of oxygen, metabolism, and bioenergetics, and hibernating organisms have learned to exploit all the underlying capacities of molecular pathways to survive. Critical Issues: Despite such drastic changes in phenotype, tissues and organs of hibernators sustain no metabolic or histological damage during hibernation or upon awakening from hibernation. This was made possible by the fascinating integration of redox-metabolic regulatory networks whose molecular mechanisms remain undisclosed to this day. Future Directions: Discovering these molecular mechanisms is not warranted only to understand hibernation in itself but to help explain complex medical conditions (hypoxia/reoxygenation, organ transplantation, diabetes, and cancer) and to even help overcome limitations associated with space travel. This is a review of integrated redox-metabolic orchestration in hibernation. Antioxid. Redox Signal. 40, 345–368. [ABSTRACT FROM AUTHOR]

The close cooperation between breast cancer and cancer-associated adipose tissue (CAAT) shapes the malignant phenotype, but the role of mitochondrial metabolic reprogramming and obesity in breast cancer remains undecided, especially in premenopausal women. Here, we examined mitochondrial metabolic dynamics in paired biopsies of malignant versus benign breast tumor tissue and CAAT in normal-weight and overweight/obese premenopausal women. Lower protein level of pyruvate dehydrogenase and citrate synthase in malignant tumor tissue indicated decreased carbon flux from glucose into the Krebs cycle, whereas the trend was just the opposite in malignant CAAT. Simultaneously, stimulated lipolysis in CAAT of obese women was followed by upregulated β-oxidation, as well as fatty acid synthesis enzymes in both tumor tissue and CAAT of women with malignant tumors, corroborating their physical association. Further, protein level of electron transport chain complexes was generally increased in tumor tissue and CAAT from women with malignant tumors, respective to obesity. Preserved mitochondrial structure in malignant tumor tissue was also observed. However, mitochondrial DNA copy number and protein levels of PGC-1α were dependent on both malignancy and obesity in tumor tissue and CAAT. In conclusion, metabolic cooperation between breast cancer and CAAT in premenopausal women involves obesity-related, synchronized changes in mitochondrial metabolism. [ABSTRACT FROM AUTHOR]

Adaptive responses to environmental and physiological challenges, including exposure to low environmental temperature, require extensive structural, redox, and metabolic reprogramming. Detailed molecular mechanisms of such processes in the skin are lacking, especially the role of nuclear factor erythroid 2‐related factor 2 (Nrf2) and other closely related redox‐sensitive transcription factors Nrf1, Nrf3, and nuclear respiratory factor (NRF1). To investigate the role of Nrf2, we examined redox and metabolic responses in the skin of wild‐type (WT) mice and mice lacking functional Nrf2 (Nrf2 KO) at room (RT, 24 ± 1°C) and cold (4 ± 1°C) temperature. Our results demonstrate distinct expression profiles of major enzymes involved in antioxidant defense and key metabolic and mitochondrial pathways in the skin, depending on the functional Nrf2 and/or cold stimulus. Nrf2 KO mice at RT displayed profound alterations in redox, mitochondrial and metabolic responses, generally akin to cold‐induced skin responses in WT mice. Immunohistochemical analyses of skin cell compartments (keratinocytes, fibroblasts, hair follicle, and sebaceous gland) and spatial locations (nucleus and cytoplasm) revealed synergistic interactions between members of the Nrf transcription factor family as part of redox‐metabolic reprogramming in WT mice upon cold acclimation. In contrast, Nrf2 KO mice at RT showed loss of NRF1 expression and a compensatory activation of Nrf1/Nrf3, which was abolished upon cold, concomitant with blunted redox‐metabolic responses. These data show for the first time a novel role for Nrf2 in skin physiology in response to low environmental temperature, with important implications in human connective tissue diseases with altered thermogenic responses. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic syndrome arises from abnormal adipose function accompanied by insulin resistance. As early factors reflecting/impacting lipid storage dysfunction of adipose tissues, we sought to determine adipokine levels in subcutaneous and visceral adipose tissues (SAT and VAT).Material and Methods: Gene and protein expression levels of leptin, adiponectin, and resistin were analysed in SAT and VAT of normal-weight and overweight/obese women, subclassified according to insulin resistance index, triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels into metabolically healthy and "at risk" groups.Results: Compared with normal-weight women, obese women had higher serum leptin levels (p < 0.05), as well as increased leptin gene and protein expression in VAT. Conversely, expression levels of leptin were lower in SAT of obese women, and minor in the SAT of "at risk" groups of women, compared with weight-matched healthy groups. In addition, lower adiponectin levels were detected in SAT of metabolically healthy obese women (p < 0.01), and lower in SAT and VAT (p < 0.05) of "at risk" obese women compared to healthy, obese women. Significant differences in resistin levels were only observed in obese women; resistin gene expression was higher in VAT and SAT of obese, compared to normal-weight women. However, higher gene expression was not consistent with protein expression of resistin.Conclusions: Low adiponectin in both examined adipose tissues and inappropriate leptin expression levels in SAT appear to be important characteristics of obesity-related metabolic syndrome. Intriguingly, this adipokine dysregulation is primary seen in SAT, suggesting that endocrine dysfunction in this abdominal depot may be an early risk sign of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Infertility is a significant global health problem that currently affects one of six couples in reproductive age. The quality of male reproductive cells dramatically decreased over the last years and almost every aspect of modern life additionally worsen sperm functional parameters that consequently markedly increase male infertility. This clearly points out the importance of finding a new approach to treat male infertility. Redox signaling mediated by reactive oxygen, nitrogen and sulfur species (ROS, RNS, and RSS respectively), has appeared important for sperm reproductive function. Present review summarizes the current knowledge of ROS, RNS, and RSS in male reproductive biology and identifies potential targets for development of novel pharmacological and therapeutic approaches for male infertility by targeted therapeutic modulation of redox signaling. [ABSTRACT FROM AUTHOR]

Protein expression/activity of antioxidative defense enzymes (AD) in seminal plasma of fertile men might be used as biomarkers of male fertility status. To test this concept, the present study examined the semen parameters of males among 14 normal idiopathic (normozoospermia) and 84 subnormal (teratozoospermia, oligoteratozoospermia, oligoasthenoteratozoospermia) infertile individuals\. We investigated levels of protein expression/activity of Cu, Zn superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), catalase and glutathione peroxidase (GSH-Px), their association with functional sperm parameters, as well as their potential to serve as biomarkers of specific sperm pathologies. Although the activity of CuZnSOD and protein expression of catalase were significantly correlated with several sperm parameters, underlying their potential role in etiology of various sperm abnormalities, investigation of their potential usefulness as a biomarker of semen quality showed that these AD enzymes could not distinguish subtle differences between various sperm pathologies. In contrast, GSH-Px activity was decreased in all groups with sperm pathologies and was a very good indicator of aberrations in functional sperm parameters, explaining up to 94.6% of infertility cases where functional sperm parameters were affected. Therefore, assessment of GSH-Px activity showed the potential to discriminate between infertile males with normal and subnormal semen characteristics and may prove useful in the evaluation of male (in)fertility. Abbreviations: AD: antioxidative defense; Cu, Zn SOD: copper, zinc superoxide dismutase; GSH-Px: glutathione peroxidase; MnSOD: manganese superoxide dismutase; NS: normospermia; OATS: oligoasthenoteratozoospermia; OTS: oligoteratozoospermia; ROC: receiver operating characteristic; ROS: reactive oxygen species; TS: teratozoospermia; WHO: world health organization [ABSTRACT FROM AUTHOR]

Environmental noise is a well‐recognized health risk and part of the external exposome—the World Health Organization estimates that 1 million healthy life years are lost annually in Western Europe alone due to noise‐related complications, including increased incidence of hypertension, heart failure, myocardial infarction, and stroke. Previous data suggest that noise works through two paired pathways in a proposed reaction model for noise exposure. As a nonspecific stressor, chronic low‐level noise exposure can cause a disruption of sleep and communication leading to annoyance and subsequent sympathetic and endocrine stress responses leading to increased blood pressure, heart rate, stress hormone levels, and in particular more oxidative stress, being responsible for vascular dysfunction and representing changes of the internal exposome. Chronic stress generates cardiovascular risk factors on its own such as increased blood pressure, blood viscosity, blood glucose, and activation of blood coagulation. To this end, persistent chronic noise exposure increases cardiometabolic diseases, including arterial hypertension, coronary artery disease, arrhythmia, heart failure, diabetes mellitus type 2, and stroke. The present review discusses the mechanisms of the nonauditory noise‐induced cardiovascular and metabolic consequences, focusing on mental stress signaling pathways, activation of the hypothalamic–pituitary–adrenocortical axis and sympathetic nervous system, the association of these activations with inflammation, and the subsequent onset of oxidative stress and vascular dysfunction. © 2019 BioFactors, 45 (4):495–506, 2019 [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a signaling molecule responsible for initiation of molecular events that influence sperm functionality in a concentration-dependent manner. It is still not fully understood how seminal plasma NO contributes to sperm pathologies. The aim of this study was to elucidate whether and how NO is implicated in etiology of different sperm abnormalities. To this end we determine NO, nitrite and 3-nitrotyrosine (3-NT) content in seminal plasma of infertile men with specific pathologies (terato-, oligoterato- and oligoasthenoteratospermia) and relate it to infertile normospermic samples. To gain further understanding of NO metabolism in seminal plasma we determine protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Here we show that NO, nitrite and 3-NT levels in seminal plasma of men with suboptimal semen parameters are significantly lower compared to normospermic men. An increase in protein expression of eNOS and no change in protein expression of iNOS is observed in men with sperm pathologies. Association of seminal plasma 3-NT level with functional sperm parameters is observed - positive correlation with sperm count, motility and morphology in normospermia, teratospermia and oligoteratospermia, as well as negative correlation with sperm morphology and motility in oligoasthenoteratospermia. Present study revealed that suboptimal seminal plasma NO content is found in all examined sperm pathologies. This result unequivocally shows the importance of NO for sperm function and involvement of suboptimal NO level in etiology of sperm abnormalities. Lower seminal plasma 3-NT level and its significant association with sperm parameters, found in pathologies, strongly indicates that protein nitration is important for spermatozoa function and that failure to establish this post-translational protein modification might be involved in etiology of sperm abnormalities. According to our results, NO measurement can discriminate infertile men with sperm pathologies from infertile normospermic men but is not indicative of a specific type of sperm pathology. [ABSTRACT FROM AUTHOR]

In the present study we hypothesized that myocardial adaptive phenotype in mammalian hibernation involves rearrangement of mitochondria bioenergetic pathways providing protective pattern in states of reduced metabolism and low temperature. European ground squirrels ( Spermophilus citellus ) were exposed to low temperature (4 ± 1 °C) and then divided into two groups: (1) animals that fell into torpor (hibernating group) and (2) animals that stayed active and euthermic for 1, 3, 7, 12, or 21 days (cold-exposed group). Protein levels of selected components of the electron transport chain and ATP synthase in the heart increased after prolonged cold acclimation (mainly from day 7–21 of cold exposure) and during hibernation. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was also upregulated under both cold exposure and hibernating conditions. The phosphorylation state (Thr172) of 5′-AMP-activated protein kinase α increased early in cold exposure (at day 1 and 3) along with increased protein levels of phosphofructokinase and pyruvate dehydrogenase, whereas hypoxia inducible factor 1α protein levels showed no changes in response to cold exposure or hibernation. Hibernation also resulted in protein upregulation of three antioxidant defense enzymes (manganese and copper/zinc superoxide dismutases and glutathione peroxidase) and thioredoxin in the heart. Cold-exposed and hibernation-related phenotypes of the heart are characterized by improved molecular basis for mitochondrial energy-producing and antioxidant capacities that are achieved in a controlled manner. The recapitulation of such adaptive mechanisms found in hibernators could have broad application for myocardial protection from ishemia/reperfusion to improve hypothermic survival and cold preservation of hearts from non-hibernating species, including humans. [ABSTRACT FROM AUTHOR]

Great progress has been made in our understanding of the browning process in white adipose tissue (WAT) in rodents. The recognition that i) adult humans have physiologically inducible brown adipose tissue (BAT) that may facilitate resistance to obesity and ii) that adult human BAT molecularly and functionally resembles beige adipose tissue in rodents, reignited optimism that obesity and obesity-related diabetes type 2 can be battled by controlling the browning of WAT. In this review the main cellular mechanisms and molecular mediators of browning of WAT in different physiological states are summarized. The relevance of browning of WAT in metabolic health is considered primarily through a modulation of biological role of fat tissue in overall metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Considering the vital role of skeletal muscle in control of whole-body metabolism and the severity of long-term diabetic complications, we aimed to reveal the molecular pattern of early diabetes-related skeletal muscle phenotype in terms of energy metabolism, focusing on regulatory mechanisms, and the possibility to improve it using two redox modulators, l -arginine and superoxide dismutase (SOD) mimic. Alloxan-induced diabetic rats (120 mg/kg) were treated with l -arginine or the highly specific SOD mimic, M40403, for 7 days. As appropriate controls, non-diabetic rats received the same treatments. We found that l -arginine and M40403 restored diabetes-induced impairment of phospho-5′-AMP-activated protein kinase α (AMPKα) signaling by upregulating AMPKα protein itself and its downstream effectors, peroxisome proliferator-activated receptor-γ coactivator-1α and nuclear respiratory factor 1. Also, there was a restitution of the protein levels of oxidative phosphorylation components (complex I, complex II and complex IV) and mitofusin 2. Furthermore, l -arginine and M40403 induced translocation of glucose transporter 4 to the membrane and upregulation of protein of phosphofructokinase and acyl coenzyme A dehydrogenase, diminishing negative diabetic effects on limiting factors of glucose and lipid metabolism. Both treatments abolished diabetes-induced downregulation of sarcoplasmic reticulum calcium-ATPase proteins (SERCA 1 and 2). Similar effects of l -arginine and SOD mimic treatments suggest that disturbances in the superoxide/nitric oxide ratio may be responsible for skeletal muscle mitochondrial and metabolic impairment in early diabetes. Our results provide evidence that l -arginine and SOD mimics have potential in preventing and treating metabolic disturbances accompanying this widespread metabolic disease. [ABSTRACT FROM AUTHOR]

Insulin sensitivity and metabolic homeostasis depend on the capacity of adipose tissue to take up and utilize excess glucose and fatty acids. The key aspects that determine the fuel-buffering capacity of adipose tissue depend on the physiological levels of the small redox molecule, nitric oxide (NO). In addition to impairment of NO synthesis, excessive formation of the superoxide anion (О2•- ) in adipose tissue may be an important interfering factor diverting the signalling of NO and other reactive oxygen and nitrogen species in obesity, resulting in metabolic dysfunction of adipose tissue over time. Besides its role in relief from superoxide burst, enhanced NO signalling may be responsible for the therapeutic benefits of different superoxide dismutase mimetics, in obesity and experimental diabetes models. This review summarizes the role of NO in adipose tissue and highlights the effects of NO/О2•- ratio 'teetering' as a promising pharmacological target in the metabolic syndrome.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

Developmental dysfunction in embryos, such as a lethal level of fragmentation, is assumed to be mitochondrial in origin. This study investigated the molecular basis of mitochondrial impairment in embryo fragmentation. Transcription patterns of factors that determine mitochondrial functionality: (i) components of the oxidative phosphorylation (OXPHOS) – complex I, cytochrome b, complex IV and ATP synthase; (ii) mitochondrial membrane potential (MMP); (iii) mitochondrial DNA (mtDNA) content and (iv) proteins involved in mitochondrial dynamics, mitofusin 1 (Mfn1) and dynamin related protein 1 (Drp1) were examined in six-cells Day 3 non-fragmented (control), low-fragmented (LF) and high-fragmented (HF) human embryos. Gene expression of mitochondria-encoded components of complex I and IV, cytochrome b and mtDNA were increased in HF embryos compared with control and LF embryos. In LF embryos, expression of these molecules was decreased compared with control and HF embryos. Both classes of fragmented embryos had decreased MMP compared with control. LF embryos had increased gene expression of Mfn1 accompanied by decreased expression of Drp1, while HF embryos had decreased Mfn1 expression but increased Drp1 expression. The study revealed that each improper transcriptional (in)activation of mitochondria-encoded components of the OXPHOS during early in vitro embryo development is associated with a decrease in MMP and with embryo fragmentation. The results also showed the importance of mitochondrial dynamics in fragmentation, at least in the extent of this process. [ABSTRACT FROM AUTHOR]

Key points White to brown adipose tissue conversion and thermogenesis can be ignited by different conditions or agents and its sustainability over the long term is still unclear., Browning of rat retroperitoneal white adipose tissue (rpWAT) during cold acclimation involves two temporally apparent components: (1) a predominant non-selective browning of most adipocytes and an initial sharp but transient induction of uncoupling protein 1, peroxisome proliferator-activated receptor (PPAR) coactivator-1α, PPARγ and PPARα expression, and (2) the subsistence of relatively few thermogenically competent adipocytes after 45 days of cold acclimation., The different behaviours of two rpWAT beige/brown adipocyte subsets control temporal aspects of the browning process, and thus regulation of both components may influence body weight and the potential successfulness of anti-obesity therapies., Abstract Conversion of white into brown adipose tissue may have important implications in obesity resistance and treatment. Several browning agents or conditions ignite thermogenesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in a brownish/burning mode over the long term, we investigated the progression of the rat retroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the early stages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularization and thermogenic-profile induction, as demonstrated by the presence of a multitude of uncoupling protein 1 (UCP1)-immunopositive paucilocular adipocytes containing peroxisome proliferator-activated receptor (PPAR) coactivator-1α (PGC-1α) and PR domain-containing 16 (PRDM16) in their nuclei. After 45 days, all adipocytes remained PRDM16 immunopositive, but only a few multilocular adipocytes rich in mitochondria remained UCP1/PGC-1α immunopositive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred following cold exposure, but returned to starting levels after cold acclimation. Compared with controls (22 ± 1°C), levels of UCP1 mRNA increased in parallel with PPARγ (PPARα from days 1 to 7 and PGC-1α on day 1). Transcriptional recruitment of rpWAT was followed by an increase in UCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocytes within rpWAT underwent transient brown-fat-like thermogenic recruitment upon stimulation, but only a minority of cells retained a brown adipose tissue-like phenotype after the attainment of cold acclimation. Therefore, browning of WAT is dependent on both maintaining the thermogenic response and retaining enough brown-like thermogenically competent adipocytes in the long-term. Both aspects of browning could be important for long-term energy homeostasis and body-weight regulation. [ABSTRACT FROM AUTHOR]

Background. Semen analysis is the cornerstone in the evaluation of male (in)fertility. However, there are men with normal semen tests but with impaired fertilizing ability, as well as fertile men with poor sperm characteristics. Thus, there is rising interest to find novel parameters that will help to predict and define the functional capacity of spermatozoa. Methods. We examined whether there is a correlation between semen parameters (count, progressive motility, and morphology) and protein expression/activity of antioxidative defense enzymes in seminal plasma from 10 normospermic subjects. Results. Sperm progressive motility was in positive correlation with seminal plasma protein expression of both superoxide dismutase (SOD) isoforms (MnSOD and CuZnSOD) and catalase. Also, positive correlation was observed between sperm count and MnSOD protein expression, as well as between sperm morphology and protein expression of catalase in seminal plasma. In contrast, protein expression of glutathione peroxidase was not in correlation with any sperm parameter, while its activity negatively correlated with sperm morphology and motility. Conclusions. These data suggest that evaluation of protein expression of antioxidative defense enzymes in seminal plasma might be of importance in the evaluation of male fertility status and that could be used as an additional biomarker along with classic semen analysis in assessment of semen quality. [ABSTRACT FROM AUTHOR]

Background and aims: Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are important intestinal neurotransmitters that coexist in the gut enteric nervous system and play an important role in intestinal physiology (e.g., absorption, motility, fluid secretion and smooth muscle relaxation). It is also known that cold exposure alters several aspects of gastrointestinal physiology and induces hyperphagia to meet increased metabolic demands, but there are no data regarding NO and VIP involvement in intestinal response during acclimation to cold. The objective of this study was to determine the influence of long-term l-arginine supplementation on the expression of the three isoforms of nitric oxide synthase (NOS) and VIP in small intestine of rats acclimated to room temperature or cold. Methods: Animals (six per group) acclimated to room temperature (22 ± 1 °C) and cold (4 ± 1 °C), respectively, were treated with 2.25 % l-arginine, a substrate for NOSs, or with 0.01 % N-nitro- l-arginine methyl ester, an inhibitor of NOSs, for 45 days. The topographical distribution of VIP and NOSs expression in small intestine was studied by immunohistochemistry, and ImageJ software was used for semiquantitative densitometric analysis of their immunoexpression. Results: Long-term dietary l-arginine supplementation increases VIP and NOSs immunoexpression at room temperature while at cold increases the endothelial NOS, inducible NOS and VIP but decrease neuronal NOS in rat small intestine. Conclusion: Our results demonstrate that long-term dietary l-arginine supplementation modulates NOSs and VIP immunoexpression in rat small intestine with respect to ambient temperature, pointing out the eNOS as a predominant NOS isoform with an immunoexpression pattern similar to VIP. [ABSTRACT FROM AUTHOR]

This study examined the molecular basis of energy-related regulatory mechanisms underlying metabolic recruitment of skeletal muscle during cold acclimation and possible involvement of the L-arginine/nitric oxide-producing pathway. Rats exposed to cold (4±1°C) for periods of 1, 3, 7, 12, 21 and 45 days were divided into three groups: untreated, L-arginine treated and Nɷ-nitro-Larginine methyl ester (L-NAME) treated. Compared with controls (22±1°C), there was an initial increase in the protein level of 5'- AMP-activated protein kinase a (day 1), followed by an increase in peroxisome proliferator-activated receptor-? coactivator-1a (PGC-1ɑ) and peroxisome proliferator-activated receptors (PPARs): PPARa and PPARɣ from day 1 and PPARd from day 7 of cold acclimation. Activation of the PGC-1ɑ/PPAR transcription program was accompanied by increased protein expression of the key metabolic enzymes in ß-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation, with the exceptions in complex I (no changes) and ATP synthase (decreased at day 1). Cold did not affect hexokinase and GAPDH protein levels, but increased lactate dehydrogenase activity compared with controls (1-45 days). L-arginine sustained, accelerated and/or intensified cold-induced molecular remodeling throughout cold acclimation. L-NAME exerted phase-dependent effects: similar to L-arginine in early cold acclimation and opposite after prolonged cold exposure (from day 21). It seems that upregulation of the PGC-1ɑ/PPAR transcription program early during cold acclimation triggers the molecular recruitment of skeletal muscle underlying the shift to more oxidative metabolism during prolonged cold acclimation. Our results suggest that nitric oxide has a role in maintaining the skeletal muscle oxidative phenotype in late cold acclimation but question its role early in cold acclimation. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined endocrine and metabolic signaling in rat retroperitoneal white adipose tissue remodeling during cold acclimation. Male Mill Hill hybrid hooded rats were housed under a 12/12 hour reverse light/dark cycle and were fed standard chow and water. It was observed that adiponectic was an important endocrine regulator in metabolic adaptation to cold acclimation.

Background/Aims: Study elucidates and compares the mitochondrial bioenergetic-related molecular basis of sevoflurane and propofol cardioprotection during aortic valve replacement surgery due to aortic valve stenosis. Methods: Twenty-two patients were prospectively randomized in two groups regarding the anesthetic regime: sevoflurane and propofol. Hemodynamic parameters, biomarkers of cardiac injury and brain natriuretic peptide (BNP) were measured preoperatively and postoperatively. In tissue samples, taken from the interventricular septum, key mitochondrial molecules were determined by Western blot, real time PCR, as well as confocal microscopy and immunohisto- and immunocyto-chemical analysis. Results: The protein levels of cytochrome c oxidase and ATP synthase were higher in sevoflurane than in propofol group. Nevertheless, cytochrome c protein content was higher in propofol than sevoflurane receiving patients. Propofol group also showed higher protein level of connexin 43 (Cx43) than sevoflurane group. Besides, immunogold analysis showed its mitochondrial localization. The mRNA level of mtDNA and uncoupling protein (UCP2) were higher in propofol than sevoflurane patients, as well. On the other hand, there were no significant differences between groups in hemodynamic assessment, intensive care unit length of stay, troponin I and BNP level. Conclusions: Our data indicate that sevoflurane and propofol lead to cardiac protection via different mitochondrially related molecular mechanisms. It appears that sevoflurane acts regulating cytochrome c oxidase and ATP synthase, while the effects of propofol occur through regulation of cytochrome c, Cx43, mtDNA transcription and UCP2. [ABSTRACT FROM AUTHOR]

Abstract: Background: Brown adipose tissue thermogenic program includes complex molecular and structural changes. However, energetic aspects of this process are poorly depicted. Methods: We investigated time-dependent reprogramming of interscapular brown adipose tissue (IBAT) energy metabolism during cold-acclimation, as well as the effects of nitric oxide ( NO) on those changes. Rats were exposed to cold (4±1°C) for periods of 1, 3, 7, 12, 21, and 45days, and divided into three groups: control, treated with L-arginine, and treated with Nω-nitro-L-arginine methyl ester (L-NAME). Results: In the early phase of cold-acclimation (up to 7days), the protein levels of all metabolic parameters and oxidative phosphorylation components were below the control. However, metabolic parameters and respiratory chain components entered a new homeostatic level in the late phase of cold-acclimation. These changes were accompanied with increased protein levels of phospho-AMP-dependent protein kinase-α (phospho-AMPKα) on the first day of cold-acclimation, and hypoxia-inducible factor-1α (HIF-1α) throughout early cold-acclimation. L-arginine positively affected protein expression of enzymes involved in glucose metabolism and β-oxidation of fatty acids in the early phase of cold-acclimation, and oxidative phosphorylation components throughout cold-acclimation. In contrast, L-NAME had the opposite effects. Conclusion: Results suggest that IBAT structural remodeling is followed by energy metabolism reprogramming, which control might be orchestrated by the action of AMPKα and HIF-1α. Data also indicated the involvement of L-arginine- NO in the regulation of IBAT metabolism. General significance: Results obtained in this study might be of great importance for elucidating regulatory pathways governing energy metabolism in both physiological and pathophysiological states. [Copyright &y& Elsevier]

Despite peroxisomes being important partners of mitochondria by carrying out fatty acid oxidation in brown adipocytes, no clear evidence concerning peroxisome origin and way(s) of biogenesis exists. Herein we used methimazole-induced hypothyroidism for 7, 15, and 21 days to study peroxisomal remodeling and origin in rat brown adipocytes. We found that peroxisomes originated via both canonic, and de novo pathways. Each pathway operates in euthyroid control and over the course of hypothyroidism, in a time-dependent manner. Hypothyroidism increased the peroxisomal number by 1.8-, 3.6- and 5.8-fold on days 7, 15, and 21. Peroxisomal presence, their distribution, and their degree of maturation were heterogeneous in brown adipocytes in a Harlequin-like manner, reflecting differences in their origin. The canonic pathway, through numerous dumbbell-like and "pearls on strings" structures, supported by high levels of Pex11β and Drp1, prevailed on day 7. The de novo pathway of peroxisomal biogenesis started on day 15 and became dominant by day 21. The transition of peroxisomal biogenesis from canonic to the de novo pathway was driven by increased levels of Pex19, PMP70, Pex5S, and Pex26 and characterized by numerous tubular structures. Furthermore, specific peroxisomal origin from mitochondria, regardless of thyroid status, indicates their mutual regulation in rat brown adipocytes. [ABSTRACT FROM AUTHOR]

Simple Summary: Specific metabolic phenotypes of breast cancer result from local interactions such as cancer-adipocyte cross-talk and systemic metabolic influences such as obesity. Here we examined key regulatory enzymes involved in glucose metabolism in breast cancer tissue and cancer-associated adipose tissue of normal-weight and overweight/obese premenopausal women in comparison to benign breast tumor tissue and adipose tissue of weight-matched women. We show a simultaneous increase in 5′-AMP-activated protein kinase (AMPK) protein expression with glucose utilization favoring glycolysis and pentose phosphate pathway in breast cancer tissue. In parallel, we show an increased AMPK protein expression with glucose utilization favoring the pentose phosphate pathway in cancer-associated adipose tissue. Moreover, specific features of cancer tissue glycolysis and glycogen metabolism differ between normal-weight and overweight/obese women. The results suggest context-dependent induction of tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue. Typical features of the breast malignant phenotype rely on metabolic reprogramming of cancer cells and their interaction with surrounding adipocytes. Obesity is strongly associated with breast cancer mortality, yet the effects of obesity on metabolic reprogramming of cancer and cancer-associated adipose tissue remain largely unknown. Paired biopsies of breast tumor tissue and adipose tissue from premenopausal women were divided according to pathohistological analyses and body mass index on normal-weight and overweight/obese with benign or malignant tumors. We investigated the protein expression of key regulatory enzymes of glycolysis, pentose phosphate pathway (PPP), and glycogen synthesis. Breast cancer tissue showed a simultaneous increase in 5′-AMP-activated protein kinase (AMPK) protein expression with typical features of the Warburg effect, including hexokinase 2 (HK 2) overexpression and its association with mitochondrial voltage-dependent anion-selective channel protein 1, associated with an overexpression of rate-limiting enzymes of glycolysis (phosphofructokinase 1—PFK-1) and pentose phosphate pathway (glucose-6-phosphate dehydrogenase—G6PDH). In parallel, cancer-associated adipose tissue showed increased AMPK protein expression with overexpression of HK 2 and G6PDH in line with increased PPP activity. Moreover, important obesity-associated differences in glucose metabolism were observed in breast cancer tissue showing prominent glycogen deposition and higher glycogen synthase kinase-3 protein expression in normal-weight women and higher PFK-1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein expression in overweight/obese women. In conclusion, metabolic reprogramming of glycolysis contributes to tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming that favors high glycolytic flux with lactate production in normoxia is among cancer hallmarks. Lactate is an essential oncometabolite regulating cellular redox homeostasis, energy substrate partitioning, and intracellular signaling. Moreover, malignant phenotype's chief characteristics are dependent on the interaction between cancer cells and their microenvironment. In breast cancer, mammary adipocytes represent an essential cellular component of the tumor milieu. We analyzed lactate concentration, lactate dehydrogenase (LDH) activity, and isozyme pattern, and LDHA/LDHB protein expression and tissue localization in paired biopsies of breast cancer tissue and cancer-associated adipose tissue in normal-weight and overweight/obese premenopausal women, compared to benign breast tumor tissue and adipose tissue in normal-weight and overweight/obese premenopausal women. We show that higher lactate concentration in cancer tissue is concomitant with a shift in isozyme pattern towards the "muscle-type" LDH and corresponding LDHA and LDHB protein expression changes. In contrast, significantly higher LDH activity in cancer-associated adipose tissue seems to be directed towards lactate oxidation. Moreover, localization patterns of LDH isoforms varied substantially across different areas of breast cancer tissue. Invasive front of the tumor showed cell-specific protein localization of LDHA in breast cancer cells and LDHB in cancer-associated adipocytes. The results suggest a specific, lactate-centric relationship between cancer tissue and cancer-associated adipose tissue and indicate how cancer-adipose tissue cross-talk may be influenced by obesity in premenopausal women. [ABSTRACT FROM AUTHOR]

The effects of insulin on the bioenergetic and thermogenic capacity of brown adipocyte mitochondria were investigated by focusing on key mitochondrial proteins. Two-month-old male Wistar rats were treated acutely or chronically with a low or high dose of insulin. Acute low insulin dose increased expression of all electron transport chain complexes and complex IV activity, whereas high dose increased complex II expression. Chronic low insulin dose decreased complex I and cyt c expression while increasing complex II and IV expression and complex IV activity. Chronic high insulin dose decreased complex II, III, cyt c, and increased complex IV expression. Uncoupling protein (UCP) 1 expression was decreased after acute high insulin but increased following chronic insulin treatment. ATP synthase expression was increased after acute and decreased after chronic insulin treatment. Only a high dose of insulin increased ATP synthase activity in acute and decreased it in chronic treatment. ATPase inhibitory factor protein expression was increased in all treated groups. Confocal microscopy showed that key mitochondrial proteins colocalize differently in different mitochondria within a single brown adipocyte, indicating mitochondrial mosaicism. These results suggest that insulin modulates the bioenergetic and thermogenic capacity of rat brown adipocytes in vivo by modulating mitochondrial mosaicism. [ABSTRACT FROM AUTHOR]

Evidence linking obesity to breast cancer in premenopausal women remains inconclusive. We aimed to reveal redox status related to malignant phenotype and its relationship with obesity. To this end, premenopausal women with breast tumors were divided into four groups: normal-weight (non-obese) with benign tumors, obese with benign tumors, non-obese with malignant tumors and obese with malignant tumors. We examined activity and protein expression of main antioxidant defense (AD) enzymes (copper, zinc- and manganese- superoxide dismutase, catalase and glutathione peroxidase) in breast tumor tissue and tumor-associated adipose tissue. Activity and protein expression of AD enzymes were generally increased in malignant tumors of non-obese and obese women, in comparison to their respective benign counterparts. In tumor-associated adipose tissue of non-obese women, activity and protein expression of AD enzymes were increased in subjects with malignant tumors in comparison to those with benign tumors. In conclusion, the effect of malignancy on the redox signature of tumor tissue is evident in both non-obese and obese subjects, while in adipose tissue the effect is pronounced mostly in non-obese subjects, suggesting redox sensitive interplay between obesity and cancer. [ABSTRACT FROM AUTHOR]

Duchenne-Becker muscular dystrophy (DBMD) might be caused by a widespread genetic defect in surface membranes, which could be expressed in membranes not pathologically involved in DBMD. This hypothesis was supported by a substantial amount of evidence of abnormalities in erythrocytes from patients with DBMD. Catalases are well studied enzymes that play critical roles in protecting cells against the toxic effects of hydrogen peroxide. In previous years a lot of papers on oxidative status in DBMD are mostly confirmed increased activity of enzymes involved in the elimination of reactive oxygen species in order to protect the cells from damage, including superoxide dismutase, catalase and glutathione peroxidase. Immunohistochemistry and immunogold labeling were used to study erythrocytes from patients with Duchenne-Becker muscular dystrophy and from age-matched normal boys. There were significant differences in the catalase localization of erythrocytes from Duchenne patients when compared to controls. Hence, the internal catalase localization in the erythrocyte is atypical in DBMD, supporting the concept that a membrane and cytoskeletal defect involving multiple tissues is present in this disorder. [ABSTRACT FROM AUTHOR]

Clarification of molecular mechanisms underlying lipid buffering capacity of white adipose tissue (WAT) may aid in the improvement of therapeutic options for obesity and diabetes prevention. Results of our studies have shown that cold-induced regression of WAT involves transient increase of tissue lipid oxidation, uncoupling capacity, an occurrence of browning allsynchronized with increase in adiponectin and resistin synthesis and profound glutathione (GSH) depletion. This GSH decrease prompted us to examine if a decrement of GSH a priori recapitulates cold-induced favorable phenotype of WAT. To this end, room-temperature and cold-exposed rats were treated with L-buthionine-S,R-sulfoximine (BSO). Indeed, BSO treatment reduced rat body weight and lipid content in fat tissue on account of increased OXPHOS and uncoupling capacity of WAT in both, cold-exposed and room-temperature maintained rats. However, in comparison to control, BSO decreased expressions of adiponectin and resistin at room temperature and attenuated their adaptive increase on cold exposure. Decrement of GSH raise lipid burning phenotype in WAT, but it may interfere with endocrine role of WAT in overall metabolic homeostasis maintenance. [ABSTRACT FROM AUTHOR]

Global rise in male infertility give importance to find a new approach to increase fertility. Redox signaling emerged recently as important for spermatozoa functioning. Accordingly, we just showed great therapeutic potential of redox modulator SOD mimic M40403. Molecular mechanisms underlying beneficial effects of M40403 indicate NO involvement, but remain unsolved; we aimed to reveal this herein. Compared to the control, incubation of spermatozoa in Tyrode's medium for 3 h, decreased sperm motility, mitochondrial membrane potential (MMP), level of NO, expression of NO synthases (NOSs), and completely abolished nuclear localization of NF-E2-related nuclear factor 2 (Nrf2) that was followed by decrease in SODs, catalase and GPX expression. Treatment with M40403 decreased levels of O 2 •– , increased level of NO, restored expression of NOSs and MMP, and triggered marked nuclear translocation of Nrf2 followed by up-regulation of SODs, catalase and GPX and increase in sperm motility. In turn, M40403 + L-NAME treatment nullified all beneficial effects of M40403. These data reveal the redox based mechanisms of beneficial effects of M40403 SOD mimic in sperm cells, suggesting NO/Nrf2 signaling as a central pathway. Utilization of a redox modulator, M40403, as an inducer of Nrf2 is a promising pharmacological approach for the improvement of sperm fertilizing potential and beat infertility. [ABSTRACT FROM AUTHOR]

Redox homeostasis disturbance, mainly caused by increased O 2 •– level and/or decreased NO bioavailability, represents an important contributing factor in the (ethio)pathology of diabetes. We examined whether targeting of O 2 •– /NO ratio by two redox-modulating compounds, L-arginine (substrate for NO synthases) and Mn(II) pentaazamacrocyclic mimics of SOD, could improve diabetic state and associated impairment of energy metabolism. Multiple beneficial effects of L-arginine and SOD mimics in alloxan-induced diabetes were observed. First of all, acting directly on pancreas, L-arginine and SOD mimic induce β-cells regeneration. In skeletal muscle, those treatments restore diabetes-induced impairment in mitochondrial energy metabolism (OXPHOS) and glucose transport (GLUT4) by targeting AMPKα signaling. Similarly, SOD mimic improves energy metabolism in hippocampus of diabetic rats. L-arginine and SOD mimic stabilize diabetes-induced redox disbalance in diabetic skin acting on NO producing (NOS) and O 2 •– /H 2 O 2 removing (MnSOD and GPx) systems. The data suggest that fine settings of O 2 •– /NO ratio by L-arginine and SOD mimic could have beneficial implications for several pathological hallmarks of diabetes: impaired insulin synthesis and sensitivity as well as accompanying metabolic complications and speak in favor of therapeutic potential of these redox-active agents in diabetic conditions. [ABSTRACT FROM AUTHOR]

Maintaining heart viability in states of unfavorable metabolite/oxygen supply has become a prime challenge in cardiac medicine. Mitochondria have been recognised as key actors in cardioprotection. Our goal was to reveal the myocardial protective phenotype related to mitochondrial bioenergetic pathways in the state of limited metabolite supply and low temperature using the physiological model of mammalian hibernation. European ground squirrels (Spermophilus citellus) were exposed to cold (4 ± 1 °C) and divided into two groups: (1) animals that fell into torpor (hibernating group) and (2) animals that stayed active and euthermic for 1, 3, 7, 12, or 21 days (cold-exposed group). We found increased protein levels of electron transport chain components and ATP synthase in late cold acclimation and in hibernation. Also, protein level of PGC-1α was upregulated. Phospho-AMPKα protein content was increased during early cold acclimation. HIF1α protein level was unchanged. Protein levels of manganese and copper-zinc superoxide dismutase and glutathione peroxidase were increased in hibernation. The hibernation related phenotype of the heart is characterised by controlled improvement of mitochondrial energy and antioxidative capacity. Its reproduction could have broad implications, from myocardial protection in ischaemia/reperfusion to the hypothermic survival and cold preservation of organs. [ABSTRACT FROM AUTHOR]

Setting the correct ratio of superoxide anion (O2•-) and nitric oxide (•NO) radicals seems to be crucial in restoring disrupted redox signaling in diabetic skin and improvement of•NO physiological action for prevention and treatment of skin injuries in diabetes. In this study we examined the effects ofL-arginine and manganese(II)-pentaazamacrocyclic superoxide dismutase (SOD) mimic – M40403 in diabetic rat skin. Following induction of diabetes by alloxan (blood glucose level ≥12 mMol l −1) non-diabetic and diabetic male Mill Hill hybrid hooded rats were divided into three subgroups: (i) control, and receiving: (ii)L-arginine, (iii) M40403. Treatment of diabetic animals started after diabetes induction and lasted for 7 days. Compared to control, lower cutaneous immuno-expression of endothelial NO synthase (eNOS), heme oxygenase 1 (HO1), manganese SOD (MnSOD) and glutathione peroxidase (GSH-Px), in parallel with increased NFE2-related factor 2 (Nrf2) and nitrotyrosine levels characterized diabetic skin.L-arginine and M40403 treatments normalized alloxan-induced increase in nitrotyrosine. This was accompanied by the improvement/restitution of eNOS and HO1 or MnSOD and GSH-Px protein expression levels in diabetic skin followingL-arginine, i.e. SOD mimic treatments, respectively. The results indicate thatL-arginine and M40403 stabilize redox balance in diabetic skin and suggest the underlying molecular mechanisms. Restitution of skin redox balance byL-arginine and M40403 may represent an effective strategy to ameliorate therapy of diabetic skin. [ABSTRACT FROM AUTHOR]

Natural hypothermia, in addition to allowing energy saving in hostile conditions, has been associated with delayed aging and increased longevity. However, the molecular basis responsible for observed correlations between the use of daily torpor/hibernation and indices of rate of aging is hitherto unclear. Considering central role of mitochondria dysfunction in the ageing process, we examined several mechanisms that might be involved in mitochondrial protection against oxidative damage during euthermia-hypothermia (and vice versa) transition, in brown adipose tissue (BAT) of the European Ground Squirrel ( Spermophilus citellus ). Results showed that in hibernation increased protein expression of Mn superoxide dismutase coincides with decreased content of ATP synthase and uncoupling protein 1. This suggests that BAT mitochondria during hibernation are protected from oxidative injuries by suppressed oxidative capacity, as well as by upregulated antioxidant defense. Also, the data indicate that such molecular pattern of changes is initiated already during prehibernating period. Namely, in this period we observed accumulations of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor (erythroid 2-related)-like 2, which are probably responsible for suppressed oxidative metabolism, i.e. increased antioxidant capacity, respectively. Increased expression of the mitofusin 1 and detection of the megamitochondria in the prehibernating period indicate intensive mitofusion process in the BAT. This may be another mechanism of protection of mitochondrial content/function during euthermia-hypothermia transition. The results of the study suggest mechanisms that might be associated with increased resistance of “hibernating” mitochondria to the oxidative damage. Also, the data showed that biochemistry responsible for redox balance within the cell involves integration of antioxidant response and transcription control of overall metabolism. Finally, the results go in favor of the previous reports that suggested HIF-1 as a negative modulator of aging. [ABSTRACT FROM AUTHOR]