The Warburg Effect in Endothelial Cells and its Potential as an Anti-angiogenic Target in Cancer

Endothelial cells (ECs) make up the lining of our blood vessels and they ensure optimal nutrient and oxygen delivery to the parenchymal tissue. In response to oxygen and/or nutrient deprivation, ECs become activated and sprout into hypo-vascularized tissues forming new vascular networks in a process termed angiogenesis. New sprouts are led by migratory tip cells and extended through the proliferation of trailing stalk cells. Activated ECs rewire their metabolism to cope with the increased energetic and biosynthetic demands associated with migration and proliferation. Moreover, metabolic signaling pathways interact and integrate with angiogenic signaling events. These metabolic adaptations play essential roles in determining EC fate and function, and are perturbed during pathological angiogenesis, as occurs in cancer. The angiogenic switch, or the growth of new blood vessels into an expanding tumor, increases tumor growth and malignancy. Limiting tumor angiogenesis has therefore long been a goal for anticancer therapy but the traditional growth factor targeted anti-angiogenic treatments have met with limited success. In recent years however, it has become increasingly recognized that focusing on altered tumor EC metabolism provides an attractive alternative anti-angiogenic strategy. In this review, we will describe the EC metabolic signature and how changes in EC metabolism affect EC fate during physiological sprouting, as well as in the cancer setting. Then, we will discuss the potential of targeting EC metabolism as a promising approach to develop new anti-cancer therapies

Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation

Age-related skeletal muscle sarcopenia is linked with increases in falls, fractures, and death and therefore has important socioeconomic consequences. The molecular mechanisms controlling age-related muscle loss in humans are not well understood, but are likely to involve multiple signaling pathways. This study investigated the regulation of several genes and proteins involved in the activation of key signaling pathways promoting muscle hypertrophy, including GH/STAT5, IGF-1/Akt/GSK-3&beta;/4E-BP1, and muscle atrophy, including TNF&alpha;/SOCS-3 and Akt/FKHR/atrogene, in muscle biopsies from 13 young (20 &plusmn; 0.2 years) and 16 older (70 &plusmn; 0.3 years) males. In the older males compared to the young subjects, muscle fiber cross-sectional area was reduced by 40&ndash;45% in the type II muscle fibers. TNF&alpha; and SOCS-3 were increased by 2.8 and 1.5 fold, respectively. Growth hormone receptor protein (GHR) and IGF-1 mRNA were decreased by 45%. Total Akt, but not phosphorylated Akt, was increased by 2.5 fold, which corresponded to a 30% reduction in the efficiency of Akt phosphorylation in the older subjects. Phosphorylated and total GSK-3&beta; were increased by 1.5 and 1.8 fold, respectively, while 4E-BP1 levels were not changed. Nuclear FKHR and FKHRL1 were decreased by 73 and 50%, respectively, with no changes in their atrophy target genes, atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated by 2 and 1.4 fold. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signaling proteins such as GHR, IGF-1, and Akt. TNF&alpha;, SOCS-3, and myostatin are potential candidates influencing this anabolic perturbation.<br /

Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia

A central response to insufficient cerebral oxygen delivery is a profound reprograming of metabolism, which is mainly regulated by the Hypoxia Inducible Factor (HIF). Among other responses, HIF induces the expression of the atypical mitochondrial subunit NDUFA4L2. Surprisingly, NDUFA4L2 is constitutively expressed in the brain in non-hypoxic conditions. Analysis of publicly available single cell transcriptomic (scRNA-seq) data sets coupled with high-resolution multiplexed fluorescence RNA in situ hybridization (RNA F.I.S.H.) revealed that in the murine and human brain NDUFA4L2 is exclusively expressed in mural cells with the highest levels found in pericytes and declining along the arteriole-arterial smooth muscle cell axis. This pattern was mirrored by COX4I2, another atypical mitochondrial subunit. High NDUFA4L2 expression was also observed in human brain pericytes in vitro, decreasing when pericytes are muscularized and further induced by HIF stabilization in a PHD2/PHD3 dependent manner. In vivo, Vhl conditional inactivation in pericyte targeting Ng2-cre transgenic mice dramatically induced NDUFA4L2 expression. Finally NDUFA4L2 inactivation in pericytes increased oxygen consumption and therefore the degree of HIF pathway induction in hypoxia. In conclusion our work reveals that NDUFA4L2 together with COX4I2 is a key hypoxic-induced metabolic marker constitutively expressed in pericytes coupling mitochondrial oxygen consumption and cellular hypoxia respons

Agrarische ondernemers over de mestwetgeving : beleving van het mestbeleid: draagvlak, knelpunten en oplossingen

Akkerbouwers, melkveehouders en varkenshouders vinden het goed dat er een mestbeleid is en hebben de intentie om hier nauwkeurig aan te blijven voldoen, ook als het verder wordt aangescherpt. Het draagvlak voor het huidige mestbeleid, ofwel de mate waarin ondernemers achter het beleid staan, is echter gering bij agrarische ondernemers en andere belanghebbenden. Dit is een belangrijke conclusie uit het onderzoek naar de beleving van het mestbeleid door agrarische ondernemers en andere belanghebbenden dat is uitgevoerd in het kader van de evaluatie van de mestwetgeving in 2016

H3K18 lactylation marks tissue-specific active enhancers

Background: Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation. Results: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers. Keywords: Adipocyte; CUT&Tag; ChromHMM; Embryonic stem cell; Enhancer; Epigenetics; H3K18la; Histone post-translational modification; Lactate; Lactylation; Macrophage; Muscle; Promoter

Resting natural killer cell homeostasis relies on tryptophan/NAD+^{+} metabolism and HIF-1α

Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1α as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD$^{+}$ ) levels. The HIF-1α/NAD$^{+}$ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady-state conditions. In contrast, in activated NK cells under hypoxia, HIF-1α is required for glycolysis, and forced HIF-1α expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1α interferes with NK cell metabolism. While HIF-1α-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1α-dependent tryptophan/NAD$^{+}$ metabolism

Внешнеторговое сотрудничество Республики Корея со странами Северо-Восточной Азии

Вследствие быстрого развития и усложнения мирохозяйственных связей и торгово-экономического взаимодействия государств, тенденции развитие международного сотрудничества приобретают особую актуальность. Северо-Восточная Азия (СВА) – это регион, в котором очень тонко переплетаются исторические, идеологические, политические особенности и экономическая целесообразность торговли. Страновой состав региона Северо-Восточной Азии может рассматриваться с разных точек зрения, в рамках данного исследования под странами данного региона понимаются Республика Корея, Китай, Япония и вся Россия. Взаимодействие Республики Корея с каждым из трех государств имеет уникальную историю, достаточный потенциал для развития торговли, а также свои особенности формирования внешнеэкономических связей. Усиление роли Китая в качестве торгового партнера, снижение значимости Японии и сложная экономическая ситуация в России на текущий момент оказывают существенное влияние на развитие Республики Корея, опорой экономического роста которой традиционно являлась торговля. Эти три страны являются одними из важнейших партнеров для Республики Корея, поэтому изучение процессов формирования внешнеэкономических связей в рамках региона Северо-Восточной Азии необходимо для определения основных тенденций, качественных изменений и факторов, определяющих вектор торговых отношений. Цель исследования – выявить основные тенденции сотрудничества Республики Корея и стран Северо-Восточной Азии в сфере внешней торговли. Практическая значимость работы состоит в возможности получения всестороннего анализа внешнеторгового сотрудничества Республики Корея и стран Северо-Восточной Азии, глубоко раскрытия данной тематики, что может послужить основой для дальнейших исследований торговли Республики Корея со странами региона и определения будущих перспектив в сотрудничестве для формирования внешнеторговой политики страны.The final project is devoted to trade cooperation of the Republic of Korea and North-East Asian countries. This region is influenced by many factors and analyses of dynamics and structure of trade are extremely significant to reveal the reasons of current trends of international cooperation between countries

Metabolic adaptations to exercise in the fasted state

It is well established that the metabolic substrate pool for energy production during exercise when fed carbohydrates is shifted from fat to carbohydrates. The magnitude of the shift towards increased carbohydrate oxidation versus decreased fat oxidation is highly dependent on the timing of the carbohydrate intake. In this respect, it has been shown that pre-exercise carbohydrate ingestion limits fat oxidation through both inhibition of peripheral lipolysis and inhibition of intramuscular fat oxidation, whereas glucose intake during exercise only marginally blunts peripheral lipolysis without affecting total fat oxidation. It has thus been argued that the presence of a high insulin concentration already at the onset of exercise is of major importance in promoting decreased rates of fat oxidation. Carbohydrate intake before and during endurance exercise is a standard ‘ergogenic’ procedure. Still, the vast majority of literature studies that have looked at muscle metabolism in endurance exercise, have used the fasted state as the ‘standard’ dietary condition, while in fact the carbohydrate-fed state is recommended as the optimal nutritional state for endurance exercise. Thus, it was the primary aim of this dissertation to evaluate the acute and short term metabolic properties of exercise in the fasted (F) versus carbohydrate fed (CHO) state. In addition, the effect of acute metabolic state and training on intramyocellular lipid (IMCL) content will be specificially highlighted. Indeed, IMCL have been shown to be involved in the pathogenesis of peripheral insulin resistance. The development of exercise strategies that increase IMCL breakdown can therefore increase the effect of non-pharmacological strategies on insulin sensitivity. In first study, the acute effect of exercise in the fasted state versus exercise with carbohydrate intake was evaluated. We could show that IMCL breakdown during prolonged submaximal exercise in the fasted state takes place in type I fibres predominantly. Furthermore, IMCL breakdown during exercise was prevented in the carbohydrate-fed state. In addition, the combination of both glucose intake both before and during exercise decreased glycogen breakdown in type IIa fibres. Exercise in the fasting state enhances the post-exercise insulin response to glucose ingestion which in turn likely contributes to stimulation of post exercise muscle glycogen resynthesis. Finally, carbohydrate ingestion, either before, during or after exercise is a potent inhibitor of the exercise-induced increase in metabolic gene expression. Thus, exercise in the fasted state stimulates fat oxidation and glycogen breakdown when compared with exercise after the intake of a breakfast and with additional carbohydrate intake . It was however unclear whether exercise in the fasted state could affect training adaptations. Therefore, a second study investigated the effect of a short-term endurance training period (6 weeks, 3 days/week, 1-2 h, 75% VO2peak) in the fasted state or with carbohydrate intake on training adaptations and substrate utilisation during a standardised exercise bout with carbohydrate intake. Regular exercise in the fasted state did not affect the increase in exercise capacity. Training adaptations in muscle (enzyme activity, GLUT4, HKII, UCP3) were basically similar between both experimental conditions. However, gene expression, as measured via mRNA content, was markedly different between groups. Training did not affect IMCL content whereas glycogen content increased after training with carbohydrate intake but not after training in the fasted state. During exercise, fat oxidation rates nor IMCL breakdown was influenced by training. On the opposite, regular exercise in the fasted state decreased glycogen breakdown versus an increase in blood glucose oxidation. Although a decrease in glycogen breakdown after exercise in the fasted state can have major implications on performance, we could not show major differences in overall training adaptations.status: publishe

Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications

As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization.status: publishe