The lack of physical activity and overnutrition in our modern lifestyle culminates in what we now experience as the current obesity and diabetes pandemic. Medical research performed over the past 20 ...years identified chronic low‐grade inflammation as a mediator of these metabolic disorders. Hence, finding therapeutic strategies against this underlying inflammation and identifying molecules implicated in this process is of significant importance. Following the observation of an increased plasma concentration of interleukin‐6 (IL‐6) in obese patients, this protein, known predominantly as a pro‐inflammatory cytokine, came into focus. In an attempt to clarify its importance, several studies implicated IL‐6 as a co‐inducer of the development of obesity‐associated insulin resistance, which precedes the development of type 2 diabetes. However, the identification of IL‐6 as a myokine, a protein produced and secreted by skeletal muscle to fulfil paracrine or endocrine roles in the insulin‐sensitizing effects following exercise, provides a contrasting and hence paradoxical identity of this protein in the context of metabolism. We review here the literature considering the complex, pleiotropic role of IL‐6 in the context of metabolism in health and disease.
Metabolism and pathogen defense are essential requirements for survival. Mounting an immune response requires major changes to metabolic processes, and immune mediators (such as cytokines) also dictate changes in metabolism, including endocrine regulation of substrate utilization. The April 2014 issue contains a Special Feature on Immunometabolism: The interface of immune and metabolic responses in disease. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.
Obesity is currently at epidemic levels worldwide and is associated with a wide range of diseases such as type 2 diabetes, cardiovascular disease, fatty liver disease and certain forms of cancer. ...Obesity‐induced chronic inflammation is central to the disrupted metabolic homeostasis which underlies many of these conditions. While research over the past decade has identified many of the cells and signalling molecules that contribute to obesity‐induced inflammation, perhaps the best characterised are the stress‐activated c‐Jun NH2‐terminal kinases (JNKs). JNKs are activated in obesity in numerous metabolically important cells and tissues such as adipose tissue, macrophages, liver, skeletal muscle and regions of the brain and pituitary. Elegant in vivo mouse studies using Cre‐LoxP‐mediated recombination of the JNK1 and JNK2 genes have revealed the remarkably diverse roles that JNKs play in the development of obesity‐induced inflammation, impaired glucose homeostasis and hepatic steatosis. While JNK activation in classical metabolically active tissues such as skeletal muscle and adipose tissue only appears to play a minor role on the induction of the above‐mentioned pathologies, recent studies have clearly established the important roles JNK signalling fulfils in macrophages, the liver and cells of the anterior pituitary. Collectively, these studies place JNKs as important mediators of obesity and obesity‐associated disruptions to metabolic homeostasis.
A HFD leads to the activation of JNKs in numerous cell and tissue types and contributes to metabolic dysfunction.
Oxidation of nitric oxide is one of the main steps in the Ostwald process for industrial nitric acid production. This work summarises the use of γ-Al2O3 supported Ru catalyst to study the oxidation ...of NO to NO2 at ambient and 4 bar pressure with a feed of 10% NO, 6% O2, 15% H2O, and rest Ar. The catalyst was synthesised using wet impregnation and characterised by BET, CO chemisorption, H2-TPR, XPS, XRD, in-situ XAS-XRD and DRIFTS. We report the activity and kinetics of supported ruthenium catalyst for NO oxidation under realistic nitric acid plant conditions. The catalyst exhibited a promising low-temperature activity of 72% at 340 °C in complete nitric acid condition and 37% at 420 °C in partial nitric acid condition. An apparent activation energy of 152 kJ/mol was observed and the overall rate was determined to be r =kf.KG.PNO2.PO2PNO2, where kf and KG represents forward rate and equilibrium rate constants respectively. The reaction was found to be second order with respect to NO, first order with respect to O2 and inversely dependent on NO2 partial pressure. The stability of the catalyst was also tested during 45 h of isothermal NO oxidation at ambient pressure. From in-situ XAS-XRD and DRIFTS experiments it was revealed that during isothermal NO oxidation the reaction oscillates as the ruthenium surface goes through redox cycles. A plausible reaction mechanism that fits with our experimental observations and the oxidative nature of ruthenium is proposed. This study demonstrates and explains the capacity of supported ruthenium catalysts to oxidise NO to NO2 in industrial nitric acid production conditions.
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•Ru/γ-Al2O3 catalyst exhibited an activity of 72% at 340 °C in industrial condition.•An apparent Ea 152 kJ/mol was observed and reaction orders were determined.•In-situ XAS-XRD revealed surface redox cycles on ruthenium during NO oxidation.
Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their ...functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo 1. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.
Abstract
CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse (
dCas9a-SAM
KI
) ...for inducing gene expression in vivo and in vitro. Using
dCas9a-SAM
KI
primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in
Eµ-Myc
T/+
;dCas9a-SAM
KI/+
haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard
Eµ-Myc
lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
Exercise increases the expression of the prototypical myokine IL-6, but the precise mechanism by which this occurs has yet to be identified. To mimic exercise conditions, C2C12 myotubes were ...mechanically stimulated via electrical pulse stimulation (EPS). We compared the responses of EPS with the pharmacological Ca2+ carrier calcimycin (A23187) because contraction induces marked increases in cytosolic Ca2+ levels or the classical IκB kinase/NFκB inflammatory response elicited by H2O2. We demonstrate that, unlike H2O2-stimulated increases in IL-6 mRNA, neither calcimycin- nor EPS-induced IL-6 mRNA expression is under the transcriptional control of NFκB. Rather, we show that EPS increased the phosphorylation of JNK and the reporter activity of the downstream transcription factor AP-1. Furthermore, JNK inhibition abolished the EPS-induced increase in IL-6 mRNA and protein expression. Finally, we observed an exercise-induced increase in both JNK phosphorylation and IL-6 mRNA expression in the skeletal muscles of mice after 30 min of treadmill running. Importantly, exercise did not increase IL-6 mRNA expression in skeletal muscle-specific JNK-deficient mice. These data identify a novel contraction-mediated transcriptional regulatory pathway for IL-6 in skeletal muscle.
Background: IL-6 is up-regulated by contraction in skeletal muscle.
Results: Contraction-induced IL-6 expression is blunted by JNK inhibition.
Conclusion: The JNK/AP-1 pathway regulates IL-6 expression in contracting muscle.
Significance: This highlights a novel contraction-mediated transcriptional pathway for IL-6 in skeletal muscle.
Let $f:2^X \rightarrow \cal R_+$ be a monotone submodular set function, and let $(X,\cal I)$ be a matroid. We consider the problem ${\rm max}_{S \in \cal I} f(S)$. It is known that the greedy ...algorithm yields a $1/2$-approximation M. L. Fisher, G. L. Nemhauser, and L. A. Wolsey, Math. Programming Stud., no. 8 (1978), pp. 73-87 for this problem. For certain special cases, e.g., ${\rm max}_{|S| \leq k} f(S)$, the greedy algorithm yields a $(1-1/e)$-approximation. It is known that this is optimal both in the value oracle model (where the only access to f is through a black box returning $f(S)$ for a given set S) G. L. Nemhauser and L. A. Wolsey, Math. Oper. Res., 3 (1978), pp. 177-188 and for explicitly posed instances assuming $P \neq NP$ U. Feige, J. ACM, 45 (1998), pp. 634-652. In this paper, we provide a randomized $(1-1/e)$-approximation for any monotone submodular function and an arbitrary matroid. The algorithm works in the value oracle model. Our main tools are a variant of the pipage rounding technique of Ageev and Sviridenko J. Combin. Optim., 8 (2004), pp. 307-328, and a continuous greedy process that may be of independent interest. As a special case, our algorithm implies an optimal approximation for the submodular welfare problem in the value oracle model J. Vondrák, Proceedings of the $38$th ACM Symposium on Theory of Computing, 2008, pp. 67-74. As a second application, we show that the generalized assignment problem (GAP) is also a special case; although the reduction requires $|X|$ to be exponential in the original problem size, we are able to achieve a $(1-1/e-o(1))$-approximation for GAP, simplifying previously known algorithms. Additionally, the reduction enables us to obtain approximation algorithms for variants of GAP with more general constraints. PUBLICATION ABSTRACT
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and ...leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
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•Inflammatory signaling in AgRP neurons promotes obesity and insulin resistance•JNK and IKK activations in AgRP neurons have distinct metabolic consequences•JNK activation in AgRP neurons causes cellular and systemic leptin resistance•IKK activation in AgRP neurons leads to cellular and systemic insulin resistance
Inflammatory signaling in the CNS is crucial in the development of obesity-associated insulin and leptin resistance. Tsaousidou et al. demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons is sufficient to induce weight gain and leptin resistance in mice, whereas IKK2 activation fails to cause obesity but blunts insulin signaling and impairs systemic glucose homeostasis. The data reveal distinct effects of c-Jun N-terminal kinase (JNK)- and inhibitor of nuclear factor kappa-B kinase (IKK)-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. ...Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency.
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•Cardiomyocytes steadily accumulate mitochondrial DNA deletions with aging•This leads to the development of a tissue mosaic of mitochondrial deficiency•Impaired mitochondrial function in few cells promotes cardiac arrhythmia
Baris et al. test the idea of mosaic respiratory chain deficiency contributing to aging-related human cardiac disease. Using a genetic mouse model of accelerated accumulation of mtDNA deletions in the heart, they show that a few cardiomyocytes with mitochondrial DNA deletions progressively accumulate during aging, leading to cardiac arrhythmias.
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