Growth hormone inhibits hepatic de novo lipogenesis in adult mice

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients

What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Stilbenes are naturally occurring phytoalexins that generally exist as their more stable E isomers. The most well known natural stilbene is resveratrol (Res), firstly isolated in 1939 from roots of Veratrum grandiflorum (white hellebore) (1) and since then found in various edible plants, notably in Vitis vinifera L. (Vitaceae) (2). The therapeutic potential of Res covers a wide range of diseases, and multiple beneficial effects on human health such as antioxidant, anti-inflammatory and anti-cancer activities have been suggested based on several in vitro and animal studies (3). In particular, Res has been reported to be an inhibitor of carcinogenesis at multiple stages via its ability to inhibit cyclooxygenase, and is an anticancer agent with a role in antiangiogenesis (4). Moreover, both in vitro and in vivo studies showed that Res induces cell cycle arrest and apoptosis in tumor cells (4). However, clinical studies in humans evidenced that Res is rapidly absorbed after oral intake, and that the low level observed in the blood stream is caused by a fast conversion into metabolites that are readily excreted from the body (5). Thus, considerable efforts have gone in the design and synthesis of Res analogues with enhanced metabolic stability. Considering that reduced Res (dihydro- resveratrol, D-Res) conjugates may account for as much as 50% of an oral Res dose (5), and that D-Res has a strong proliferative effect on hormone-sensitive cancer cell lines such as breast cancer cell line MCF7 (6), we recently devoted our synthetic efforts to the preparation of trans-restricted analogues of Res in which the E carbon-carbon double bond is embedded into an imidazole nucleus. To keep the trans geometry, the two aryl rings were linked to the heteroaromatic core in a 1,3 fashion. Based on this design, we successfully prepared a variety of 1,4-, 2,4- and 2,5-diaryl substituted imidazoles including Res analogues 1, 2 and 3, respectively, by procedures that involve transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions and highly selective N-H or C-H direct arylation reactions as key synthetic steps. The anticancer activity of compounds 1–3 was evaluated against the 60 human cancer cell lines panel of the National Cancer Institute (NCI, USA). The obtained results, that will be showed and discussed along with the protocols developed for the preparation of imidazoles 1–3, confirmed that a structural optimization of Res may provide analogues with improved potency in inhibiting the growth of human cancer cell lines in vitro when compared to their natural lead. (1) Takaoka,M.J.Chem.Soc.Jpn.1939,60,1090-1100. (2) Langcake, P.; Pryce, R. J. Physiological. Plant Patology 1976, 9, 77-86. (3) Vang, O.; et al. PLoS ONE 2011, 6, e19881. doi:10.1371/journal.pone.0019881 (4) Kraft, T. E.; et al. Critical Reviews in Food Science and Nutrition 2009, 49, 782-799. (5) Walle, T. Ann. N.Y. Acad. Sci. 2011, 1215, 9-15. doi: 10.1111/j.1749-6632.2010.05842.x (6) Gakh,A.A.;etal.Bioorg.Med.Chem.Lett.2010,20,6149-6151

Roots of Sustainability in Ancient India

Archaeology of the ancient civilization discovered in the Indus Valley region (now including the re-discovered course of the river Saraswati) suggests similarities with Vedic philosophy pre-dating the classical Vedic period. Linking proto-Vedic origins with Harrapan and pre-Harrapan culture makes sense as the "Aryan Invasion Theory" is increasingly discredited from lack of evidence, and as evidence of a relatively undisturbed proto-Vedic cultural succession in the Indus-Saraswati region builds. A tentative link should thus be made between Vedic philosophy, for which no exogenous cultural origin as been found, with the Indus-Saraswati civilizations, which reveal clear evidence lending to Vedic interpretation. Textual, Geophysical, archaeological, philosophical, and genetic evidence are consistent with origin and sustainable practice of prototypical Vedic holism in the Indus/Saraswati region from at least 3000BC until decline and/or dispersion of the culture from 1900BC to 600BC, probably due to climate and hydrological changes. The new timeline suggests an early practice of Vedic holism that appears to have been sustainable for a surprising length of time.  We examine the possible basis of that holistic belief in terms of similarities between Vedic literature, images found on archaeological artefacts, and a recent systems theory of cyclical causation that also corresponds with Vedic thought.  The collapse of this highly productive, influential, and yet peaceful civilization, which was apparently a centre of holistic belief, corresponds with a dramatic rise of dualistic thinking that spread widely along with the development of Abrahamic religions, both having strong influences on Greek philosophy and the development of modern science.  Our present situation of proliferating technology in the absence of systemic comprehension of its impact on society and nature may thus be attributed to this dramatic pre-historical shift from holistic to dualistic thought. We conclude with recommending an international education and research agenda, applying modern system thinking to better understand the ancient concepts of holism. We also recommend much greater international attention to archaeology and other studies of the Indus/Saraswati region

Information as Communication: The New Eco-Informatics

The goal of eco-informatics is to represent natural biodiversity and ecosystem phenomena, and to communicate such information to society, for science, valuation, management, and policy. Communication is the key, for without it information does not inform. We argue that past approaches to building databases and information systems were incomplete, and thus less communicative than needed regarding ecological phenomena. Information systems until recently have been limited to data about the physical state of the environment and biological components. While this worked well for physical systems, which can be modeled mechanistically, based on observable states and the application of general mechanistic laws, living systems have entailments beyond such mechanisms. They tend to generate additional system-dependent laws, or ‘functions’ that are internal to the natural system, and correspondingly must be represented as internal to the informatics system. Robert Rosen’s theory of ‘relational complexity’ is an appropriate foundation for new thinking about the entailment structure of living systems, and how to reflect that in informatics so it may represent living systems better. We derive from Rosen’s work, specifically his ‘modeling relation,’ a working theory of natural communication that can be implemented in informatics. This approach represents nature in terms of a complementarity between states and ‘functions.’ Functions act as system attractors or potentials, inducing but not determining change. The relationship is inherently complex, and when implemented in informatics it can support exploration of complex behaviors through simulations and scenario-building. Ecological functions, the ‘missing element’ in informatics, can be represented (but not totally specified) in the informatics architecture as a generalized form of ecological ‘niche’ model. A generalized form of niche model can be integrated with the database design. Relational complexity itself describes a natural form of communication. Designing informatics in an analogous manner suggests that it too will have better communication capacities. This, we argue, will allow informatics to accomplish its goal to communicate and inform. Various traditions, most notably from the East, present a view of the world as fundamentally complex and in constant communication with itself. To have a scientific way of representing this concept will improve integration across society and with various approaches to valuation, including indigenous values and perspectives. These needs are met in the proposed relational design for eco-informatics and enterprise development. A demonstration of how niche modeling can be used to represent an ecological function (the primary productivity of India) is appended. We believe the theory and implementation described here is a promising foundation on which advanced informatics capabilities may immediately be built to address the complexities of ecosystem management and to help meet pressing societal needs

The Atomistic Structure of Relationship: Robert Rosen’s Implicate Order

A careful synthesis of Robert Rosen’s theories about relational entities resulted in discovery of an entailment pattern between ontology and epistemology. We have called this “the relational atom” to emphasize its foundational status within a relationally analytical framework. This framework constitutes a natural philosophy and underlies material descriptions of reality, including current mechanistic theory. We believe this model represents, in essence, the natural structure of relationship, from which both traditionally objective and traditionally subjective entities arise. The essence of this understanding, however, is to objectify the entire model. The model and some of its possible applications are discussed

Growth hormone inhibits hepatic de novo lipogenesis in adult mice

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients

Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients