Chinese herbal formulae and non-alcoholic fatty liver disease : a preliminary investigation in an experimental animal model

University of Technology, Sydney. Faculty of Science.Background: Non-alcoholic Fatty Liver Disease (NAFLD) embodies the hepatic manifestation of metabolic syndrome, commonly associated with obesity, hyperinsulinaemia, peripheral insulin resistance, diabetes, hypertension, hypercholesterolaemia and hypertriglyceridaemia (Sanyal, 2002). NAFLD is recently conceded to be a global epidemic burden, being ranked as the second leading cause of preventative death (Younossi, 2008). Since the pathogenesis of NAFLD remains controversial, no established pharmacological agent has been developed that effectively targets or prevents excessive fat accumulation in the hepatocytes and, as a result, current treatments are primarily symptomatic. Chinese herbal medicine has become a growing focus for Western medical research in the quest for more effective treatments since various Chinese herbal formulae are used in Asian countries for hepatic and metabolic syndromes (Chen et al, 2006, Hollander and Merchanick 2008). Objective: To determine whether obesity related NAFLD could be induced in healthy rats by dietary manipulation alone and to investigate the effects of three Chinese herbal formulae in these animals on relevant variables on in vivo measures and on tissue analyses post mortem. Design: The research comprised of two related studies. Study one was a between subjects equivalent group experiment with repeated measures, with the rats randomly divided among six intervention groups. Five groups were continuously fed a high fat diet (HFD) and one group fed a standard laboratory chow for 11 weeks until sacrifice. Study two entailed the collection of liver and adipose tissues immediately post mortem. These tissue weights were recorded and the livers were used to measure hepatic triglyceride content and for histological examination of the rat liver. Participants and interventions: 56 male Sprague Dawley rats, six weeks old and weighing between 170 - 210g were randomly divided among six intervention groups. Five groups were continuously fed a HFD and one group, a standard laboratory chow for 11 weeks until sacrifice. After a five week induction period, the six week intervention phase commenced with the allocated intervention administered daily by oral gavage. Blood collection occurred in the last week before sacrifice for subsequent analyses. The pharmacological interventions comprised Rosiglitazone (RSG); antidiabetic medication, SK0504 (S4), SK0506 (S6) and a decoction of SK0506 (DS6) as well as water for the two control groups. Note: S4 combines Jiao Gu Lan (Gynostemma pentaphyllum), San Qi (Panax notoginseng), Huang Lian (Rhizoma Coptidis) and Dan Shen (Salvia miltiorrhiza) and S6 combines Dan Shen (Salvia miltiorrhiza) and Zhi Zi (Fructus Gardenia Jasminodis). Main outcome measures: Bodyweight, food and energy food intake; biochemical and hepatic analyses (plasma glucose, Non-esterified Fatty Acids (NEFA), cholesterol, triglycerides (TG), High Density Lipoprotein-Cholesterol (HDL-C), Alanine Transaminase (ALT), Aspartate Transaminase (AST) and hepatic triglycerides); and histopathological staining (to observe hepatic morphology) were measured. Results: The results for the five week induction phase suggest that despite the difference in diet (HFD or standard chow) the rats regulated their energy intake as there was no significant difference in the increase in mean weight for the two diets. During the intervention phase there were further increases in body weight that plateaued after four weeks, quite independent of diet or intervention. However, there was no clear relationship between caloric intake and weight gain in that there were significant differences between the two S6 groups and the others and yet this did not equate to any difference in weight gain. At the end of the intervention period there was no significant difference between most groups in blood glucose levels and typically animals were within the healthy range. Therefore high fat feeding alone, particularly in a short period of time of ten weeks did not cause hyperglycaemia. Within the intervention groups there was evidence of marked hyperlipidaemia with the HFD as evidenced by significant increases in NEFA, TG and cholesterol. In general, this was attenuated by the interventions. Notably both forms of the S6 intervention had a cardioprotective effect illustrated by the elevation of levels of HDL-C. There were potentially hepatotoxic effects indicated by elevation of liver enzymes associated with HFD feeding alone that were supported by histopathological changes in the liver. Post mortem comparisons included weights of adipose tissues, hepatic tissue and hepatic morphology for evidence of NAFLD. With the epidydimal, subcutaneous and inguinal fat deposits, there was a significant degree of fat accumulation in the HFD group compared with the chow group. RSG showed no beneficial effect with regard to fat accumulation, which contrasts with the effects of the two herbal formulae S4 and S6. There was no evidence of hepatomegaly in any group. High fat feeding resulted in excess hepatic triglyceride levels which was attenuated by RSG, S4 and S6, with S6 being the most effective. Note that no intervention completely prevented this high fat feeding accumulation. The significant increase in hepatic TG accumulation and plasma biochemical analysis (NEFA, TG and cholesterol) with the high fat feeding in control groups was supported from the histological findings of macro- and microvesicular steatosis fed the HFD alone. These histological changes were absent in animals fed the other HFD based interventions (S6, S4 and RSG). There was no discernible fibrosis in any of the groups. Conclusion: HFD feeding alone produced NAFLD as hypertriglyceraemia, hypercholesterolaemia and histological evidence of steatosis was observed. The three herbal formulae all attenuated the HFD’s hyperlipidaemic effects in relation to plasma TG, NEFA, cholesterol, HDL-C and hepatic TG as no steatosis was formed. However lack of difference in weights between standard chow and HFD fed rats during the induction and intervention phases suggests the model failed to produce obesity which may be due to the short period of 11 weeks of the dietary manipulation. S4 and S6 both attenuated the effects on liver enzymes of the high fat diet, possibly indicating possible hepatoprotective effects with the values falling towards those for the Chow group. RSG by contrast elevated AST levels above those for HFD. The two forms of S6; powder and decoction, compared in study one showed generally similar results

The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE^-/- mice

© 2015 Elsevier Ireland Ltd. The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE-/- mice fed a high fat diet (HFD). Methods: ApoE-/- mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. Results: High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD-fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. Conclusions: These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, TEMPOL had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. TEMPOL may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability

A framework to move forward on the path to eco-innovation in the construction industry: implications to improve firms´ sustainable orientation

This paper examines key aspects in the innovative behavior of the construction firms that determine their environmental orientation while innovating. Structural equation modeling was used and data of 222 firms retrieved from the Spanish Technological Innovation Panel (PITEC) for 2010 to analyse the drivers of environmental orientation of the construction firms during the innovation process. The results show that the environmental orientation is positively affected by the product and process orientation of construction firms during the innovation process. Furthermore, the positive relation between the importance of market information sources and environmental orientation, mediated by process and product orientation, is discussed. Finally, a model that explains these relations is proposed and validated. 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Finished Genome of the Fungal Wheat Pathogen Mycosphaerella graminicola Reveals Dispensome Structure, Chromosome Plasticity, and Stealth Pathogenesis.

The plant-pathogenic fungus Mycosphaerella graminicola (asexual stage: Septoria tritici) causes septoria tritici blotch, a disease that greatly reduces the yield and quality of wheat. This disease is economically important in most wheat-growing areas worldwide and threatens global food production. Control of the disease has been hampered by a limited understanding of the genetic and biochemical bases of pathogenicity, including mechanisms of infection and of resistance in the host. Unlike most other plant pathogens, M. graminicola has a long latent period during which it evades host defenses. Although this type of stealth pathogenicity occurs commonly in Mycosphaerella and other Dothideomycetes, the largest class of plant-pathogenic fungi, its genetic basis is not known. To address this problem, the genome of M. graminicolawas sequenced completely. The finished genome contains 21 chromosomes, eight of which could be lost with no visible effect on the fungus and thus are dispensable. This eight-chromosome dispensome is dynamic in field and progeny isolates, is different from the core genome in gene and repeat content, and appears to have originated by ancient horizontal transfer from an unknown donor. Synteny plots of the M. graminicola chromosomes versus those of the only other sequenced Dothideomycete, Stagonospora nodorum, revealed conservation of gene content but not order or orientation, suggesting a high rate of intra-chromosomal rearrangement in one or both species. This observed “mesosynteny” is very different from synteny seen between other organisms. A surprising feature of the M. graminicolagenome compared to other sequenced plant pathogens was that it contained very few genes for enzymes that break down plant cell walls, which was more similar to endophytes than to pathogens. The stealth pathogenesis of M. graminicola probably involves degradation of proteins rather than carbohydrates to evade host defenses during the biotrophic stage of infection and may have evolved from endophytic ancestors

Concentration-Dependent, Size-Independent Toxicity of Citrate Capped AuNPs in Drosophila melanogaster

The expected potential benefits promised by nanotechnology in various fields have led to a rapid increase of the presence of engineered nanomaterials in a high number of commercial goods. This is generating increasing questions about possible risks for human health and environment, due to the lack of an in-depth assessment of the physical/chemical factors responsible for their toxic effects. In this work, we evaluated the toxicity of monodisperse citrate-capped gold nanoparticles (AuNPs) of different sizes (5, 15, 40, and 80 nm) in the model organism Drosophila melanogaster, upon ingestion. To properly evaluate and distinguish the possible dose- and/or size-dependent toxicity of the AuNPs, we performed a thorough assessment of their biological effects, using two different dose-metrics. In the first approach, we kept constant the total surface area of the differently sized AuNPs (Total Exposed Surface area approach, TES), while, in the second approach, we used the same number concentration of the four different sizes of AuNPs (Total Number of Nanoparticles approach, TNN). We observed a significant AuNPs-induced toxicity in vivo, namely a strong reduction of Drosophila lifespan and fertility performance, presence of DNA fragmentation, as well as a significant modification in the expression levels of genes involved in stress responses, DNA damage recognition and apoptosis pathway. Interestingly, we found that, within the investigated experimental conditions, the toxic effects in the exposed organisms were directly related to the concentration of the AuNPs administered, irrespective of their size

Polymorphous adenocarcinoma of the salivary glands : reappraisal and update

Although relatively rare, polymorphous adenocarcinoma (PAC) is likely the second most common malignancy of the minor salivary glands (MiSG). The diagnosis is mainly based on an incisional biopsy. The optimal treatment comprises wide surgical excision, often with adjuvant radiotherapy. In general, PAC has a good prognosis. Previously, PAC was referred to as polymorphous low-grade adenocarcinoma (PLGA), but the new WHO classification of salivary gland tumours has also included under the PAC subheading, the so-called cribriform adenocarcinoma of minor salivary glands (CAMSG). This approach raised controversy, predominantly because of possible differences in clinical behaviour. For example, PLGA (PAC, classical variant) only rarely metastasizes, whereas CAMSG often shows metastases to the neck lymph nodes. Given the controversy, this review reappraises the definition, epidemiology, clinical presentation, diagnostic work-up, genetics, treatment modalities, and prognosis of PAC of the salivary glands with a particular focus on contrasting differences with CAMSG.Peer reviewe

Supplementation with carnosine decreases plasma triglycerides andmodulates atherosclerotic plaque composition in diabetic apoE^-/- mice

Objective: Carnosine has been shown to modulate triglyceride and glycation levels in cell and animal systems. In this study we investigated whether prolonged supplementation with carnosine inhibits atherosclerosis and markers of lesion stability in hyperglycaemic and hyperlipidaemic mice. Methods: Streptozotocin-induced diabetic apo E-/- mice were maintained for 20 weeks, post-induction of diabetes. Half of the animals received carnosine (2g/L) in their drinking water. Diabetes was confirmed by significant increases in blood glucose and glycated haemoglobin, plasma triglyceride and total cholesterol levels, brachiocephalic artery and aortic sinus plaque area; and lower body mass. Results: Prolonged carnosine supplementation resulted in a significant (~20-fold) increase in plasma carnosine levels, and a significant (~23%) lowering of triglyceride levels in the carnosine-supplemented groups regardless of glycaemic status. Supplementation did not affect glycaemic status, blood cholesterol levels or loss of body mass. In the diabetic mice, carnosine supplementation did not diminish measured plaque area, but reduced the area of plaque occupied by extracellular lipid (~60%) and increased both macrophage numbers (~70%) and plaque collagen content (~50%). The area occupied by α-actin-positive smooth muscle cells was not significantly increased. Conclusions: These data indicate that in a well-established model of diabetes-associated atherosclerosis, prolonged carnosine supplementation enhances plasma levels, and has novel and significant effects on atherosclerotic lesion lipid, collagen and macrophage levels. These data are consistent with greater lesion stability, a key goal in treatment of existing cardiovascular disease. Carnosine supplementation may therefore be of benefit in lowering triglyceride levels and suppressing plaque instability in diabetes-associated atherosclerosis. © 2013 Elsevier Ireland Ltd