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Cancer cells (CCs) predominantly use aerobic glycolysis (Warburg effect) for their metabolism. This important characteristic of CCs represents a potential metabolic pathway to be targeted in the context of tumor treatment. Being this mechanism related to nutrient oxidation, dietary manipulation has been hypothesized as an important strategy during tumor treatment. Ketogenic diet (KD) is a dietary pattern characterized by high fat intake, moderate-to-low protein consumption, and very-low-carbohydrate intake (

Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UnAG) forms. AG represents ~10% of total plasma ghrelin, has an appetite-stimulating effect and is the only form for which a receptor has been identified. UnAG has no orexigenic effects, and its circulating levels are positively associated with insulin sensitivity in metabolic syndrome patients. Skeletal muscle oxidative stress and inflammation are key negative modulators of tissue and whole-body insulin action, and UnAG was recently reported to reduce oxidative stress in non-muscle cells in-vitro. Its potential direct involvement in the regulation of muscle intermediate metabolism in vivo and its clinical impact remain however largely unknown. In the current studies, we first investigated potential associations between plasma AG, UnAG and HOMA insulin resistance index in the general population. In 719 individuals from the North-East-Italy MoMa epidemiological study, TG and UnAG but not of AG were negatively associated with HOMA after adjusting for gender and body mass both at baseline and at 5-year follow-up, and changes in TG and UnAG but not AG were negatively associated with changes in HOMA independently of potential confounders. We next tested the hypothesis that UnAG increases insulin sensitivity by modulating oxidative stress, inflammation and insulin action in skeletal muscle tissue. In healthy male rats, UnAG administration consistently reduced muscle mitochondrial ROS production, reduced inflammation and activated insulin-anabolic signalling. Analogous findings were observed in transgenic mice with systemic UnAG overexpression, and in UnAG-treated myotubes in vitro, thereby supporting a potential direct hormone effect. Importantly, these findings were not observed with AG administration nor in liver samples, thus further indicating independent and tissue specific UnAG actions. Autophagy, the removal of dysfunctional organelles, is an emerging protective mechanism in both cardiac and skeletal muscle. We therefore also hypothyzed that UnAG could reduce ROS production by inducing muscle autophagy. In cardiomiocytes UnAG reduced ROS production in association with increased dysfunctional mitochondria removal and in UnAG but not AG treated myotubes silencing of autophagy promoter ATG5 restored ROS generation. We next investigated the potential clinical relevance of UnAG actions in disease models characterized by muscle oxidative stress, inflammation and insulin resistance. In high-fat diet (HFD)-induced obese and diabetic mice, chronic UnAG overexpression prevented hyperglycemia and whole-body insulin resistance, as well as muscle oxidative stress, inflammation and altered insulin signalling. In rodent chronic kidney disease induced by 5/6 nephrectomy, protein-energy wasting, enhanced skeletal muscle ROS production, increased tissue inflammation and impaired insulin signalling were also completely normalized by UnAG treatment. Importantly, these findings were associated with a recovery of gastrocnemious muscle mass. While a specific receptor for UnAG needs to be identified, our combined findings consistently point towards a novel independent role of UnAG as a regulator of muscle metabolic pathways maintaining energy status and tissue anabolism. Underlying mechanism appear to involve the modulation of mitochondrial function with reduced ROS generation, which could be mediated at least in part by autophagy induction. Data from disease models also suggests that modulation of ghrelin acylation to enhance UnAG availability is a potential novel target in the treatment of metabolic derangements in disease states characterized by metabolic and nutritional complications.

Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy., Cell-based screening assays allow functional testing of chemicals but do not mimic the in vivo situation well. Here, the authors report a method for the discovery of secreted cytoprotective factors in mice and use it to demonstrate that the hormone ghrelin protects cardiac muscle from ischaemic damage.

BACKGROUND: Obesity [Body Mass Index (BMI) > 30 kg/m2] is a risk factor for disease conditions enhancing hospitalization and mortality risks, but higher BMI was paradoxically reported to reduce mortality in several acute and chronic diseases. Unintentional weight loss (WL) is conversely associated with disease development and may worsen patient outcome, but the impact of weight loss and its interaction with obesity in modulating risk of death in hospitalized patients remain undefined. METHODS: We investigated the ESPEN nutritionDay database of non-critically ill hospitalized patients to assess the impact of self-reported 3-month WL (WL1:2.5-6.6%; WL2: 6.6-12.6%, WL3: >12.6%) and its interaction with BMI in modulating 30-day in-hospital mortality. Multivariate Cox regression was used to estimate hazard ratios (HR), with stable weight (WL0) as reference category. RESULTS: In 110835 nDay patients, 30-day mortality increased with increasing WL. Male gender, increasing disease severity index PANDORA score (age, nutrient intake, mobility, fluid status, cancer and main patient group) and not having had surgery also predicted 30-day mortality. HR for 30-day mortality remained significantly higher compared to WL0 for WL2 and WL3 after multiple adjustment. Adjusted HR and its increments through increasing weight loss categories were comparable in lean (BMI30 kg/m2). Impact of gender, PANDORA score and surgery on 30-day mortality were conversely comparable in the three BMI groups. CONCLUSIONS: These results indicate that self-reported WL could represent a relevant prognostic factor in every hospitalized patient. Overweight and obesity per se have no protective impact against WL-associated mortality.