N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.

N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected.

Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation.

N-acetylaspartate (NAA) is synthesized by the mitochondrial enzyme NAT8L, which uses acetyl-CoA and aspartate as substrates. These metabolites are fundamental for bioenergetics and anabolic requirements of highly proliferating cells, thus, NAT8L modulation may impinge on the metabolic reprogramming of cancer cells. Specifically, aspartate represents a limiting amino acid for nucleotide synthesis in cancer.

Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells.

Impaired degradation of the transcriptional coactivator YAP1 and IL6ST (interleukin 6 cytokine family signal transducer), two proteins deregulated in liver cancer, has been shown to promote tumor growth. Here, we demonstrate that YAP1 and IL6ST are novel substrates of chaperone-mediated autophagy (CMA) in human hepatocellular carcinoma (HCC) and hepatocyte cell lines. Knockdown of the lysosomal CMA receptor LAMP2A increases protein levels of YAP1 and IL6ST, without changes in mRNA expression.

ROS-mediated activation of p38 protects hepatocellular carcinoma cells from caspase-independent death elicited by lysosomal damage.

Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancer in the world. Despite this, few effective drugs are available for its treatment, in part due to the development of resistance, and surgical resection remains the most valuable option, when applicable. Upregulation of anti-apoptotic proteins, downregulation of pro-apoptotic factors and the acquisition of mutations in signaling pathways leading to caspase activation are a few examples of mechanisms that allow cancer cells to evade caspase-dependent apoptosis and continue to grow.

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.

Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold.

Extracellular vesicles in endothelial cells: from mediators of cell-to-cell communication to cargo delivery tools.

Extracellular vesicles (EVs) are nanosized vesicles released from most cell types that play a key role in cell-to-cell communication by carrying DNA, non-coding RNAs, proteins and lipids out of cells. The composition of EVs depends on the cell or tissue of origin and changes according to their pathophysiological conditions, making EVs a potential circulating biomarker of disease. Additionally, the natural tropism of EVs for specific organs and cells has raised the interest in their use as delivery vehicles.

Overcoming Barriers to the Effective Management of Severe Asthma in Italy.

Introduction: People with severe asthma (SA) often have poor disease control and quality of life, and are at high risk of exacerbations, lung function decline and asthma-related death. The present expert opinion article aimed to identify unmet needs in the management of SA in Italy, and propose possible solutions to address these needs.

Methods: At five multidisciplinary events in Italy, attendees identified factors that interfered with the effective management of SA and suggested how these barriers could be overcome.

Inhibition of JNK increases the sensitivity of hepatocellular carcinoma cells to lysosomotropic drugs via LAMP2A destabilization.

Alteration of lysosomal homeostasis is common in cancer cells, which often feature an enlarged and peripheral distributed lysosomal compartment and the overexpression of cathepsins. These alterations accelerate the production of building blocks for the de novo synthesis of macromolecules and contribute to the degradation of the extracellular matrix, thus contributing to tumor growth and invasion. At the same time, they make lysosomes more fragile and more prone to lysosomal membrane permeabilization, a condition that can cause the release of proteases into the cytosol and the activation of cell death.

[Integrated and structured clinical networks. A new model of pro-active management of chronicity and sustainability].

The population ageing and the increase of the prevalence of chronicity and multimorbidity, require a multi-dimensional and long-term care system, overcaming the current vision "hospital-centered" toword a structured model, able to network services. The new organisational systemic model, named "Integrated and Structured Clinical Network", developed by a experimentation conducted in an Local Health Unit, in Tuscany, has highlighted very relevant results both for the health of the citizens taken in care, redusing the need for hospitalization, the demand for heavy diagnostics (and waiting times ), the access to the Emergency Room and the final costs of care pathways, largely the result of avoidable hospitalization! The project has been developed with the purpose of create a proactive medicine model to managing chronicity, complexity and fragility, in accordance with aims of "Population health management" and with Chronicity National Plan. The organizzational requirements of this new chronicity management model are rappresented by: - Estabilishment of multi-professional team - Multi-dimensional evaluation of clinical and social assistance needs - For each patient, definition of personalized "pro-active" PDTAs - Identification, in every AFT (Territorial Functional Aggregation ), of "expert" general practioners and provision of first-level diagnostic technologies - Identification of reference specialists - Structured reorganization of "Community of Practice" between primary care physicians and referral specialists - Design of an enabling information system to exchange of socio-health data and for the teleconsultation, telemedicine, remote control.

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents.

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Currently, the only therapeutic option for advanced HCC is Sorafenib, an inhibitor whose targets include RAF. Unexpectedly, RAF1 expression is reduced in human HCC samples.

Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression.

Autophagy is a catabolic process that cancer cells usually exploit during stress conditions to provide energy by recycling organelles and proteins. Beyond its prosurvival role, it is well accepted that occurrence of autophagy is often associated with a particular type of programmed cell death known as autophagic cell death (ACD). Dehydroepiandrosterone (DHEA) is an endogenous hormone showing anticancer properties even if the underlying mechanisms are not fully clear yet.

Alike but Different: RAF Paralogs and Their Signaling Outputs.

RAF links RAS, one of the most potent human oncogenes, to its effector ERK and to proliferation. This role is evolutionarily conserved, but while simpler multicellular organisms express one RAF, mammals have three. This Minireview highlights common and divergent features of RAF paralogs, their signaling outputs, and roles in tumorigenesis.

MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation.

Increased glycolytic flux is a common feature of many cancer cells, which have adapted their metabolism to maximize glucose incorporation and catabolism to generate ATP and substrates for biosynthetic reactions. Indeed, glycolysis allows a rapid production of ATP and provides metabolic intermediates required for cancer cells growth. Moreover, it makes cancer cells less sensitive to fluctuations of oxygen tension, a condition usually occurring in a newly established tumor environment.

Mitochondrial dysfunctions in cancer: genetic defects and oncogenic signaling impinging on TCA cycle activity.

The tricarboxylic acid (TCA) cycle is a central route for oxidative metabolism. Besides being responsible for the production of NADH and FADH2, which fuel the mitochondrial electron transport chain to generate ATP, the TCA cycle is also a robust source of metabolic intermediates required for anabolic reactions. This is particularly important for highly proliferating cells, like tumour cells, which require a continuous supply of precursors for the synthesis of lipids, proteins and nucleic acids.

Managing lipid metabolism in proliferating cells: new perspective for metformin usage in cancer therapy.

Cancer cells metabolically adapt to undergo cellular proliferation. Lipids, besides their well-known role as energy storage, represent the major building blocks for the synthesis of neo-generated membranes. There is increasing evidence that cancer cells show specific alterations in different aspects of lipid metabolism.

Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells.

Glutathione (γ-L-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant low molecular weight, thiol-containing compound within the cells and has a primary role in the antioxidant defense and intracellular signaling. Here we demonstrated that nutrient deprivation led to a significant decrease of intracellular GSH levels in three different carcinoma cell lines. This phenomenon was dependent on ABCC1-mediated GSH extrusion, along with GCL inhibition and, to a minor extent, the formation of GSH-protein mixed disulfides that synergistically contributed to the modulation of autophagy by shifting the intracellular redox state toward more oxidizing conditions.

Mitochondrial Stress Signalling: HTRA2 and Parkinson's Disease.

Mitochondria are cellular energy generators whose activity requires a continuous supply of oxygen. Recent genetic analysis has suggested that defects in mitochondrial quality control may be key factors in the development of Parkinson's disease (PD). Mitochondria have a crucial role in supplying energy to the brain, and their deterioration can affect the function and viability of neurons, contributing to neurodegeneration.

Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities.

Under the ROS…thiol network is the principal suspect for autophagy commitment.

Low molecular weight and protein sulphydryls undergo reactive oxygen species (ROS)-mediated oxidation. However, in contrast to the irreversible damages that oxidative conditions yield on biomolecules, the oxidation of reactive cysteines frequently results in reversible modifications, which represent the prototype of the molecular mechanisms underlying redox signaling. Many proteins involved in a wide range of cellular processes have been classified as “redoxsensitive,” thereby modulating their function/activity dependent on the redox state of their critical thiols.

Carcinoma cells activate AMP-activated protein kinase-dependent autophagy as survival response to kaempferol-mediated energetic impairment.

Kaempferol, a dietary cancer chemopreventive polyphenol, has been reported to trigger apoptosis in several tumor histotypes, but the mechanism underlying this phenomenon is not fully understood. Here, we demonstrate that in HeLa cells, kaempferol induces energetic failure due to inhibition of both glucose uptake and Complex I of the mitochondrial respiratory chain. As adaptive response, cells activate autophagy, the occurrence of which was established cytofluorometrically, upon acridine orange staining, and immunochemically, by following the increase of the autolysosome-associated form of the microtubule-associated protein light chain 3 (LC3-II).