Novel NMR-Based Approach to Reveal the 'Metabolic Fingerprint' of Cytotoxic Gold Drugs in Cancer Cells.

A combination of pathway enrichment and metabolite clustering analysis is used to interpret untargeted H NMR metabolomics data, enabling a biochemically informative comparison of the effects induced by a panel of known cytotoxic gold(I) and gold(III) compounds in A2780 ovarian cancer cells. The identification of the most dysregulated pathways for the major classes of compounds highlights specific chemical features that lead to common biological effects. The proposed approach may have broader applicability to the screening of metal-based drug candidate libraries, which is always complicated by their multitarget nature, and support the comprehensive interpretation of their metabolic actions.

Synthesis, Chemical Characterization, and Biological Evaluation of Hydrophilic Gold(I) and Silver(I) N-Heterocyclic Carbenes as Potential Anticancer Agents.

A series of new gold(I) and silver(I) N-heterocyclic carbenes bearing a 1-thio-β-d-glucose tetraacetate moiety was synthesized and chemically characterized. The compounds' stability and solubility in physiological conditions were investigated employing a multitechnique approach. Interaction studies with biologically relevant proteins, such as superoxide dismutase (SOD) and human serum albumin (HSA), were conducted via UV-vis absorption spectroscopy and high-resolution ESI mass spectrometry.

The Multiple Roles of Lactate in the Skeletal Muscle.

Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years.

Unlocking the Power of Human Ferritin: Enhanced Drug Delivery of Aurothiomalate in A2780 Ovarian Cancer Cells.

Aurothiomalate (AuTM) is an FDA-approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP-OES analysis, using three mutant ferritins and trypsinization experiments.

Cytotoxic auranofin analogues bearing phosphine, arsine and stibine ligands: A study on the possible role of the ligand on the biological activity.

Three gold(I) linear compounds, sharing the general formula [AuI(LPh)], have been synthesized and characterized. The nature of the ligand has been modified by moving down among some of the elements of group 15, i.e.

STAT3 Signalling Drives LDH Up-Regulation and Adiponectin Down-Regulation in Cachectic Adipocytes.

Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome from murine colon carcinoma CT26 induces cachectic features in both murine and human adipocytes that are associated with metabolic alterations such as enhanced lactate production and decreased oxygen consumption. The use of oxamate, which inhibits lactate dehydrogenase activity, hinders the effects induced by CT26 secretome.

The effects of two cytotoxic gold(i) carbene compounds on the metabolism of A2780 ovarian cancer cells: mechanistic inferences through NMR analysis.

NMR metabolomics is a powerful tool to characterise the changes in cancer cell metabolism elicited by anticancer drugs. Here, the large metabolic alterations produced by two cytotoxic gold carbene compounds in A2780 ovarian cancer cells are described and discussed in comparison to auranofin, in the frame of the available mechanistic knowledge.

A complex bearing TSPO PIGA ligand coordinated to the [Au(PEt)] pharmacophore is highly cytotoxic against ovarian cancer cells.

Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target.

Cellular Contact Guidance on Liquid Crystalline Networks with Anisotropic Roughness.

Cell contact guidance is widely employed to manipulate cell alignment and differentiation . The use of nano- or micro-patterned substrates allows efficient control of cell organization, thus opening up to biological models that cannot be reproduced spontaneously on standard culture dishes. In this paper, we explore the concept of cell contact guidance by Liquid Crystalline Networks (LCNs) presenting different surface topographies obtained by self-assembly of the monomeric mixture.

Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues.

A panel of four novel gold(I) complexes, inspired by the clinically established gold drug auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate), was prepared and characterized. All these compounds feature the replacement of the triethylphosphine ligand of the parent compound auranofin with a trimethylphosphite ligand. The linear coordination around the gold(I) center is completed by Cl, Br, I or by the thioglucose tetraacetate ligand (SAtg).

Pyruvate prevents the onset of the cachectic features and metabolic alterations in myotubes downregulating STAT3 signaling.

Cachexia is a systemic disease associated with several pathologies, including cancer, that leads to excessive weight loss due to enhanced protein degradation. Previously, we showed that cachectic features in myotubes are provoked by a metabolic shift toward lactic fermentation. Our previous results led us to hyphotesise that increasing pyruvate concentration could impede the metabolic modifications responsible for induction of cachexia in myotubes.

S1P Signalling Axis Is Necessary for Adiponectin-Directed Regulation of Electrophysiological Properties and Oxidative Metabolism in C2C12 Myotubes.

Background: Adiponectin (Adn), released by adipocytes and other cell types such as skeletal muscle, has insulin-sensitizing and anti-inflammatory properties. Sphingosine 1-phosphate (S1P) is reported to act as effector of diverse biological actions of Adn in different tissues. S1P is a bioactive sphingolipid synthesized by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK) 1 and 2.

Cell instructive Liquid Crystalline Networks for myotube formation.

Development of biological tissues is not a trivial task and requires the correct maturation of the selected cell line. To this aim, many attempts were done mainly by mimicking the biological environment using micro/nanopatterned or stimulated scaffolds. However, the obtainment of functional tissues is still far from being achieved.

A Metabolic Change towards Fermentation Drives Cancer Cachexia in Myotubes.

Cachexia is a disorder associated with several pathologies, including cancer. In this paper, we describe how cachexia is induced in myotubes by a metabolic shift towards fermentation, and the block of this metabolic modification prevents the onset of the cachectic phenotype. Cachectic myotubes, obtained by the treatment with conditioned medium from murine colon carcinoma cells CT26, show increased glucose uptake, decreased oxygen consumption, altered mitochondria, and increased lactate production.

The Adipokines in Cancer Cachexia.

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines.

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib.

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER)/human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib.

Oxidative stress in exercise training: the involvement of inflammation and peripheral signals.

The evidence about the health benefits of regular physical activity is well established. Exercise intensity is a significant variable and structured high-intensity interval training (HIIT) has been demonstrated to improve both whole-body and skeletal muscle metabolic health in different populations. Conversely, fatigue accumulation, if not resolved, leads to overwork, chronic fatigue syndrome (CFS), overtraining syndrome up to alterations of endocrine function, immune, systemic inflammation, and organic diseases with health threat.

Role of adiponectin in the metabolism of skeletal muscles in collagen VI-related myopathies.

The role of adiponectin has been particularly deepened in diabetic muscles while the study of adiponectin in hereditary myopathies has been marginally investigated. Here, we report the study about adiponectin effects in Col6a1 (collagen VI-null) mice. Col6a1 mice show myophatic phenotype closer to that of patients with Bethlem myopathy, thus representing an excellent animal model for the study of this hereditary disease.

Irreversible plasma and muscle protein oxidation and physical exercise.

The imbalance between the reactive oxygen (ROS) and nitrogen (RNS) species production and their handling by the antioxidant machinery (low molecular weight antioxidant molecules and antioxidant enzymes), also known as oxidative stress, is a condition caused by physiological and pathological processes. Moreover, oxidative stress may be due to an overproduction of free radicals during physical exercise. Excess of radical species leads to the modification of molecules, such as proteins - the most susceptible to oxidative modification - lipids and DNA.