Publications by authors named "Donatella Caruso"

139 Publications

Histone Deacetylase 3 Regulates Adipocyte Phenotype at Early Stages of Differentiation.

Int J Mol Sci 2021 Aug 27;22(17). Epub 2021 Aug 27.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.

Obesity is a condition characterized by uncontrolled expansion of adipose tissue mass resulting in pathological weight gain. Histone deacetylases (HDACs) have emerged as crucial players in epigenetic regulation of adipocyte metabolism. Previously, we demonstrated that selective inhibition of class I HDACs improves white adipocyte functionality and promotes the browning phenotype of murine mesenchymal stem cells (MSCs) C3H/10T1/2 differentiated to adipocytes. These effects were also observed in and diet induced obesity mouse models and in mice with adipose-selective inactivation of HDAC3, a member of class I HDACs. The molecular basis of class I HDACs action in adipose tissue is not deeply characterized and it is not known whether the effects of their inhibition are exerted on adipocyte precursors or mature adipocytes. Therefore, the aim of the present work was to explore the molecular mechanism of class I HDAC action in adipocytes by evaluating the effects of HDAC3-specific silencing at different stages of differentiation. HDAC3 was silenced in C3H/10T1/2 MSCs at different stages of differentiation to adipocytes. shRNA targeting HDAC3 was used to generate the knock-down model. Proper HDAC3 silencing was assessed by measuring both mRNA and protein levels of mouse HDAC3 via qPCR and western blot, respectively. Mitochondrial DNA content and gene expression were quantified via qPCR. HDAC3 silencing at the beginning of differentiation enhanced adipocyte functionality by amplifying the expression of genes regulating differentiation, oxidative metabolism, browning and mitochondrial activity, starting from 72 h after induction of differentiation and silencing. Insulin signaling was enhanced as demonstrated by increased AKT phosphorylation following HDAC3 silencing. Mitochondrial content/density did not change, while the increased expression of the transcriptional co-activator suggests the observed phenotype was related to enhanced mitochondrial activity, which was confirmed by increased maximal respiration and proton leak linked to reduced coupling efficiency. Moreover, the expression of pro-inflammatory markers increased with HDAC3 early silencing. To the contrary, no differences in terms of gene expression were found when HDAC3 silencing occurred in terminally differentiated adipocyte. Our data demonstrated that early epigenetic events mediated by class I HDAC inhibition/silencing are crucial to commit adipocyte precursors towards the above-mentioned metabolic phenotype. Moreover, our data suggest that these effects are exerted on adipocyte precursors.
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http://dx.doi.org/10.3390/ijms22179300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430751PMC
August 2021

Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis.

Psychoneuroendocrinology 2021 Oct 21;132:105364. Epub 2021 Jul 21.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105364DOI Listing
October 2021

PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism.

Int J Mol Sci 2021 Jun 27;22(13). Epub 2021 Jun 27.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states.
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http://dx.doi.org/10.3390/ijms22136913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268830PMC
June 2021

Elovl5 is required for proper action potential conduction along peripheral myelinated fibers.

Glia 2021 Oct 17;69(10):2419-2428. Epub 2021 Jun 17.

Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Italy.

Elovl5 elongates fatty acids with 18 carbon atoms and in cooperation with other enzymes guarantees the normal levels of very long-chain fatty acids, which are necessary for a proper membrane structure. Action potential conduction along myelinated axons depends on structural integrity of myelin, which is maintained by a correct amount of fatty acids and a proper interaction between fatty acids and myelin proteins. We hypothesized that in Elovl5 mice, the lack of elongation of Elovl5 substrates might cause alterations of myelin structure. The analysis of myelin ultrastructure showed an enlarged periodicity with reduced G-ratio across all axonal diameters. We hypothesized that the structural alteration of myelin might affect the conduction of action potentials. The sciatic nerve conduction velocity was significantly reduced without change in the amplitude of the nerve compound potential, suggesting a myelin defect without a concomitant axonal degeneration. Since Elovl5 is important in attaining normal amounts of polyunsaturated fatty acids, which are the principal component of myelin, we performed a lipidomic analysis of peripheral nerves of Elovl5-deficient mice. The results revealed an unbalance, with reduction of fatty acids longer than 18 carbon atoms relative to shorter ones. In addition, the ratio of saturated to unsaturated fatty acids was strongly increased. These findings point out the essential role of Elovl5 in the peripheral nervous system in supporting the normal structure of myelin, which is the key element for a proper conduction of electrical signals along myelinated nerves.
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http://dx.doi.org/10.1002/glia.24048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453547PMC
October 2021

Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target.

J Med Chem 2021 04 12;64(8):4553-4566. Epub 2021 Apr 12.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.

Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine -methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154553PMC
April 2021

Alginate coating modifies the biological effects of cerium oxide nanoparticles to the freshwater bivalve Dreissena polymorpha.

Sci Total Environ 2021 Jun 4;773:145612. Epub 2021 Feb 4.

Department of Biosciences, Università degli Studi di Milano, Italy.

The adsorption of biomacromolecules is a fundamental process that can alter the behaviour and adverse effects of nanoparticles (NPs) in natural systems. While the interaction of NPs with natural molecules present in the environment has been described, their biological impacts are largely unknown. Therefore, this study aims to provide a first evidence of the influence of biomolecules sorption on the toxicity of cerium oxide nanoparticles (CeONPs) towards the freshwater bivalve Dreissena polymorpha. To this aim, we compared naked CeONPs and coated with alginate and chitosan, two polysaccharides abundant in aquatic environments. Mussels were exposed to the three CeONPs (naked, chitosan- and alginate-coated) up to 14 days at 100 μg L, which is a concentration higher than the environmental one predicted for this type of NP. A suite of biomarkers related to oxidative stress and energy metabolism was applied, and metabolomics was also carried out to identify metabolic pathways potentially targeted by CeONPs. Results showed that the coating with chitosan reduced NP aggregation and increased the stability in water. Nonetheless, the Ce accumulation in mussels was similar in all treatments. As for biological effects, all three types of CeONPs reduced significantly the level of reactive oxygen species and the activity of superoxide dismutase, glutathione peroxidase and glutathione-S-transferase. The effect was more pronounced in individuals exposed to CeONPs coated with alginate, which also significantly induced the activity of the electron transport system. Metabolomics analysis of amino acid metabolism showed modulation only in mussels treated with CeONPs coated with alginate. In this group, 25 metabolites belonging to nucleotides, lipids/sterols and organic osmolytes were also modulated, suggesting that the nanoparticles affect energetic metabolism and osmoregulation of mussels. This study highlights the key role of the interaction between nanoparticles and natural molecules as a driver of nanoparticle ecotoxicity.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145612DOI Listing
June 2021

Zc3h10 regulates adipogenesis by controlling translation and F-actin/mitochondria interaction.

J Cell Biol 2021 03;220(3)

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.

The commitment of mesenchymal stem cells to preadipocytes is stimulated by hormonal induction. Preadipocytes induced to differentiate repress protein synthesis, remodel their cytoskeleton, and increase mitochondrial function to support anabolic pathways. These changes enable differentiation into mature adipocytes. Our understanding of the factors that coordinately regulate the early events of adipocyte differentiation remains incomplete. Here, by using multipronged approaches, we have identified zinc finger CCCH-type containing 10 (Zc3h10) as a critical regulator of the early stages of adipogenesis. Zc3h10 depletion in preadipocytes resulted in increased protein translation and impaired filamentous (F)-actin remodeling, with the latter detrimental effect leading to mitochondrial and metabolic dysfunction. These defects negatively affected differentiation to mature adipocytes. In contrast, Zc3h10 overexpression yielded mature adipocytes with remarkably increased lipid droplet size. Overall, our study establishes Zc3h10 as a fundamental proadipogenic transcription factor that represses protein synthesis and promotes F-actin/mitochondria dynamics to ensure proper energy metabolism and favor lipid accumulation.
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http://dx.doi.org/10.1083/jcb.202003173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879490PMC
March 2021

Gut Microbiota Functional Dysbiosis Relates to Individual Diet in Subclinical Carotid Atherosclerosis.

Nutrients 2021 Jan 21;13(2). Epub 2021 Jan 21.

Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, 20125 Milan, Italy.

Gut Microbiota (GM) dysbiosis associates with Atherosclerotic Cardiovascular Diseases (ACVD), but whether this also holds true in subjects without clinically manifest ACVD represents a challenge of personalized prevention. We connected exposure to diet (self-reported by food diaries) and markers of Subclinical Carotid Atherosclerosis (SCA) with individual taxonomic and functional GM profiles (from fecal metagenomic DNA) of 345 subjects without previous clinically manifest ACVD. Subjects without SCA reported consuming higher amounts of cereals, starchy vegetables, milky products, yoghurts and bakery products versus those with SCA (who reported to consume more mechanically separated meats). The variety of dietary sources significantly overlapped with the separations in GM composition between subjects without SCA and those with SCA (RV coefficient between nutrients quantities and microbial relative abundances at genus level = 0.65, -value = 0.047). Additionally, specific bacterial species ( in the absence of SCA and in the presence of SCA) are directly related to over-representation of metagenomic pathways linked to different dietary sources (sulfur oxidation and starch degradation in absence of SCA, and metabolism of amino acids, syntheses of palmitate, choline, carnitines and Trimethylamine -oxide in presence of SCA). These findings might contribute to hypothesize future strategies of personalized dietary intervention for primary CVD prevention setting.
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http://dx.doi.org/10.3390/nu13020304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911134PMC
January 2021

"The Loss of Golden Touch": Mitochondria-Organelle Interactions, Metabolism, and Cancer.

Cells 2020 11 21;9(11). Epub 2020 Nov 21.

DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milano, Italy.

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells' biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.
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http://dx.doi.org/10.3390/cells9112519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700504PMC
November 2020

Investigating metabolism by mass spectrometry: From steady state to dynamic view.

J Mass Spectrom 2021 Jan 20;56(1):e4658. Epub 2020 Oct 20.

DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, 20133, Italy.

Metabolism is the set of life-sustaining reactions in organisms. These biochemical reactions are organized in metabolic pathways, in which one metabolite is converted through a series of steps catalyzed by enzymes in another chemical compound. Metabolic reactions are categorized as catabolic, the breaking down of metabolites to produce energy, and/or anabolic, the synthesis of compounds that consume energy. The balance between catabolism of the preferential fuel substrate and anabolism defines the overall metabolism of a cell or tissue. Metabolomics is a powerful tool to gain new insights contributing to the identification of complex molecular mechanisms in the field of biomedical research, both basic and translational. The enormous potential of this kind of analyses consists of two key aspects: (i) the possibility of performing so-called targeted and untargeted experiments through which it is feasible to verify or formulate a hypothesis, respectively, and (ii) the opportunity to run either steady-state analyses to have snapshots of the metabolome at a given time under different experimental conditions or dynamic analyses through the use of labeled tracers. In this review, we will highlight the most important practical (e.g., different sample extraction approaches) and conceptual steps to consider for metabolomic analysis, describing also the main application contexts in which it is used. In addition, we will provide some insights into the most innovative approaches and progress in the field of data analysis and processing, highlighting how this part is essential for the proper extrapolation and interpretation of data.
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http://dx.doi.org/10.1002/jms.4658DOI Listing
January 2021

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenesis in subcutaneous adipose tissue.

Redox Biol 2020 09 9;36:101633. Epub 2020 Jul 9.

Department Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy. Electronic address:

Low-protein/high-carbohydrate (LPHC) diet has been suggested to promote metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1-and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.
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http://dx.doi.org/10.1016/j.redox.2020.101633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358542PMC
September 2020

Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons.

Cells 2020 08 11;9(8). Epub 2020 Aug 11.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.

Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain.
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http://dx.doi.org/10.3390/cells9081874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465687PMC
August 2020

Glial cell activation and altered metabolic profile in the spinal-trigeminal axis in a rat model of multiple sclerosis associated with the development of trigeminal sensitization.

Brain Behav Immun 2020 10 10;89:268-280. Epub 2020 Jul 10.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. Electronic address:

Trigeminal neuralgia is often an early symptom of multiple sclerosis (MS), and it generally does not correlate with the severity of the disease. Thus, whether it is triggered simply by demyelination in specific central nervous system areas is currently questioned. Our aims were to monitor the development of spontaneous trigeminal pain in an animal model of MS, and to analyze: i) glial cells, namely astrocytes and microglia in the central nervous system and satellite glial cells in the trigeminal ganglion, and ii) metabolic changes in the trigeminal system. The subcutaneous injection of recombinant MOG protein fragment to Dark Agouti male rats led to the development of relapsing-remitting EAE, with a first peak after 13 days, a remission stage from day 16 and a second peak from day 21. Interestingly, orofacial allodynia developed from day 1 post injection, i.e. well before the onset of EAE, and worsened over time, irrespective of the disease phase. Activation of glial cells both in the trigeminal ganglia and in the brainstem, with no signs of demyelination in the latter tissue, was observed along with metabolic alterations in the trigeminal ganglion. Our data show, for the first time, the spontaneous development of trigeminal sensitization before the onset of relapsing-remitting EAE in rats. Additionally, pain is maintained elevated during all stages of the disease, suggesting the existence of parallel mechanisms controlling motor symptoms and orofacial pain, likely involving glial cell activation and metabolic alterations which can contribute to trigger the sensitization of sensory neurons.
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http://dx.doi.org/10.1016/j.bbi.2020.07.001DOI Listing
October 2020

Lipidomic analysis of cancer cells cultivated at acidic pH reveals phospholipid fatty acids remodelling associated with transcriptional reprogramming.

J Enzyme Inhib Med Chem 2020 Dec;35(1):963-973

Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.

Cancer cells need to modulate the biosynthesis of membrane lipids and fatty acids to adapt themselves to an accelerated rate of cell division and survive into an extracellular environment characterised by a low pH. To gain insight this crucial survival process, we investigated the lipid composition of Mel 501 melanoma cells cultured at either physiological or acidic pH and observed the remodelling of phospholipids towards longer and more unsaturated acyl chains at low pH. This modification was related to changes in gene expression profile, as we observed an up-regulation of genes involved in acyl chain desaturation, elongation and transfer to phospholipids. PC3 prostate and MCF7 breast cancer cells adapted at acidic pH also demonstrated phospholipid fatty acid remodelling related to gene expression changes. Overall findings clearly indicate that low extracellular pH impresses a specific lipid signature to cells, associated with transcriptional reprogramming.
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http://dx.doi.org/10.1080/14756366.2020.1748025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191909PMC
December 2020

Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids.

Mol Metab 2020 02 24;32:97-108. Epub 2019 Dec 24.

Department of Pharmaceutical Sciences, University of Milan, Italy; Center of Excellence on Neurodegenerative Diseases, University of Milan, Italy. Electronic address:

Objective: Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract this pathology might strongly rely on estrogen signaling. In female mammals, estrogen receptor alpha (ERα) is highly expressed in the liver, where it acts as a sensor of the nutritional status and adapts the metabolism to the reproductive needs. As in the male liver this receptor is little expressed, we here hypothesize that hepatic ERα might account for sex differences in the ability of males and females to cope with an excess of dietary lipids and counteract the accumulation of lipids in the liver.

Methods: Through liver metabolomics and transcriptomics we analyzed the relevance of hepatic ERα in the metabolic response of males and females to a diet highly enriched in fats (HFD) as a model of diet-induced obesity.

Results: The study shows that the hepatic ERα strongly contributes to the sex-specific response to an HFD and its action accounts for opposite consequences for hepatic health in males and females.

Conclusion: This study identified hepatic ERα as a novel target for the design of sex-specific therapies against fatty liver and its cardio-metabolic consequences.
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http://dx.doi.org/10.1016/j.molmet.2019.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957843PMC
February 2020

L. Phytosome Improves Cognitive Performance by Promoting Bdnf Expression in Rat Prefrontal Cortex.

Nutrients 2020 Jan 29;12(2). Epub 2020 Jan 29.

Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.

A wide range of people in the world use natural remedies as primary approaches against illnesses. Accordingly, understanding the mechanisms of action of phytochemicals has become of great interest. In this context, L. is extensively used, not only as anti-inflammatory or antioxidant agent but also as brain tonic. On this basis, the purpose of this study was to evaluate whether the chronic administration of L. to adult male rats was able to improve the expression of , one of the main mediators of brain plasticity. Moreover, we assessed whether the treatment could affect the cognitive performance in the novel object recognition (NOR) test. We confirmed the presence of the main compounds in the plasma. Furthermore, L. administration induced an increase of in the prefrontal cortex, and the administration of the higher dose of the extract was able to improve cognitive performance. Finally, the increase in the preference index in the NOR test was paralleled by a further increase in expression. Overall, we highlight the ability of L. to affect brain functions by increasing expression and by enhancing the cognitive performance.
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http://dx.doi.org/10.3390/nu12020355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071263PMC
January 2020

Inhibition of class I HDACs imprints adipogenesis toward oxidative and brown-like phenotype.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 04 2;1865(4):158594. Epub 2020 Jan 2.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

Obesity is characterized by uncontrolled expansion of adipose tissue mass, resulting in adipocyte hypertrophy (increased adipocyte size) and hyperplasia (increased number of adipocytes). The number of adipose cells is directly related to adipocyte differentiation process from stromal vascular cells to mature adipocytes. It is known that epigenetic factors influence adipose differentiation program. However, how specific epigenome modifiers affect white adipocyte differentiation and metabolic phenotype is still matter of research. Here, we provide evidence that class I histone deacetylases (HDACs) are involved both in the differentiation of adipocytes and in determining the metabolic features of these cells. We demonstrate that inhibition of class I HDACs from the very first stage of differentiation amplifies the differentiation process and imprints cells toward a highly oxidative phenotype. These effects are related to the capacity of the inhibitor to modulate H3K27 acetylation on enhancer regions regulating Pparg and Ucp1 genes. These epigenomic modifications result in improved white adipocyte functionality and metabolism and induce browning. Collectively, our results show that modulation of class I HDAC activity regulates the metabolic phenotype of white adipocytes via epigenetic imprinting on a key histone mark.
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http://dx.doi.org/10.1016/j.bbalip.2019.158594DOI Listing
April 2020

Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid.

J Clin Med 2019 Dec 24;9(1). Epub 2019 Dec 24.

Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

Given to its ability to irreversibly acetylate the platelet cyclooxygenase-1 enzyme, acetylsalicylic acid (ASA) is successfully employed for the prevention of cardiovascular disease. Recently, an antitumoral effect of ASA in colorectal cancer has been increasingly documented. However, the molecular and metabolic mechanisms by which ASA exerts such effect is largely unknown. Using a new, untargeted liquid chromatography-mass spectrometry approach, we have analyzed urine samples from seven healthy participants that each ingested 100 mg of ASA once daily for 1 week. Of the 2007 features detected, 25 metabolites differing after ASA ingestion (nominal < 0.05 and variable importance in projection (VIP) score > 1) were identified, and pathway analysis revealed low levels of glutamine and of metabolites involved in histidine and purine metabolisms. Likewise, consistent with an altered fatty acid -oxidation process, a decrease in several short- and medium-chain acyl-carnitines was observed. An abnormal -oxidation and a lower than normal glutamine availability suggests reduced synthesis of acetyl-Co-A, as they are events linked to one another and experimentally related to ASA antiproliferative effects. While giving an example of how untargeted metabolomics allows us to explore new clinical applications of drugs, the present data provide a direction to be pursued to test the therapeutic effects of ASA-e.g., the antitumoral effect-beyond cardiovascular protection.
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http://dx.doi.org/10.3390/jcm9010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020007PMC
December 2019

A Case Report of Accidental Intoxication following Ingestion of Foxglove Confused with Borage: High Digoxinemia without Major Complications.

Case Rep Cardiol 2019 29;2019:9707428. Epub 2019 Nov 29.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, Milan, Italy.

Foxglove ( L.) leaves are frequently confused with borage ( L.), which is traditionally used as a food ingredient. Due to the presence of the cardiac glycosides, mostly digitoxin, foxglove leaves are poisonous to human and may be fatal if ingested. A 55-year-old Caucasian woman complaining weakness, fatigue, nausea, and vomiting was admitted to the Emergency Department. Her symptoms started following consumption of a home-made savory pie with 5 leaves from a plant bought in a garden nursery as borage. Digoxinemia was high (10.4 g/L). The patient was admitted to the cardiac intensive care unit for electrocardiographic monitoring. Two days after admission, a single episode of advanced atrioventricular (AV) block was recorded by telemetry, followed by a second-degree AV block episode. Plasma samples at day 11 were analysed by LC-MS spectrometry, and gitoxin was identified suggesting that this compound may be responsible for the clinical toxicity rather than digoxin. In the case of spp. poisoning, laboratory data should be interpreted according to the clinical picture and method of analysis used since a variety of glycosides, which are chemically similar to the cardioactive glycosides but without or with fewer cardiac effects, may be incorrectly recognized as digoxin by the test, giving misleading results.
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http://dx.doi.org/10.1155/2019/9707428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906804PMC
November 2019

Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role.

Front Neuroendocrinol 2020 01 2;56:100804. Epub 2019 Nov 2.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

The nervous system, in addition to be a target for steroid hormones, is the source of a variety of neuroactive steroids, which are synthesized and metabolized by neurons and glial cells. Recent evidence indicates that the expression of neurosteroidogenic proteins and enzymes and the levels of neuroactive steroids are different in the nervous system of males and females. We here summarized the state of the art of neuroactive steroids, particularly taking in consideration sex differences occurring in the synthesis and levels of these molecules. In addition, we discuss the consequences of sex differences in neurosteroidogenesis for the function of the nervous system under healthy and pathological conditions and the implications of neuroactive steroids and neurosteroidogenesis for the development of sex-specific therapeutic interventions.
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http://dx.doi.org/10.1016/j.yfrne.2019.100804DOI Listing
January 2020

DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering.

Nat Commun 2019 10 25;10(1):4887. Epub 2019 Oct 25.

Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.
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http://dx.doi.org/10.1038/s41467-019-12640-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814737PMC
October 2019

Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry.

Nutrients 2019 Oct 17;11(10). Epub 2019 Oct 17.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italia.

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid β-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. β-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.
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http://dx.doi.org/10.3390/nu11102497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836190PMC
October 2019

Mitochondrial dysfunction increases fatty acid β-oxidation and translates into impaired neuroblast maturation.

FEBS Lett 2019 11 31;593(22):3173-3189. Epub 2019 Aug 31.

Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy.

The metabolic transition from anaerobic glycolysis and fatty acid β-oxidation to glycolysis coupled to oxidative phosphorylation is a key process for the transition of quiescent neural stem cells to proliferative neural progenitor cells. However, a full characterization of the metabolic shift and the involvement of mitochondria during the last step of neurogenesis, from neuroblasts to neuron maturation, is still elusive. Here, we describe a model of neuroblasts, Neuro2a cells, with impaired differentiation capacity due to mitochondrial dysfunction. Using a detailed biochemical characterization consisting of steady-state metabolomics and metabolic flux analysis, we find increased fatty acid β-oxidation as a peculiar feature of neuroblasts with altered mitochondria. The consequent metabolic switch favors neuroblast proliferation at the expense of neuron maturation.
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http://dx.doi.org/10.1002/1873-3468.13584DOI Listing
November 2019

HPTLC-PCA Complementary to HRMS-PCA in the Case Study of Antioxidant Phenolic Profiling.

Foods 2019 Jul 27;8(8). Epub 2019 Jul 27.

Department of Chemistry and Pharmacy, University of Sassari, Via F. Muroni, 23/b, 07100 Sassari, Italy.

A comparison between High-Performance Thin-Layer Chromatography (HPTLC) analysis and Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS), coupled with Principal Component Analysis (PCA) was carried out by performing a combined metabolomics study to discriminate () plants. For a rapid digital record of extracts (leaves, yellow fruit, and red fruit collected in La Maddalena and Sassari, Sardinia), HPTLC was used. Data were then analysed by PCA with the results of the ability of this technique to discriminate samples. Similarly, extracts were acquired by non-targeted LC-HRMS followed by unsupervised PCA, and then by LC-HRMS (MS) to identify secondary metabolites involved in the differentiation of the samples. As a result, we demonstrated that HPTLC may be applied as a simple and reliable untargeted approach to rapidly discriminate extracts based on tissues and/or geographical origins, while LC-HRMS could be used to identify which metabolites are able to discriminate samples.
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http://dx.doi.org/10.3390/foods8080294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723518PMC
July 2019

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study.

Endocr Connect 2019 Aug;8(8):1118-1125

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Context: Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear.

Objective: To study whether epigenetic modifications occur in PFS patients.

Methods: Retrospective analysis of a multicentric, prospective, longitudinal, case-control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples.

Results: SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects.

Conclusions: For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.
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http://dx.doi.org/10.1530/EC-19-0199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652249PMC
August 2019

Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.

Parkinsonism Relat Disord 2019 06 7;63:191-194. Epub 2019 Mar 7.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

Introduction: Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study.

Methods: Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3.

Results: We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded.

Conclusions: Long-term DHA supplementation is an eligible treatment for SCA38.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.040DOI Listing
June 2019

High-Density Lipoprotein Function Is Reduced in Patients Affected by Genetic or Idiopathic Hypogonadism.

J Clin Endocrinol Metab 2019 08;104(8):3097-3107

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Context: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk. In particular, the assessment of the functional capacities of high-density lipoproteins (HDLs) may provide insights besides traditional risk factors.

Design: To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol (HDL-C) efflux capacity (CEC) and serum cholesterol loading capacity (CLC).

Participants: Genetic and idiopathic hypogonadal patients (n = 20) and control subjects (n = 17).

Results: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP-binding cassette transporter G1 (ABCG1)-, and aqueous diffusion-mediated CEC (-19.6%, -40.9%, and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2 = 0.359, P = 0.0001) and ABCG1 HDL CEC (r2 = 0.367, P = 0.0001) were observed. Conversely, serum CLC was markedly raised (+43%) in hypogonadals, increased, to a higher extent, in primary vs secondary hypogonadism (18.45 ± 2.78 vs 15.15 ± 2.10 µg cholesterol/mg protein) and inversely correlated with testosterone levels (r2 = 0.270, P = 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1, and ABCA1) or serum CLC.

Conclusions: In hypogonadal patients, proatherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.
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http://dx.doi.org/10.1210/jc.2018-02027DOI Listing
August 2019

Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.

Cancer Chemother Pharmacol 2019 03 12;83(3):493-500. Epub 2018 Dec 12.

Servizio di Farmacologia Clinica, Dipartimento di Medicina, Università di Padova, Padua, Italy.

Purpose: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms.

Methods: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints.

Results: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms.

Conclusions: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.
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http://dx.doi.org/10.1007/s00280-018-3751-0DOI Listing
March 2019

Interplay between Plasmodium falciparum haemozoin and L-arginine: implication for nitric oxide production.

Malar J 2018 Dec 6;17(1):456. Epub 2018 Dec 6.

Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, 20133, Milan, MI, Italy.

Background: Plasmodium falciparum haemozoin, a detoxification product of digested haemoglobin from infected erythrocytes, is released into the bloodstream upon schizont rupture and accumulates in leukocytes. High levels of haemozoin correlate with disease severity. Some studies have shown that concentrations of the substrate of inducible nitric oxide synthase (iNOS), L-arginine, as well as nitric oxide are low in patients infected with P. falciparum malaria. The present study investigates, in vitro, the role of P. falciparum haemozoin on nitric oxide production, iNOS expression in macrophages, and the possible interaction between L-arginine and haemozoin.

Methods: Plasmodium falciparum haemozoin was obtained from in vitro cultures through magnetic isolation. Phagocytosis of haemozoin by immortalized bone marrow derived macrophages was detected by confocal reflection combined with fluorescence microscopy. Nitrite concentrations in the supernatants was evaluated by Griess assay as a standard indication of nitric oxide production, while iNOS expression was detected on cell extracts by western blotting. Detection of L-arginine in haemozoin-treated or untreated media was achieved by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: Haemozoin synergizes in vitro with interferon-gamma to produce nitric oxide. However, when mouse macrophages were stimulated with haemozoin, a proportional increase of nitric oxide was observed up to 25 μM of haemozoin, followed by a decrease with doses up to 100 μM, when nitric oxide release was completely abrogated. This was not due to reactive oxygen species production, nor to an effect on iNOS activity. Interestingly, when at 24 h, haemozoin-treated macrophages were washed and incubated in fresh medium for further 24 h, the nitric oxide production was restored in a dose-response manner. Similar results were seen when L-arginine-enriched media was used in the stimulation. Moreover, muramyldipeptide, a strong nitric oxide inducer, was unable to activate macrophages to release nitric oxide in the presence of haemozoin-treated medium. By LC-MS/MS a complete depletion of L-arginine was observed in this haemozoin-treated, conditioned medium.

Conclusions: It is proposed that haemozoin interacts with L-arginine reducing its availability for iNOS, and thus decreasing nitric oxide production. The clinical (or pathological) implications of these results are discussed.
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http://dx.doi.org/10.1186/s12936-018-2602-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282336PMC
December 2018

Enhanced axonal neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model.

Hum Mol Genet 2019 03;28(6):992-1006

DIBIT, Divisions of Genetics and Cell Biology.

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.
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http://dx.doi.org/10.1093/hmg/ddy411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400047PMC
March 2019
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