Thermogenic flux induced by lignoceric acid in peroxisomes isolated from HepG2 cells and from X- adrenoleukodystrophy and control fibroblasts

This work analyzes the thermogenic flux induced by the very long-chain fatty acid (VLCFA) lignoceric acid (C24:0) in isolated peroxisomes. Specific metabolic alterations of peroxisomes are related to a variety of disorders, the most frequent one being the neurodegenerative inherited disease X-linked adrenoleukodystrophy (X-ALD). A peroxisomal transport protein is mutated in this disorder. Due to reduced catabolism and enhanced fatty acid elongation, VLCFA accumulate in plasma and in all tissues, contributing to the clinical manifestations of this disorder. During peroxisomal metabolism, heat is produced but it is considered lost. Instead, it is a form of energy that could play a role in molecular mechanisms of this pathology and other neurodegenerative disorders. The thermogenic flux induced by lignoceric acid (C24:0) was estimated by isothermal titration calorimetry in peroxisomes isolated from HepG2 cells and from fibroblasts obtained from X-linked adrenoleukodystrophy patients and healthy subjects. Heat flux induced by lignoceric acid in HepG2 peroxisomes was exothermic, indicating normal peroxisomal metabolism. In X-ALD peroxisomes the heat flux was endothermic, indicating the requirement of heat/energy, possibly for cellular metabolism. In fibroblasts from healthy subjects the effect was less pronounced than in HepG2, a kind of cell known to have greater FA metabolism than fibroblasts. Our hypothesis is that heat is not lost but it could act a s an activator, for example on the heat-sensitive pathway related to TRVP2 receptors. To investigate this hypothesis we focused on peroxisomal metabolism, considering that impaired heat generation could contribute to the development of peroxisomal neurodegenerative disorders

Unsaturated fatty acids esterified with androgens as active and safer compounds for androgen-required therapy

Unsaturated fatty acids esterified with androgens as active and safer compounds for androgen-required therapy A. Petroni1, F. Aiello2, A. Garofalo2, S. Banni3, M. Blasevich1 and A.M. Aloisi4 [email protected], [email protected], Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita\u300 di Milano, 20133 Milano, Italy; [email protected], [email protected], Dipartimento di Farmacia e Scienze della Salute e della Nutrizione Universita\u300 della Calabria, 87036 Rende (Cs), Italy; [email protected], Dipartimento Scienze Biomediche, Universita' degli Studi Cagliari, Cittadella Universitaria, 09042 Monserrato (CA), Italy; [email protected], Dipartimento di Medicina, Chirurgia e Neuroscienze, via Aldo Moro 2, 53100 Siena, Italy Testosterone and its powerful metabolite dihydrotestosterone can be used in a variety of disorders to improve the symptoms or restore androgen plasma levels. To increase their duration and effects, androgens are administered in different pharmaceutical forms, in particular as esters of carboxylic acids. The goal of our research was to use specific unsaturated fatty acids esterified with androgens to improve the pharmaceutical characteristics of the esters as well as their biological effects and safety. Oleic acid, linoleic acid and the n-3 fatty acids, alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid, were esterified with androgens. Their cytotoxicity was evaluated in mouse NIH3T3 and human astrocyte cell lines. The esters showed good tolerability and no in vitro cytotoxic effects in both cell cultures. Due to the influence of androgens in pain processes and the common opioid- induced hypogonadism, in vivo studies were carried out to investigate their long-term administration in a pain model of persistent pain. Androgen therapy can also be required in neurodegenerative disorders, for instance in X-linked adrenoleukodystrophy, an inherited pathology. Lipid alterations are the major cause of the disorder and hypogonadism can be a secondary event. In this specific disorder and in chronic pathologies with unbalanced lipid and steroid hormone metabolism, the use of the described esters, which are more \u201cphysiological\u201d than the ones currently available, should be carefully considered

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-Type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs. awx326media1 5680039660001 The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.We thank the Medical Research Council (J.J.C., Career Development Award, G1100340), Wellcome Trust (200183/ Z/15/Z and 101054/Z/13/Z) and Arthritis Research UK (20200) for generous support and Shionogi for an academic research grant (165302). Thanks to the University of Siena for partially funding this research. J.T.B. is supported by a Research Fellowship from the Alzheimer�s Society. J.D.R. received funding from the Wellcome Trust through the London Pain Consortium and from Colciencias through a Francisco Jose de Caldas Scholarship (LASPAU, Harvard University). D.L.H.B. is a Wellcome senior clinical scientist (ref. no. 095698z/11/z and 202747/Z/16/Z) and member of the Wellcome Pain Consortium.Scopu

Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus–infected mice

Tertiary lymphoid organs (TLOs) are organized aggregates of B and T cells formed in postembryonic life in response to chronic immune responses to infectious agents or self-antigens. Although CD11c+ dendritic cells (DCs) are consistently found in regions of TLO, their contribution to TLO organization has not been studied in detail. We found that CD11chi DCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a form of TLO induced in the lungs after influenza virus infection. Elimination of DCs after the virus had been cleared from the lung resulted in iBALT disintegration and reduction in germinal center (GC) reactions, which led to significantly reduced numbers of class-switched plasma cells in the lung and bone marrow and reduction in protective antiviral serum immunoglobulins. Mechanistically, DCs isolated from the lungs of mice with iBALT no longer presented viral antigens to T cells but were a source of lymphotoxin (LT) β and homeostatic chemokines (CXCL-12 and -13 and CCL-19 and -21) known to contribute to TLO organization. Like depletion of DCs, blockade of LTβ receptor signaling after virus clearance led to disintegration of iBALT and GC reactions. Together, our data reveal a previously unappreciated function of lung DCs in iBALT homeostasis and humoral immunity to influenza virus

Esiste nei confronti del dolore una medicina di genere?

1nonenoneAloisi A.M.Aloisi, ANNA MARI