Dual targeted 2-Benzylideneindanone pendant hydroxamic acid group exhibits selective HDAC6 inhibition along with tubulin stabilization effect.

Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.

Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets.

Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes' transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs.

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 µM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 µM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

Bovine Serum Amine Oxidase and Polyamine Analogues: Chemical Synthesis and Biological Evaluation Integrated with Molecular Docking and 3-D QSAR Studies.

Natural polyamines (PAs) are key players in cellular homeostasis by regulating cell growth and proliferation. Several observations highlight that PAs are also implicated in pathways regulating cell death. Indeed, the PA accumulation cytotoxic effect, maximized with the use of bovine serum amine oxidase (BSAO) enzyme, represents a valuable strategy against tumor progression. In the present study, along with the design, synthesis, and biological evaluation of a series of new spermine (Spm) analogues (1-23), a mixed structure-based (SB) and ligand-based (LB) protocol was applied. Binding modes of BSAO-PA modeled complexes led to clarify electrostatic and steric features likely affecting the BSAO-PA biochemical kinetics. LB and SB three-dimensional quantitative structure-activity relationship (Py-CoMFA and Py-ComBinE) models were developed by means of the 3d-qsar.com portal, and their analysis represents a strong basis for future design and synthesis of PA BSAO substrates for potential application in oxidative stress-induced chemotherapy.

trans-Dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) Complexes: In Search of New Scaffolds to Circumvent Cisplatin Resistance.

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure-activity relationships useful to face the resistance phenotype.

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles.

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI50 values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism.

Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase.

Fourteen polyamine analogues, asymmetric or symmetric substituted spermine (1-9) or methoctramine (10-14) analogues, were evaluated as potential inhibitors or substrates of two enzymes of the polyamine catabolic pathway, spermine oxidase (SMOX) and acetylpolyamine oxidase (PAOX). Compound 2 turned out to be the best substrate for PAOX, having the highest affinity and catalytic efficiency with respect to its physiological substrates. Methoctramine (10), a well-known muscarinic M2 receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (Ki = 10 nM), endowed with very good selectivity compared with SMOX (Ki=1.2 µM vs SMOX). The efficacy of methoctramine in inhibiting PAOX activity was confirmed in the HT22 cell line. Methoctramine is a very promising tool in the design of drugs targeting the polyamine catabolism pathway, both to understand the physio-pathological role of PAOX vs SMOX and for pharmacological applications, being the polyamine pathway involved in various pathologies.

Redox status in a model of cancer stem cells.

Reversible oxidation of Cys residues is a crucial element of redox homeostasis and signaling. According to a popular concept in oxidative stress signaling, the oxidation of targets of signals can only take place following an overwhelming of the cellular antioxidant capacity. This concept, however, ignores the activation of feedback mechanisms possibly leading to a paradoxical effect. In a model of cancer stem cells (CSC), stably overexpressing the TAZ oncogene, we observed that the increased formation of oxidants is associated with a globally more reduced state of proteins. Redox proteomics revealed that several proteins, capable of undergoing reversible redox transitions, are indeed more reduced while just few are more oxidized. Among the proteins more oxidized, G6PDH emerges as both more expressed and activated by oxidation. This accounts for the observed more reduced state of the NADPH/NADP+ couple. The dynamic redox flux generating this apparently paradoxical effect is rationalized in a computational system biology model highlighting the crucial role of G6PDH activity on the rate of redox transitions eventually leading to the reduction of reversible redox switches.

Exploiting the repertoire of CK2 inhibitors to target DYRK and PIM kinases.

Advantage has been taken of the relative promiscuity of commonly used inhibitors of protein kinase CK2 to develop compounds that can be exploited for the selective inhibition of druggable kinases other than CK2 itself. Here we summarize data obtained by altering the scaffold of CK2 inhibitors to give rise to novel selective inhibitors of DYRK1A and to a powerful cell permeable dual inhibitor of PIM1 and CK2. In the former case one of the new compounds, C624 (naphto [1,2-b]benzofuran-5,9-diol) displays a potency comparable to that of the first-in-class DYRK1A inhibitor, harmine, lacking however the drawback of drastically inhibiting monoamine oxidase-A (MAO-A) as harmine does. On the other hand the promiscuous CK2 inhibitor 4,5,6,7-tetrabromo-1H-benzimidazole (TBI,TBBz) has been derivatized with a sugar moiety to generate a 1-(ß-D-2'-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) compound which inhibits PIM1 and CK2 with comparably high efficacy (IC50 values<100nM) and remarkable selectivity. TDB, unlike other dual PIM1/CK2 inhibitors described in the literature is readily cell permeable and displays a cytotoxic effect on cancer cells consistent with concomitant inhibition of both its onco-kinase targets. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).

Cardiolipin drives the catalytic activity of GPX4 on membranes: Insights from the R152H mutant.

The aim of this study was to examine, in biochemical detail, the functional role of the Arg152 residue in the selenoprotein Glutathione Peroxidase 4 (GPX4), whose mutation to His is involved in Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD). Wild-type and mutated recombinant enzymes with selenopcysteine (Sec) at the active site, were purified and structurally characterized to investigate the impact of the R152H mutation on enzymatic function. The mutation did not affect the peroxidase reaction's catalytic mechanism, and the kinetic parameters were qualitatively similar between the wild-type enzyme and the mutant when mixed micelles and monolamellar liposomes containing phosphatidylcholine and its hydroperoxide derivatives were used as substrate. However, in monolamellar liposomes also containing cardiolipin, which binds to a cationic area near the active site of GPX4, including residue R152, the wild-type enzyme showed a non-canonical dependency of the reaction rate on the concentration of both enzyme and membrane cardiolipin. To explain this oddity, a minimal model was developed encompassing the kinetics of both the enzyme interaction with the membrane and the catalytic peroxidase reaction. Computational fitting of experimental activity recordings showed that the wild-type enzyme was surface-sensing and prone to "positive feedback" in the presence of cardiolipin, indicating a positive cooperativity. This feature was minimal, if any, in the mutant. These findings suggest that GPX4 physiology in cardiolipin containing mitochondria is unique, and emerges as a likely target of the pathological dysfunction in SSMD.

2-Hydroxyoleic Acid as a Self-Assembly Inducer for Anti-Cancer Drug-Centered Nanoparticles.

A potent nontoxic antitumor drug, 2-hydroxyoleic acid (6, 2OHOA) used for membrane lipid therapy, was selected as a self-assembly inducer due to its ability to form nanoparticles (NPs) in water. For this purpose, it was conjugated with a series of anticancer drugs through a disulfide-containing linker to enhance cell penetration and to secure drug release inside the cell. The antiproliferative evaluation of the synthesized NP formulations against three human tumor cell lines (biphasic mesothelioma MSTO-211H, colorectal adenocarcinoma HT-29, and glioblastoma LN-229) showed that nanoassemblies 16-22a,bNPs exhibit antiproliferative activity at micromolar and submicromolar concentrations. Furthermore, the ability of the disulfide-containing linker to promote cellular effects was confirmed for most nanoformulations. Finally, 17bNP induced intracellular ROS increase in glioblastoma LN-229 cells similarly to free drug 8, and such elevated production was decreased by pretreatment with the antioxidant N-acetylcysteine. Also, nanoformulations 18bNP and 21bNP confirmed the mechanism of action of the free drugs.

Spermine Oxidase-Substrate Electrostatic Interactions: The Modulation of Enzyme Function by Neighboring Colloidal ɣ-Fe2O3.

Protein-nanoparticle hybridization can ideally lead to novel biological entities characterized by emerging properties that can sensibly differ from those of the parent components. Herein, the effect of ionic strength on the biological functions of recombinant His-tagged spermine oxidase (i.e., SMOX) was studied for the first time. Moreover, SMOX was integrated into colloidal surface active maghemite nanoparticles (SAMNs) via direct self-assembly, leading to a biologically active nano-enzyme (i.e., SAMN@SMOX). The hybrid was subjected to an in-depth chemical-physical characterization, highlighting the fact that the protein structure was perfectly preserved. The catalytic activity of the nanostructured hybrid (SAMN@SMOX) was assessed by extracting the kinetics parameters using spermine as a substrate and compared to the soluble enzyme as a function of ionic strength. The results revealed that the catalytic function was dominated by electrostatic interactions and that they were drastically modified upon hybridization with colloidal ɣ-Fe2O3. The fact that the affinity of SMOX toward spermine was significantly higher for the nanohybrid at low salinity is noteworthy. The present study supports the vision of using protein-nanoparticle conjugation as a means to modulate biological functions.

Synthetic polyamines as potential amine oxidase inhibitors: a preliminary study.

In the last few decades, medicinal chemists have carried out extensive research on synthetic polyamines for use as anticancer drugs and multitarget-directed ligands in neurodegenerative diseases. The aim of this study was to evaluate the effect of some synthetic polyamines as inhibitors of two new potential targets, human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) and monoamine oxidases B (MAO B), enzymes involved in various multi-factorial diseases such as Alzheimer's disease. N,N'-Dibenzyl-dodecane-1,12-diamine (Bis-Bza-Diado), a newly synthesised compound, and ELP 12, a muscarinic cholinergic M(2) receptor antagonist, were found to behave as reversible and mixed non-competitive inhibitors of both amine oxidases (dissociation constants of about 100 µM). ELP 12 was found to be more selective for SSAO/VAP-1. Combining kinetic and structural approaches, the binding mode of ELP 12 to SSAO/VAP-1 was investigated. ELP 12 may bind at the entrance of the active site channel by ionic interactions with ASP446 and/or ASP180; one end of the polyamine may be accommodated inside the channel, reaching the TPQ cofactor area. The binding of ELP 12 induces rearrangement of the secondary structure of the enzyme and impedes substrate entry and/or product release and catalysis. These structural data reveal that the entrance and the first part of the SSAO/VAP-1 channel may be considered as a new target area, or a "secondary binding site", for modulators of human SSAO/VAP-1 activity. These results indicate ELP 12 and Bis-Bza-Diado as new "skeletons" for the development of novel SSAO/VAP-1 and MAO B inhibitors.

Coinage Metal Compounds With 4-Methoxy-Diphenylphosphane Benzoate Ligand Inhibit Female Cancer Cell Growth.

In the continuous effort to find new metal-based compounds as alternatives to platinum-related anticancer drugs, 11th group metal phosphane compounds have been thoroughly taken into consideration. Tris-arylphosphane metal derivatives have been extensively considered as heteroleptic metal compounds exhibiting remarkable cytotoxic activities. Functional groups in the aryl moieties modulate the activity reinforcing or eliminating it. Previous works have highlighted that the presence of hydrophilic groups in the phosphane ligands, such as COOH or OH, hampers the anticancer activity of gold azolate/PPh3 compounds. To increase the polarity of the triarylphosphane ligand without affecting the activity, we considered the preparation of esters starting from the 4-diphenylphosphane-benzoic acid. The resulting phosphanes are poorer donators than the PPh3, leading to poly-phosphane M(I) compounds, and they exhibit intense emissive properties. A homologous series of L3MX-type compounds (where M = Au and X = Cl, M = Cu and X = BF4, and M = Ag and X = PF6) were obtained with the 4-methoxy-diphenylphosphane benzoate. The homologous metal compounds have been characterized by analytical and spectroscopic methods and, remarkably, their formation was associated with high frequencies of 31P NMR chemical shift variations (5-35 ppm in CDCl3). The new complexes and the ligand were evaluated on sensitive and cisplatin-resistant human tumor cell lines. The ligand is ineffective on cells while the complexes exert a notable antiproliferative effect. The homologous series of the L3MX complexes were able to significantly reduce the cell viability of human triple-negative breast cancer cells (MDA-MB-231), representing the most aggressive subtype of breast cancer, and of ovarian carcinoma (A2780). Among these coinage metal compounds, L3AgPF6 results the most interesting, showing the lowest GI50 values in all cell lines. Interestingly, this silver complex is more cytotoxic than cisplatin, taken as reference drug. The investigation of the mechanism of action of L3AgPF6 in A2780 cells highlighted the induction of the apoptotic pathway, the depolarization of the mitochondrial inner membrane, and a significant accumulation in cells.

TAT-mediated aequorin transduction: an alternative approach for effective calcium measurements in plant cells.

Cell-penetrating peptides are short cationic peptides with the property of translocating across the plasma membrane and transferring macromolecules otherwise unable to permeate cell membranes. We investigated the potential ability of the protein transduction domain derived from amino acids 47-57 of the human immunodeficiency virus type 1 (HIV-1) TAT (transactivator of transcription) protein to be used as a nanocarrier for the delivery of aequorin, a Ca(2+)-sensitive photoprotein widely used as a reliable Ca(2+) reporter in cell populations. The TAT peptide, either covalently linked to apoaequorin or ionically bound to plasmids encoding differentially targeted aequorin, was supplied to plant suspension-cultured cells. The TAT-aequorin fusion protein was found to be rapidly and effectively translocated into plant cells. The chimeric molecule was internalized in fully active biological form and at levels suitable to monitor intracellular Ca(2+) concentrations. Plant cells incubated for just 5 min with TAT-aequorin responded to different environmental stimuli with the expected Ca(2+) signatures. On the other hand, TAT-mediated plasmid internalization did not provide the necessary level of transformation efficiency to allow calibration of luminescence signals into Ca(2+) concentration values. These results indicate that TAT-mediated aequorin transduction is a promising alternative to traditional plant transformation methods to monitor intracellular Ca(2+) dynamics rapidly and effectively in plant cells.

Preliminary studies of the effects of vascular adhesion protein-1 inhibitors on experimental corneal neovascularization.

Vascular adhesion protein-1 (VAP-1) controls the adhesion of lymphocytes to endothelial cells and is upregulated at sites of inflammation. Moreover, it expresses amine oxidase activity, due to the sequence identity with semicarbazide-sensitive amine oxidase. Recent studies indicate a significant role for VAP-1 in neovascularization, besides its contribution to inflammation. Pathological blood vessel development in severe ocular diseases (such as diabetes, age-related macula degeneration, trauma and infections) might lead to decreased visual acuity and finally to blindness, yet there is no clear consensus as to its appropriate treatment. In the present case study, the effects of two VAP-1 inhibitors on experimentally induced corneal neovascularization in rabbits were compared with the effects of a known inhibitor of angiogenesis, bevacizumab, an anti-vascular endothelial growth factor antibody. In accordance with recent literature data, the results of the preliminary study reported here indicate that the administration of VAP-1 inhibitors is a potentially valuable therapeutic option in the treatment of corneal neovascularization.

Hydrogen peroxide toxicity on auditory cells: An in vitro study.

In recent decades, interest has increased in the role of reactive oxygen species (ROS) in health and disease. The ROS are key causative factors in several hearing loss pathologies including ototoxicity, noise trauma, cochlear ageing and ischemic injury. In order to investigate ROS effects on inner ear cells and counteract them, we developed an in vitro model of oxidative stress by exposing the inner ear cell line OC-k3 to hydrogen peroxide (H2O2) at concentrations able to affect in vivo cellular components but allowing cell survival. The treatment with high concentrations (20 and 30 µM) resulted in reduction of cell viability, activation of apoptosis/necrosis and alteration of morphology, cell cycle progression and antioxidant defences. The ROS effects in inner ear cells are difficult to assess in vivo. Organocultures may provide preservation of tissue architecture but involve ethical issues and can be used only for a limited time. An in vitro model that could be commercially available and easy to handle is necessary to investigate inner ear oxidative stress and the ways to counteract it. The OC-k3 line is a suitable in vitro model to study ROS effects on inner ear cells because the observed cell alterations and damages were similar to those reported in studies investigating ROS effects of ototoxic drugs, noise trauma and cochlear ageing.

Design, physico-chemical characterization and in vitro biological activity of organogold(III) glycoconjugates.

To develop new metal-based glycoconjugates as potential anticancer agents, four organometallic gold(iii)-dithiocarbamato glycoconjugates of the type [AuIII(2-Bnpy)(SSC-Inp-GlcN)](PF6) (2-Bnpy: 2-benzylpyridine; Inp: isonipecotic moiety; GlcN: amino-glucose scaffold; Au3-Au6) and the corresponding model non-glycosylated counterparts [AuIII(2-Bnpy)(SSC-Inp-R)](PF6) (R: OEt (Au1), NH2 (Au2)) have been generated and characterized by means of several analytical techniques (elemental analysis, FT-IR, 1H-/13C-NMR, ESI-MS, UV-Vis, X-ray crystallography). Their stability under physiologically-relevant conditions (PBS solution) and n-octanol/PBS distribution coefficient (D7.4) have also been evaluated. Gold(iii) glycoconjugates showed an antiproliferative effect against ovarian carcinoma A2780 cells, with GI50 values in the low micromolar range. Remarkably, their cell growth inhibitory effect increases upon the addition of a glucose transporter 1 (GLUT1) inhibitor, thus ruling out the involvement of GLUT1 in their transport inside the cell. Additional mechanistic studies have been carried out in A2780 cells, supporting the hypothesis of a facilitated diffusion mechanism (possibly mediated by glucose transporters other than GLUT1), and revealing their capability to act as topoisomerase I and II inhibitors and to disrupt mitochondrial membrane integrity, leading to the generation of ROS, thus resulting in the promotion of oxidative stress and, eventually, cell death.

Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase-B.

A library of monosubstituted chalcones (1-17) bearing electron-donating and electron-withdrawing groups on both aromatic rings were selected. The cell viability on human tumor cell lines was evaluated first. The compounds unable to induce detectable cytotoxicity (1, 13, and 14) were tested using the monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B, acting as competitive inhibitors, with 13 and 14 showing the best profiles. In particular, 13 exhibited a potency higher than that of safinamide, taken as a reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similar to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-selective inhibitors for the treatment of neurodegenerative diseases.

Dietary ω-3 Fatty Acid Supplementation Improves Murine Sickle Cell Bone Disease and Reprograms Adipogenesis.

Sickle cell disease (SCD) is a genetic disorder of hemoglobin, leading to chronic hemolytic anemia and multiple organ damage. Among chronic organ complications, sickle cell bone disease (SBD) has a very high prevalence, resulting in long-term disability, chronic pain and fractures. Here, we evaluated the effects of ω-3 (fish oil-based, FD)-enriched diet vs. ω-6 (soybean oil-based, SD)- supplementation on murine SBD. We exposed SCD mice to recurrent hypoxia/reoxygenation (rec H/R), a consolidated model for SBD. In rec H/R SS mice, FD improves osteoblastogenesis/osteogenic activity by downregulating osteoclast activity via miR205 down-modulation and reduces both systemic and local inflammation. We also evaluated adipogenesis in both AA and SS mice fed with either SD or FD and exposed to rec H/R. FD reduced and reprogramed adipogenesis from white to brown adipocyte tissue (BAT) in bone compartments. This was supported by increased expression of uncoupling protein 1(UCP1), a BAT marker, and up-regulation of miR455, which promotes browning of white adipose tissue. Our findings provide new insights on the mechanism of action of ω-3 fatty acid supplementation on the pathogenesis of SBD and strengthen the rationale for ω-3 fatty acid dietary supplementation in SCD as a complementary therapeutic intervention.