Sex-dependent monoamine oxidase isoforms expression patterns during human brain ageing.

Human behavior is influenced by both genetic and environmental factors. Monoamine oxidase A (MAOA) is among the most investigated genetic determinants of violent behaviors, while the monoamine oxidase B (MAOB) is explored in Parkinson's disease. We collected twenty-four post-mortem brain tissue datasets of 3871 and 1820 non-demented males and females, respectively, who died from causes not attributable to neurodegenerative diseases. The gene expressions of MAOA and MAOB (MAO genes) were analyzed in these subjects, who were further stratified according to age into eleven groups ranging from late Infancy (5-9 months) to centenarians (>100 years). MAO genes were differently expressed in brains during the entire life span. In particular, maximal and minimal expression levels were found in early life and around the teen years. Females tended to have higher MAO gene levels throughout their lives than those found in age-matched males, even when expressions were separately measured in different brain regions. We demonstrated the existence of age- and sex- related variations in the MAO transcript levels in defined brain regions. More in-depth protein studies are needed to confirm our preliminary results obtained only on messenger RNAs in order to establish the role played by MAO genes in human development.

Focus on Osteosclerotic Progression in Primary Myelofibrosis.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.

Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib.

Iron plays a major role in multiple processes involved in cell homeostasis such as metabolism, respiration and DNA synthesis. Cancer cells exhibit pronounced iron retention as compared to healthy counterpart. This phenomenon also occurs in multiple myeloma (MM), a hematological malignancy characterized by terminally differentiated plasma cells (PCs), in which serum ferritin levels have been reported as a negative prognostic marker. The aim of current study is to evaluate the potential role of iron metabolism in promoting drug resistance in myeloma cancer cells with particular regard to the interactions between PCs and tumor-associated macrophages (TAMs) as a source of iron. Our data showed that myeloma cell lines are able to intake and accumulate iron and thus, increasing their scavenger antioxidant-related genes and mitochondrial mass. We further demonstrated that PCs pre-treated with ferric ammonium citrate (FAC) decreased bortezomib (BTZ)-induced apoptosis in vitro and successfully engrafted in zebrafish larvae treated with BTZ. Treating human macrophages with FAC, we observed a switch toward a M2-like phenotype associated with an increased expression of anti-inflammatory markers such as ARG1, suggesting the establishment of an iron-mediated immune suppressive tumor microenvironment favouring myeloma growth. Using mfap4:tomato mutant zebrafish larvae, we further confirmed the increase of PCs-monocytes interactions after FAC treatment which favour BTZ-resistance. Taken together our data support the hypothesis that targeting iron trafficking in myeloma microenvironment may represent a promising strategy to counteract a tumor-supporting milieu and drug resistance.

The Role of Inflammation and Inflammasome in Myeloproliferative Disease.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are rare hematological conditions known as myeloproliferative neoplasms (MPNs). They are characterized for being BCR-ABL negative malignancies and affected patients often present with symptoms which can significantly impact their quality of life. MPNs are characterized by a clonal proliferation of an abnormal hematopoietic stem/progenitor cell. In MPNs; cells of all myeloid lineages; including those involved in the immune and inflammatory response; may belong to the malignant clone thus leading to an altered immune response and an overexpression of cytokines and inflammatory receptors; further worsening chronic inflammation. Many of these cytokines; in particular, IL-1ß and IL-18; are released in active form by activating the inflammasome complexes which in turn mediate the inflammatory process. Despite this; little is known about the functional effects of stem cell-driven inflammasome signaling in MPN pathogenesis. In this review we focused on the role of inflammatory pathway and inflammasome in MPN diseases. A better understanding of the inflammatory-state-driving MPNs and of the role of the inflammasome may provide new insights on possible therapeutic strategies.

Role of 17ß-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells.

Gliomas are the most common primary tumors of the central nervous system (CNS) in the adult. Previous data showed that estrogen affects cancer cells, but its effect is cell-type-dependent and controversial. The present study aimed to analyze the effects of estradiol (E2, 5 nM) in human glioblastoma multiforme U87-MG cells and how it may impact on cell proliferation and mitochondrial fitness. We monitored cell proliferation by xCELLigence technology and mitochondrial fitness by assessing the expression of genes involved in mitochondrial biogenesis (PGC1α, SIRT1, and TFAM), oxidative phosphorylation (ND4, Cytb, COX-II, COX IV, NDUFA6, and ATP synthase), and dynamics (OPA1, MNF2, MNF1, and FIS1). Finally, we evaluated Nrf2 nuclear translocation by immunocytochemical analysis. Our results showed that E2 resulted in a significant increase in cell proliferation, with a significant increase in the expression of genes involved in various mechanisms of mitochondrial fitness. Finally, E2 treatment resulted in a significant increase of Nrf2 nuclear translocation with a significant increase in the expression of one of its target genes (i.e., heme oxygenase-1). Our results suggest that E2 promotes proliferation in glioblastoma cells and regulate the expression of genes involved in mitochondrial fitness and chemoresistance pathway.

Simultaneous Activation of Mu and Delta Opioid Receptors Reduces Allodynia and Astrocytic Connexin 43 in an Animal Model of Neuropathic Pain.

Neuropathic pain is a chronic condition triggered by lesions to the somatosensory nervous system in which pain stimuli occur spontaneously or as pathologically amplified responses. In this scenario, the exchange of signaling molecules throughout cell-to-cell and cell-to-extracellular environment communications plays a key role in the transition from acute to chronic pain. As such, connexin 43 (Cx43), the core glial gap junction and hemichannel-forming protein, is considered a triggering factor for disease chronicization in the central nervous system (CNS). Drugs targeting µ opioid receptors (MOR) are currently used for moderate to severe pain conditions, but their use in chronic pain is limited by the tolerability profile. δ opioid receptors (DOR) have become attractive targets for the treatment of persistent pain and have been associated with the inhibition of pain-sustaining factors. Moreover, it has been shown that simultaneous targeting of MOR and DOR leads to an improved pharmacological fingerprint. Herein, we aimed to study the effects of the benzomorphan ligand LP2, a multitarget MOR/DOR agonist, in an experimental model of neuropathic pain induced by the unilateral sciatic nerve chronic constriction injury (CCI) on male Sprague-Dawley rats. Results showed that LP2 significantly ameliorated mechanical allodynia from the early phase of treatment up to 21 days post-ligatures. We additionally showed that LP2 prevented CCI-induced Cx43 alterations and pro-apoptotic signaling in the CNS. These findings increase the knowledge of neuropathic pain development and the role of spinal astrocytic Cx43, suggesting new approaches for the treatment of neuropathic pain.

α-Lipoic Acid Reduces Iron-induced Toxicity and Oxidative Stress in a Model of Iron Overload.

Iron toxicity is associated with organ injury and has been reported in various clinical conditions, such as hemochromatosis, thalassemia major, and myelodysplastic syndromes. Therefore, iron chelation therapy represents a pivotal therapy for these patients during their lifetime. The aim of the present study was to assess the iron chelating properties of α-lipoic acid (ALA) and how such an effect impacts on iron overload mediated toxicity. Human mesenchymal stem cells (HS-5) and animals (zebrafish, n = 10 for each group) were treated for 24 h with ferric ammonium citrate (FAC, 120 µg/mL) in the presence or absence of ALA (20 µg/mL). Oxidative stress was evaluated by reduced glutathione content, reactive oxygen species formation, mitochondrial dysfunction, and gene expression of heme oxygenase-1b and mitochondrial superoxide dismutase; organ injury, iron accumulation, and autophagy were measured by microscopical, cytofluorimetric analyses, and inductively coupled plasma‒optical mission Spectrometer (ICP-OES). Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment. In conclusion, ALA possesses excellent iron chelating properties that may be exploited in a clinical setting for organ preservation, as well as exhibiting a good safety profile and low cost for the national health system.

The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

Heme Oxygenase Inhibition Sensitizes Neuroblastoma Cells to Carfilzomib.

Neuroblastoma (NB) is an embryonic malignancy affecting the physiological development of adrenal medulla and paravertebral sympathetic ganglia in early infancy. Proteasome inhibitors (PIs) (i.e., carfilzomib (CFZ)) may represent a possible pharmacological treatment for solid tumors including NB. In the present study, we tested the effect of a novel non-competitive inhibitor of heme oxygenase-1 (HO-1), LS1/71, as a possible adjuvant therapy for the efficacy of CFZ in neuroblastoma cells. Our results showed that CFZ increased both HO-1 gene expression (about 18-fold) and HO activity (about 8-fold), following activation of the ER stress pathway. The involvement of HO-1 in CFZ-mediated cytotoxicity was further confirmed by the protective effect of pharmacological induction of HO-1, significantly attenuating cytotoxicity. In addition, HO-1 selective inhibition by a specific siRNA increased the cytotoxic effect following CFZ treatment in NB whereas SnMP, a competitive pharmacological inhibitor of HO, showed no changes in cytotoxicity. Our data suggest that treatment with CFZ produces ER stress in NB without activation of CHOP-mediated apoptosis, whereas co-treatment with CFZ and LS1/71 led to apoptosis activation and CHOP expression induction. In conclusion, our study showed that treatment with the non-competitive inhibitor of HO-1, LS1 / 71, increased cytotoxicity mediated by CFZ, triggering apoptosis following ER stress activation. These results suggest that PIs may represent a possible pharmacological treatment for solid tumors and that HO-1 inhibition may represent a possible strategy to overcome chemoresistance and increase the efficacy of chemotherapic regimens.

Inhibition of aldose-reductase-2 by a benzofuroxane derivative bf-5m increases the expression of kcne1, kcnq1 in high glucose cultured H9c2 cardiac cells and sudden cardiac death.

Long QT syndrome (LQTS) is characterized by prolonged QT interval, leading to sudden cardiac death. Hyperglycemia is an important risk factor for LQTS, inhibiting the cardiac rapid component delayed rectifier K+ current (Iks), responsible for QT interval. We previously showed that the new ALR2 inhibitor BF-5m supplies cardioprotection from QT prolongation induced by high glucose concentration in the medium, reducing QT interval prolongation and preserving morphology. Here we investigated the effects of BF-5m on cell cytotoxicity and viability in H9c2 cells, and on cellular potassium ion channels expression. H9c2 cells were grown in medium with high glucose and high glucose plus the BF-5m by assessing the cytotoxic effects and the cell survival rate. In addition, KCNE1 and KCNQ1 expression in plasma and mitochondrial membranes were monitored. Also, the expression levels of miR-1 proved to suppress KCNQ1 and KCNE1, were analyzed. BF-5m treatment reduced the cytotoxic effects of high glucose on H9c2 cells by increasing cell survival rate and improving H9c2 morphology. Plasmatic KCNE1 and KCNQ1 expression levels were restored by BF-5m in H9c2 exposed to high glucose, down-regulating miR-1. These results suggest that BF-5m exerts cardioprotection from high glucose in rat heart ventricle H9c2 cells exposed to high glucose.

Occupational exposure to fluoro-edenite and prevalence of anti-nuclear autoantibodies.

An environmental contamination due to an asbestiform mineral fiber, fluoro-edenite (FE), caused a significantly increased mortality rate for malignant mesothelioma in Biancavilla, Italy. Exposure to fluoro-edenite has been associated with inflammatory processes as an early response to inhaled fibers. The aim was to explore prevalence of anti-nuclear autoantibodies (ANA) in a group of construction workers residing and working in the contaminated area. Prevalences for samples positive to ANA were 60% (n = 9) and 13% (n = 2), for exposed and nonexposed, respectively (p-value <0.05), the odds ratio was 9.75 (95% CI: 1.59-59.69). The significance of elevated ANAs in subjects exposed to fibers is unknown; additional studies may provide a better opportunity to establish a correlation between autoimmunity and environmental exposure.

Cadmium exposure and prostate cancer: insights, mechanisms and perspectives.

Cadmium (Cd) is a metal found in group 12 (IIB) of the periodic table of elements together with zinc, a metal with which it is often conjugated in nature. Occupational exposure to Cd occurs in many industrial settings, by cigarette smoking, diet and due to environmental pollution. International Agency for Research on Cancer and other epidemiological studies suggested that Cd can lead to prostate cancer and likely to kidney and lung cancers. Although epidemiological studies seem to point towards such an association, the in vitro studies have not been compelling. The aim of this article is to summarize current knowledge about the association of Cd exposure and prostate cancer, that suggests that new studies to show the role of Cd in the pathogenesis of prostatate cancer.

Fasting and Fast Food Diet Play an Opposite Role in Mice Brain Aging.

Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.

Functional Changes of Orexinergic Reaction to Psychoactive Substances.

It is becoming increasingly apparent the importance of the central nervous system (CNS) as the major contributor to the regulation of systemic metabolism. Antipsychotic drugs are used often to treat several psychiatric disorders, including schizophrenia and bipolar disorder However, antipsychotic drugs prescription, particularly the second-generation ones (SGAs), such as clozapine and olanzapine, is related to a considerable weight gain which usually leads to obesity. The aim of this paper is to assess the influence of orexin A on sympathetic and hyperthermic reactions to several neuroleptic drugs. Orexin A is a neuropeptide which effects both body temperature and food intake by increasing sympathetic activity. Orexin A-mediated hyperthermia is reduced by haloperidol and is blocked by clozapine and olanzapine. Orexin A-mediated body temperature elevation is increased by risperidone. These hyperthermic effects are delayed by quietapine. In this paper, it is discussed the orexinergic pathway activation by neuroleptic drugs and its influence on human therapeutic strategies. With the aim to determine that neuroleptic drugs mediate body temperature control through to the orexinergic system, we summarized our previously published data. Psychiatric disorders increase the risk of developing metabolic disorders (e.g., weight gain, increased blood pressure, and glucose or lipid levels). Therefore, the choice of antipsychotic drug to be prescribed, based on the relevant risks and benefits of each individual drug, has an essential role in human health prevention.

Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib.

Myeloid suppressor cells are a heterogeneous group of myeloid cells that are increased in patients with chronic myeloid leukaemia (CML) inducing T cell tolerance. In this study, we found that therapy with tyrosine kinase inhibitors (TKI) decreased the percentage of granulocytic MDSC, but only patients treated with dasatinib showed a significant reduction in the monocytic subset (M-MDSC). Moreover, a positive correlation was observed between number of persistent M-MDSC and the value of major molecular response in dasatinib-treated patients. Serum and exosomes from patients with CML induced conversion of monocytes from healthy volunteers into immunosuppressive M-MDSC, suggesting a bidirectional crosstalk between CML cells and MDSC. Overall, we identified M-MDSC as prognostic factors in patients treated with dasatinib. It might be of interest to understand whether MDSC may be a candidate predictive markers of relapse risk following TKI discontinuation, suggesting their potential significance as practice of precision medicine.

Serum lipid, lipoprotein and apolipoprotein profiles in workers exposed to low arsenic levels: Lipid profiles and occupational arsenic exposure.

Epidemiologic studies have reported that exposure to arsenic (As) is associated with higher risk of cardiovascular disease (i.e., coronary heart disease and peripheral arterial heart disease) and mortality. This cross-sectional study aimed to compare serum lipid, lipoprotein, and apolipoprotein profiles in workers exposed to As. The subjects of this study included 57 workers exposed to As and 57 controls. Demographic characteristics and occupational information were collected through questionnaires. Exposure to As was assessed in indoor air of a workplace and determined using the creatinine values in the urine. Blood samples were collected using immunochemistry and nephelometry to measure the levels of total cholesterol (CHOL), triglycerides (TRIG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), lipoprotein(a) (Lp(a)), apolipoprotein-A1 (Apo-A1), and apolipoprotein-B (Apo-B). No significant difference in the demographic data was detected between the two groups. Urinary As concentration was significantly (p<0.001) higher in exposed subjects than in the controls (13.4±6.1 and 4.4±6.1µg/gCreat, respectively). No statistically significant differences were observed in CHOL, TRIG, HDL, and LDL concentrations between the two groups. Lp(a), Apo-B, and Apo-B/Apo-A1 ratio values were significantly higher and the Apo-A1 level was significantly lower in the exposed group than in the control subjects. Regression analysis highlighted a significant (p<0.001) association between urinary As and Lp(a), Apo-A1, and Apo-B concentration, and Apo-B/Apo-A1 ratio. This study revealed the influence of As on apolipoproteins, suggesting a potential risk of cardiovascular diseases in subjects exposed to low levels of As.

The Role of Anabolic Androgenic Steroids in Disruption of the Physiological Function in Discrete Areas of the Central Nervous System.

Anabolic-androgenic steroids (AAS) abuse is often associated with a wide spectrum of adverse effects. These drugs are frequently abused by adolescents and athletes for esthetic purposes, as well as for improvement of their endurance and performances. In this literature review, we evaluated the correlation between AAS and anxiety or aggression. Two pathways are thought to be involved in AAS-induced behavioral disorders. Direct pathway via the amygdalo-fugal pathway, which connects the central nucleus of the amygdala to the brainstem, is involved in cognitive-emotive and homeostatic processes. The latter is modified by chronic AAS use, which subsequently leads to increased anxiety. Indirect pathways via the serotonergic, dopaminergic, and glutamatergic signals which are modified by AAS abuse in latero-anterior hypothalamus and can mediate the aggressive behavior. In conclusion, the molecular mechanisms underlying the behavioral alterations following AAS abuse is unclear and remains ambiguous as additional long-term studies aimed to understand the precise mechanisms are required.

Effect of Lipoic Acid on the Biochemical Mechanisms of Resistance to Bortezomib in SH-SY5Y Neuroblastoma Cells.

Neuroblastoma (NB) is an extracranial solid cancer and the most common cancer in infancy. Despite the standard treatment for NB is based on the combination of chemotherapeutic drugs such as doxorubicin, vincristine, cyclophosphamide, and cisplatin, chemoresistance occurs over the time. The aim of the present research was to evaluate the effect of bortezomib (BTZ) (50 nM) on NB cell viability and how lipoic acid (ALA) (100 µM) modifies pharmacological response to this chemotherapeutic agent. Cell viability was assessed by ATP luminescence assay whereas expression of oxidative stress marker (i.e., heme oxygenase-1) and endoplasmic reticulum stress proteins was performed by real-time PCR, western blot, and immunofluorescence. Our data showed that BTZ treatment significantly reduced cell viability when compared to untreated cultures (about 40%). Interestingly, ALA significantly reduced the efficacy of BTZ (about 30%). Furthermore, BTZ significantly induced heme oxygenase-1 as a result of increased oxidative stress and such overexpression was prevented by concomitant treatment with ALA. Similarly, ALA significantly reduced BTZ-mediated endoplasmic reticulum stress as measured by reduction in BiP1 and IRE1α, ERO1α, and PDI expression. In conclusion, our data suggest that BTZ efficacy is dependent on cellular redox status and such mechanisms may be responsible of chemoresistance to this chemotherapeutic agent.

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma.

Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ1 and σ2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ2 ligands (haloperidol and haloperidol metabolite II) and σ1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 µM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ1 and σ2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a "druggable" target to develop new chemotherapic agent for uveal melanoma.