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  • Mammana, Santa  (24)
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  • 1
    In: Basic & Clinical Pharmacology & Toxicology, December 2014, Vol.115(6), pp.499-506
    Description: Covalent attachment of the nitric oxide () moiety to the protease inhibitor Saquinavir (Saq) produced a new chemical entity, named Saquinavir‐, (Saq‐) with reduced toxicity and potent immunoregulatory influence on T lymphocytes. In this study, we have compared head‐to‐head the effects of Saq‐ and Saq on mouse and rat peritoneal macrophage cytokine secretion and production upon and conditions. The results demonstrate that Saq‐, but not Saq, potently decreased interleukin ()‐10, ‐6 and nitrite accumulation and increased the levels of ‐1β and tumour necrosis factor () in supernatants of mouse and rat macrophage cultures . Treatment of mice with Saq‐, but not Saq, inhibited secretion of ‐6 from macrophages. Consistent with these findings, Saq‐ also reduced blood levels of ‐6 in lipopolysaccharide‐treated mice. The observed inhibitory influence of Saq‐ on ‐6 generation in macrophages may be involved in the observed antitumour and immunomodulatory effects of the drug.
    Keywords: Nitric Oxide ; Saquinavir ; Interleukins ; Macrophages;
    ISSN: 1742-7835
    E-ISSN: 1742-7843
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  • 2
    Language: English
    In: Basic & clinical pharmacology & toxicology, November 2015, Vol.117(5), pp.306-15
    Description: HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non-steroidal, anti-inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect, acquires antitumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO-hybridization on two other PIs, Lopinavir and Ritonavir. The two NO-derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir-NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir-NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir-NO effects overlapped those of Ritonavir. These data demonstrate that NO-hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T-cell secretory capacity. Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis.
    Keywords: HIV Protease Inhibitors -- Pharmacology ; Hepatitis, Autoimmune -- Drug Therapy ; Immunologic Factors -- Pharmacology ; Leukocytes, Mononuclear -- Drug Effects ; Lopinavir -- Pharmacology ; Macrophages -- Drug Effects ; Nitric Oxide -- Pharmacology ; Ritonavir -- Pharmacology
    ISSN: 17427835
    E-ISSN: 1742-7843
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  • 3
    Language: English
    In: International Journal of Molecular Medicine, 9/2015, Vol.36(3), pp.747-752
    Description: Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) in the hepatic parenchyma and represents an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. Hepatic stellate cells (HSCs) are the major cell type responsible for liver fibrosis. Following liver injury, HSCs become activated and transdifferentiate into myofibroblasts (MFBs) that lead to intrahepatic ECM accumulation. In the present study, we performed a meta-analysis of datasets which included whole-genome transcriptional data on HSCs in the quiescent and activated state from two different rodent species and identified commonly regulated genes. Several of the genes identified, including ECM components, metalloproteinases and growth factors, were found to be well-known markers for HSC activation. However, other significant genes also appeared to play important roles in hepatic fibrosis. The elucidation of the molecular events underlying HSC activation may be key to the identification of potential novel pharmacological targets for the prevention and treatment of liver fibrosis.
    Keywords: Liver ; Hepatic Fibrosis ; Hepatic Stellate Cells ; Myofibrob Last ; Bioinformatics
    ISSN: 1107-3756
    E-ISSN: 1791-244X
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  • 4
    Language: English
    In: Journal of Neuroimmunology, 15 January 2016, Vol.290, pp.66-69
    Description: Multiple sclerosis (MS) is an immunoinflammatory disease of the central nervous system that seems to be influenced by DNA methylation. We sought to explore the expression pattern of genes involved in the control of DNA methylation in Secondary Progressive (SP) MS patients' PBMCs. We have found that SP MS is characterized by a significant upregulation of two genes belonging to the family genes, and , and by a downregulation of and .
    Keywords: Multiple Sclerosis ; DNA Methylation ; Epigenetics ; Medicine ; Anatomy & Physiology
    ISSN: 0165-5728
    E-ISSN: 1872-8421
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  • 5
    Language: English
    In: International Journal of Molecular Sciences, 01 March 2018, Vol.19(3), p.831
    Description: In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases.
    Keywords: Microglia ; Macrophages ; Neuroinflammation ; Alzheimer’s Disease ; Multiple Sclerosis ; Amyotrophic Lateral Sclerosis ; Biology
    E-ISSN: 1422-0067
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  • 6
    Language: English
    In: Oncotarget, 02 February 2018, Vol.9(9), pp.8263-8277
    Description: The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability.
    Keywords: Autoimmunity ; Bioinformatics ; Mtor ; Multiple Sclerosis
    E-ISSN: 1949-2553
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  • 7
    Language: English
    In: Oncotarget, 03 April 2018, Vol.9(25), pp.17951-17970
    Description: Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine expressed by a variety of cell types. Although MIF has been primarily studied for its role in the pathogenesis of autoimmune diseases, it has also been shown to promote tumorigenesis and it is over expressed in various malignant tumors. MIF is able to induce angiogenesis, cell cycle progression, and to block apoptosis. As tailored therapeutic approaches for the inhibition of endogenous MIF are being developed, it is important to evaluate the role of MIF in individual neoplastic conditions that may benefit from specific MIF inhibitors. Along with this line, in this paper, we have reviewed the evidence of the involvement of MIF in the etiopathogenesis and progression of glioblastoma and the preclinical data suggesting the possible use of specific MIF inhibition as a potential novel therapeutic strategy for brain tumors.
    Keywords: D-Dt ; Brain Tumors ; Glioblastoma ; Macrophage Migration Inhibitory Factor ; Neuro-Oncology
    E-ISSN: 1949-2553
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  • 8
    In: Basic & Clinical Pharmacology & Toxicology, January 2013, Vol.112(1), pp.63-69
    Description: Rapamycin is a macrocyclic lactone currently used for the treatment of cancer and for the prevention of transplant rejection. The primary pharmacological mode of action of rapamycin occurs through the inhibition (blocking) of the mammalian target of rapamycin (). By doing so, rapamycin interferes with the phosphoinositide 3‐kinase (3)‐kt‐ axis that controls several cellular functions involving cell growth, proliferation and angiogenesis. The frequent activation of the phosphoinositide 3‐kinase (3)/ pathway in advanced prostate cancer has provided a rationale for the use of inhibitors in this setting. We carried out a comparative study on the effects of rapamycin and temsirolimus on the and growth of the prostate cancer cell lines, nap and 3. Our results demonstrate that rapamycin and temsirolimus exert similar and anti‐proliferative effects against prostate cancer cells.
    Keywords: Cancer Cells -- Comparative Analysis ; Cancer Research -- Comparative Analysis ; Prostate Cancer -- Comparative Analysis ; Caprolactone -- Comparative Analysis ; Antineoplastic Agents -- Comparative Analysis ; Rapamycin -- Comparative Analysis;
    ISSN: 1742-7835
    E-ISSN: 1742-7843
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  • 9
    Language: English
    In: Experimental and Therapeutic Medicine, 09/2017, Vol.14(3), pp.2439-2444
    Description: P40 is a particulate fraction or fragment isolated from Corynebacterium granulosum , which exhibits a wide spectrum of pharmacological functions including antitumor, antibacterial, phagocytic, antiviral and cytokine induction effects. In the present study, the immunomodulatory potential of P40-conjugated with hyaluronic acid was assessed in a mouse model of dermatitis induced by oxazolone. Oxazolone-induced allergic contact dermatitis is a T cell-mediated Th2-like hypersensitivity reaction, which mimics the corresponding reaction in humans. Female cluster of differentiation-1 mice were sensitized on days 0 and 1 by the application of 2% oxazolone onto a shaved back. The disease was induced by re-challenge on day 7 using 15% oxazolone in the inner and outer of the left ears of the mice. Mice were topically treated with hyaluronic acid-P40 conjugate cream or with placebo to the inner and outer surface of the left ear for 7 consecutive days starting from 1 h after the sensitization. A significant reduction in ear thickness and weight and in edema and leukocyte recruitment were observed in the mice treated with hyaluronic-P40 conjugate cream compared with mice treated with the cream base alone (P〈0.05). Thus, P40-conjugated with hyaluronic acid may constitute an innovative dermatitis treatment.
    Keywords: Dermatitis ; Oxazolone ; Immunomodulation ; P40 Fraction
    ISSN: 1792-0981
    E-ISSN: 1792-1015
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  • 10
    Language: English
    In: Journal of Neuroimmunology, 15 August 2018, Vol.321, pp.41-48
    Description: Guillain-Barré syndrome (GBS) is an immune-mediated acute disorder of the peripheral nervous system. Despite treatment, there is an associated mortality and severe disability in 9 to 17% of the cases. Decitabine (DAC) is a hypomethylating drug used in myelodisplastic syndrome, that has been shown to exert immunomodulatory effects. We have evaluated the effects of DAC in two rodent models of GBS, the Experimental Allergic Neuritis (EAN). Both prophylactic and therapeutic treatment with DAC ameliorated the clinical course of EAN, increasing the numbers of thymic regulatory T cells and reducing the production of proinflammmatory cytokines. Our data suggest the possible use of decitabine for the treatment of GBS.
    Keywords: Guillain Barrè Syndrome ; Experimental Allergic Neuritis ; Decitabine ; Regulatory T Cells ; Medicine ; Anatomy & Physiology
    ISSN: 0165-5728
    E-ISSN: 1872-8421
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