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Glucocorticoids (GCs) are steroid-family hormones that regulate many essential homeostatic functions. These hormones, although normally secreted with a circadian rhythm, are also increased by stress and are important in health and disease. Synthetic and natural GCs are mainly used at pharmacological doses for anti-inflammatory and immunosuppressive therapies and represent the most important means for controlling relevant pathologies. They are also used in substitution therapies, in shock, and for tumors. However, as drugs, they cause many side/adverse effects, which when presenting together constitute iatrogenic Cushing's syndrome. GCs act through gene-based and non-gene-based mechanisms, mostly through binding to cytoplasmic GC receptors (GRs), of which various isoforms are known. Moreover, GCs also induce epigenetic effects and can thus control the activity of other transcription factors. GRs are found in all tissues, including cells of the immune system and those involved in inflammatory processes. Different GR levels, isoforms, and the number of GC-response elements in chromosomes explains the heterogeneity of biological responses in tissues to GC treatment. Here, we provide an overview of the molecular mechanisms involved in GC immunosuppressive and anti-inflammatory activities, pathologies treated with GCs, and their side/adverse effects. GCs, often considered as “old drugs,” are still successfully used in many pathologies.
Emira Ayroldi; Graziella Migliorati; Carlo Riccardi. Immunomodulatory and Anti-Inflammatory Properties of Glucocorticoids. Reference Module in Biomedical Sciences 2021, 1 .
AMA StyleEmira Ayroldi, Graziella Migliorati, Carlo Riccardi. Immunomodulatory and Anti-Inflammatory Properties of Glucocorticoids. Reference Module in Biomedical Sciences. 2021; ():1.
Chicago/Turabian StyleEmira Ayroldi; Graziella Migliorati; Carlo Riccardi. 2021. "Immunomodulatory and Anti-Inflammatory Properties of Glucocorticoids." Reference Module in Biomedical Sciences , no. : 1.
One of the most important problems in tumor immunology studies is the in vivo role of natural killer (NK) cells and, as a consequence, the regulation of NK cell development and activity. It has been demonstrated that cells and soluble factors, including cytokines and hormones, are able to modulate NK activity by regulating both the reactivity of mature effector cells and the growth and differentiation of their precursors. One of the most interesting aspects of the in vitro generation of NK cells was the study of the role of different soluble factors, possibly involved in this process. In fact, while interleukin (IL)-2 was necessary for NK cell generation it is clear that other factors are involved in the first phase of differentiation and acquisition of IL-2-responsiveness. This suggests that, as in the rat, differentiation of mouse NK cells in addition to IL-2 needs other factors which are present in the CM.
Carlo Riccardi; Emira Ayroldi; Lorenza Cannarile; Domenico Delfino; Francesca D’Adamio; Luciano D'Adamio; Graziella Migliorati. Studies on NK Cell Precursors in Mice. Tumor Immunology and Cancer Therapy 2020, 125 -132.
AMA StyleCarlo Riccardi, Emira Ayroldi, Lorenza Cannarile, Domenico Delfino, Francesca D’Adamio, Luciano D'Adamio, Graziella Migliorati. Studies on NK Cell Precursors in Mice. Tumor Immunology and Cancer Therapy. 2020; ():125-132.
Chicago/Turabian StyleCarlo Riccardi; Emira Ayroldi; Lorenza Cannarile; Domenico Delfino; Francesca D’Adamio; Luciano D'Adamio; Graziella Migliorati. 2020. "Studies on NK Cell Precursors in Mice." Tumor Immunology and Cancer Therapy , no. : 125-132.
Regulatory T (Treg) cells are crucial mediators of immune tolerance suppressing self‐reactive T cells and preventing autoimmune diseases. Besides activation of the T cell receptor (TCR), empowerment of Treg cell functions requires coaccessory signals, such as those released by the tumor necrosis factor receptor superfamily (TNFRSF) that, however, can also promote immunostimulatory responses when engaged by effector T cells. In this issue of European Journal of Immunology , Lubrano di Ricco et al. [Eur. J. Immunol. 2020. 50: XX‐XX] have taken a closer look at the important question of the functional meaning of TNFRSF‐activated signaling pathways in Treg cells. They have demonstrated that costimulation by TNFR2, 4‐1BB, GITR, DR3, but not OX40 in mouse Foxp3+ Treg cells activates the same and unique signaling pathway, i.e., canonical NF‐κB, which in turn leads to Foxp3 gene upregulation, cell expansion in vitro and in vivo , and suppressive activity in an experimental model of colitis. Moreover, induction of markers of T helper 2 (Th2) and Th17 as well as of genes encoding proteins involved in noncanonical NF‐κΒ was also observed. We here discussed how these findings further highlight the emerging concept of Treg cell plasticity in immune tolerance. This article is protected by copyright. All rights reserved
Emira Ayroldi; Ursula Grohmann. Exemplifying complexity of immune suppression by a “canonical” speech: A glimpse into TNFRSF‐activated signaling pathways in Treg cells. European Journal of Immunology 2020, 50, 944 -948.
AMA StyleEmira Ayroldi, Ursula Grohmann. Exemplifying complexity of immune suppression by a “canonical” speech: A glimpse into TNFRSF‐activated signaling pathways in Treg cells. European Journal of Immunology. 2020; 50 (7):944-948.
Chicago/Turabian StyleEmira Ayroldi; Ursula Grohmann. 2020. "Exemplifying complexity of immune suppression by a “canonical” speech: A glimpse into TNFRSF‐activated signaling pathways in Treg cells." European Journal of Immunology 50, no. 7: 944-948.
Proto-oncogene mutations and abnormal activation of mitogen-activated protein kinase (MAPK) signalling are recurrently found in thyroid cancers. Some thyroid neoplasms respond to drugs that inhibit MAPK pathway activation. Previously, we showed that pharmacological inhibition of MAPK in thyroid cancer cells inhibits cell proliferation and upregulates L-GILZ (long glucocorticoid-induced leucine zipper), a protein with anti-oncogenic and antiproliferative activity, and that L-GILZ is partially responsible for the antiproliferative activity of MAPK inhibitors. Here, we demonstrate that pharmacological inhibition of MAPK in the anaplastic thyroid cancer cell line CAL-62 upregulated L-GILZ, which bound nuclear factor κB (NF-κB) and inhibited its nuclear translocation. These data demonstrate a unique L-GILZ–mediated molecular mechanism that, by trapping NF-κB in the cytoplasm, contributes to the inhibition of proliferation induced by drugs targeting the MAPK transduction cascade. Enhanced knowledge of the mechanism of action of MAPK pathway–inhibiting drugs may improve their clinical use.
Maria Cristina Marchetti; Lorenza Cannarile; Simona Ronchetti; Domenico V. Delfino; Carlo Riccardi; Emira Ayroldi. L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells. Journal of Chemotherapy 2020, 32, 263 -267.
AMA StyleMaria Cristina Marchetti, Lorenza Cannarile, Simona Ronchetti, Domenico V. Delfino, Carlo Riccardi, Emira Ayroldi. L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells. Journal of Chemotherapy. 2020; 32 (5):263-267.
Chicago/Turabian StyleMaria Cristina Marchetti; Lorenza Cannarile; Simona Ronchetti; Domenico V. Delfino; Carlo Riccardi; Emira Ayroldi. 2020. "L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells." Journal of Chemotherapy 32, no. 5: 263-267.
Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.
Sabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Lorenza Cannarile; Trinh Thi Thuy; Tran Van Sung; Hossain Sohrab; Choudhury Mahmood Hasan; Emira Ayroldi; Carlo Riccardi; Abdul Mazid; Domenico V. Delfino. Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines. Toxins 2019, 11, 503 .
AMA StyleSabrina Adorisio, Alessandra Fierabracci, Isabella Muscari, Anna Marina Liberati, Lorenza Cannarile, Trinh Thi Thuy, Tran Van Sung, Hossain Sohrab, Choudhury Mahmood Hasan, Emira Ayroldi, Carlo Riccardi, Abdul Mazid, Domenico V. Delfino. Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines. Toxins. 2019; 11 (9):503.
Chicago/Turabian StyleSabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Lorenza Cannarile; Trinh Thi Thuy; Tran Van Sung; Hossain Sohrab; Choudhury Mahmood Hasan; Emira Ayroldi; Carlo Riccardi; Abdul Mazid; Domenico V. Delfino. 2019. "Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines." Toxins 11, no. 9: 503.
Glucocorticoid-induced leucine zipper (GILZ) is a protein with multiple biological roles that is upregulated by glucocorticoids (GCs) in both immune and non-immune cells. Importantly, GCs are immunosuppressive primarily due to their regulation of cell signaling pathways that are crucial for immune system activity. GILZ, which is transcriptionally induced by the glucocorticoid receptor (GR), mediates part of these immunosuppressive, and anti-inflammatory effects, thereby controlling immune cell proliferation, survival, and differentiation. The primary immune cells targeted by the immunosuppressive activity of GCs are T cells. Importantly, the effects of GCs on T cells are partially mediated by GILZ. In fact, GILZ regulates T-cell activation, and differentiation by binding and inhibiting factors essential for T-cell function. For example, GILZ associates with nuclear factor-κB (NF-κB), c-Fos, and c-Jun and inhibits NF-κB-, and AP-1-dependent transcription. GILZ also binds Raf and Ras, inhibits activation of Ras/Raf downstream targets, including mitogen-activated protein kinase 1 (MAPK1). In addition GILZ inhibits forkhead box O3 (FoxO3) without physical interaction. GILZ also promotes the activity of regulatory T cells (Tregs) by activating transforming growth factor-β (TGF-β) signaling. Ultimately, these actions inhibit T-cell activation and modulate the differentiation of T helper (Th)-1, Th-2, Th-17 cells, thereby mediating the immunosuppressive effects of GCs on T cells. In this mini-review, we discuss how GILZ mediates GC activity on T cells, focusing mainly on the therapeutic potential of this protein as a more targeted anti-inflammatory/immunosuppressive GC therapy.
Lorenza Cannarile; Domenico V. Delfino; Sabrina Adorisio; Carlo Riccardi; Emira Ayroldi. Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation. Frontiers in Immunology 2019, 10, 1823 .
AMA StyleLorenza Cannarile, Domenico V. Delfino, Sabrina Adorisio, Carlo Riccardi, Emira Ayroldi. Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation. Frontiers in Immunology. 2019; 10 ():1823.
Chicago/Turabian StyleLorenza Cannarile; Domenico V. Delfino; Sabrina Adorisio; Carlo Riccardi; Emira Ayroldi. 2019. "Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation." Frontiers in Immunology 10, no. : 1823.
Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the immune cells. The progressive decline of the immune system functions that occurs in aging defines immunosenescence, and includes both innate and adaptive immunity; the latter undergoes major alterations. Aging and chronic stress share the abnormal hypothalamic–pituitary–adrenal axis activation, where altered peripheral glucocorticoids (GC) levels and chronic stress have been associated with accelerated cellular aging, premature immunosenescence, and aging-related diseases. Consequently, changes in GC levels and sensitivity contribute to the signs of immunosenescence, namely fewer naïve T cells, poor immune response to new antigens, decreased cell-mediated immunity, and thymic involution. GC signaling alterations also involve epigenetic alterations in DNA methylation, with transcription modifications that may contribute to immunosenescence. Immune cell aging leads to decreased levels of immunosurveillance, thereby providing tumor cells one more route for immune system escape. Here, the contribution of GC secretion and signaling dysregulation to the increased incidence of tumorigenesis in the elderly is reviewed.
Emira Ayroldi; Lorenza Cannarile; Sabrina Adorisio; Domenico V. Delfino; Carlo Riccardi. Role of Endogenous Glucocorticoids in Cancer in the Elderly. International Journal of Molecular Sciences 2018, 19, 3774 .
AMA StyleEmira Ayroldi, Lorenza Cannarile, Sabrina Adorisio, Domenico V. Delfino, Carlo Riccardi. Role of Endogenous Glucocorticoids in Cancer in the Elderly. International Journal of Molecular Sciences. 2018; 19 (12):3774.
Chicago/Turabian StyleEmira Ayroldi; Lorenza Cannarile; Sabrina Adorisio; Domenico V. Delfino; Carlo Riccardi. 2018. "Role of Endogenous Glucocorticoids in Cancer in the Elderly." International Journal of Molecular Sciences 19, no. 12: 3774.
Emira Ayroldi. Stress, Glucocorticoid and Cancer: Happy Tumor Cells. Journal of Tumor Medicine & Prevention 2018, 3, 1 -2.
AMA StyleEmira Ayroldi. Stress, Glucocorticoid and Cancer: Happy Tumor Cells. Journal of Tumor Medicine & Prevention. 2018; 3 (1):1-2.
Chicago/Turabian StyleEmira Ayroldi. 2018. "Stress, Glucocorticoid and Cancer: Happy Tumor Cells." Journal of Tumor Medicine & Prevention 3, no. 1: 1-2.
Glucocorticoids (GCs), important therapeutic tools to treat inflammatory and immunosuppressive diseases, can also be used as part of cancer therapy. In oncology, GCs are used as anticancer drugs for lymphohematopoietic malignancies, while in solid neoplasms primarily to control the side effects of chemo/radiotherapy treatments. The molecular mechanisms underlying the effects of GCs are numerous and often overlapping, but not all have been elucidated. In normal, cancerous, and inflammatory tissues, the response to GCs differs based on the tissue type. The effects of GCs are dependent on several factors: the tumor type, the GC therapy being used, the expression level of the glucocorticoid receptor (GR), and the presence of any other stimuli such as signals from immune cells and the tumor microenvironment. Therefore, GCs may either promote or suppress tumor growth via different molecular mechanisms. Stress exposure results in dysregulation of the hypothalamic–pituitary–adrenal axis with increased levels of endogenous GCs that promote tumorigenesis, confirming the importance of GCs in tumor growth. Most of the effects of GCs are genomic and mediated by the modulation of GR gene transcription. Moreover, among the GR-induced genes, glucocorticoid-induced leucine zipper (GILZ), which was cloned and characterized primarily in our laboratory, mediates many GC anti-inflammatory effects. In this review, we analyzed the possible role for GILZ in the effects GCs have on tumors cells. We also suggest that GILZ, by affecting the immune system, tumor microenvironment, and directly cancer cell biology, has a tumor-promoting function. However, it may also induce apoptosis or decrease the proliferation of cancer cells, thus inhibiting tumor growth. The potential therapeutic implications of GILZ activity on tumor cells are discussed here.
Emira Ayroldi; Lorenza Cannarile; Domenico V. Delfino; Carlo Riccardi. A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: tumor growth promotion or suppression? Cell Death & Disease 2018, 9, 1 -12.
AMA StyleEmira Ayroldi, Lorenza Cannarile, Domenico V. Delfino, Carlo Riccardi. A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: tumor growth promotion or suppression? Cell Death & Disease. 2018; 9 (5):1-12.
Chicago/Turabian StyleEmira Ayroldi; Lorenza Cannarile; Domenico V. Delfino; Carlo Riccardi. 2018. "A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: tumor growth promotion or suppression?" Cell Death & Disease 9, no. 5: 1-12.
Long glucocorticoid-induced leucine zipper (L-GILZ) has recently been implicated in cancer cell proliferation. Here, we investigated its role in human thyroid cancer cells. L-GILZ protein was highly expressed in well-differentiated cancer cells from thyroid cancer patients and differentiated thyroid cancer cell lines, but poorly expressed in anaplastic tumors. A fusion protein containing L-GILZ, when overexpressed in an L-GILZ-deficient 8505C cell line derived from undifferentiated human thyroid cancer tissue, inhibited cellular proliferation in vitro. In addition, when this protein was injected into nude mice, in which cells from line 8505C had been transplanted, xenograft growth was reduced. Since the mitogen-activated protein kinase (MAPK) pathway is frequently hyperactivated in thyroid cancer cells as a result of the BRAFV600E or Ras mutation, we sought to further investigate the role of L-GILZ in the MAPK pathway. To this end, we analyzed L-GILZ expression and function in cells treated with MAPK inhibitors. We used 8505C cells, which have the BRAFV600E mutation, or the CAL-62 cell line, which harbors a Ras mutation. The cells were treated with the BRAF-specific drug vemurafenib (PLX4032) or the MEK1/2 inhibitor, U0126, respectively. Treatment with these agents inhibited MAPK activation, reduced cell proliferation, and upregulated L-GILZ expression. L-GILZ silencing reversed the antiproliferative activity of the MAPK inhibitors, consistent with an antiproliferative role. Treatment with MAPK inhibitors led to the phosphorylation of the cAMP/response element-binding protein (CREB), and active CREB bound to the L-GILZ promoter, contributing to its transcription. We suggest that the CREB signaling pathway, frequently deregulated in thyroid tumors, is involved in L-GILZ upregulation and that L-GILZ regulates thyroid cancer cell proliferation, which may have potential in cancer treatment.
Emira Ayroldi; Maria Grazia Petrillo; Maria Cristina Marchetti; Lorenza Cannarile; Simona Ronchetti; Erika Ricci; Luigi Cari; Nicola Avenia; Sonia Moretti; Efisio Puxeddu; Carlo Riccardi. Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation. Cell Death & Disease 2018, 9, 1 -15.
AMA StyleEmira Ayroldi, Maria Grazia Petrillo, Maria Cristina Marchetti, Lorenza Cannarile, Simona Ronchetti, Erika Ricci, Luigi Cari, Nicola Avenia, Sonia Moretti, Efisio Puxeddu, Carlo Riccardi. Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation. Cell Death & Disease. 2018; 9 (3):1-15.
Chicago/Turabian StyleEmira Ayroldi; Maria Grazia Petrillo; Maria Cristina Marchetti; Lorenza Cannarile; Simona Ronchetti; Erika Ricci; Luigi Cari; Nicola Avenia; Sonia Moretti; Efisio Puxeddu; Carlo Riccardi. 2018. "Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation." Cell Death & Disease 9, no. 3: 1-15.
Small ubiquitin-like modifier (SUMO) proteins belong to the ubiquitin-like family and act to change the function of target proteins through post-translational modifications. Through their interactions with innate immune pathways, SUMOs promote an efficient immune response to pathogenic challenge avoiding, at the same time, an excess of immune response that could lead to the development of autoimmune diseases. This report discusses the general functions of SUMO proteins; highlights SUMO involvement in the innate immune response through their role in NF-κB and interferon pathways; the involvement of SUMO proteins in autoimmune diseases; and reviews bacterial, viral, and parasitic interactions with SUMO pathways. In conclusion, we speculate that targeting SUMOs could represent a new therapeutic strategy against infections and autoimmunity.
Sabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Emira Ayroldi; Graziella Migliorati; Trinh Thi Thuy; Carlo Riccardi; Domenico V. Delfino. SUMO proteins: Guardians of immune system. Journal of Autoimmunity 2017, 84, 21 -28.
AMA StyleSabrina Adorisio, Alessandra Fierabracci, Isabella Muscari, Anna Marina Liberati, Emira Ayroldi, Graziella Migliorati, Trinh Thi Thuy, Carlo Riccardi, Domenico V. Delfino. SUMO proteins: Guardians of immune system. Journal of Autoimmunity. 2017; 84 ():21-28.
Chicago/Turabian StyleSabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Emira Ayroldi; Graziella Migliorati; Trinh Thi Thuy; Carlo Riccardi; Domenico V. Delfino. 2017. "SUMO proteins: Guardians of immune system." Journal of Autoimmunity 84, no. : 21-28.
Glucocorticoid-Induced Leucine Zipper (GILZ) is a glucocorticoid-inducible gene that mediates glucocorticoid anti-inflammatory effects. GILZ and the isoform L-GILZ are expressed in a variety of cell types, especially of hematopoietic origin, including macrophages, lymphocytes and epithelial cells, and strongly upregulated upon glucocorticoid treatment. A quantitative analysis of GILZ expression in mouse tissues is technically difficult to perform because of the presence of a pseudogene and the high homology of GILZ gene with other genes of TSC22 family. We here propose specific primer pairs to be used in Real Time PCR to avoid unwanted amplification of GILZ pseudogene and TSC-22 family member d1iso3. These primer pairs were used to determine GILZ and L-GILZ expression, in either untreated or in vivo and in vitro dexamethasone-treated tissues. Results indicate that GILZ and L-GILZ are upregulated by glucocorticoids, being GILZ more sensitive to glucocorticoid induction than L-GILZ, but they are differently expressed in all examined tissues, confirming a different role in specific cells. An inappropriate primer pair amplified also GILZ pseudogene and TSC22d1iso3, thus producing misleading results. This quantitative evaluation may be used to better characterize the role of GILZ and L-GILZ in mice and may be translated to humans.
Luigi Cari; Erika Ricci; Marco Gentili; Maria Grazia Petrillo; Emira Ayroldi; Simona Ronchetti; Giuseppe Nocentini; Carlo Riccardi. A focused Real Time PCR strategy to determine GILZ expression in mouse tissues. Results in Immunology 2015, 5, 37 -42.
AMA StyleLuigi Cari, Erika Ricci, Marco Gentili, Maria Grazia Petrillo, Emira Ayroldi, Simona Ronchetti, Giuseppe Nocentini, Carlo Riccardi. A focused Real Time PCR strategy to determine GILZ expression in mouse tissues. Results in Immunology. 2015; 5 ():37-42.
Chicago/Turabian StyleLuigi Cari; Erika Ricci; Marco Gentili; Maria Grazia Petrillo; Emira Ayroldi; Simona Ronchetti; Giuseppe Nocentini; Carlo Riccardi. 2015. "A focused Real Time PCR strategy to determine GILZ expression in mouse tissues." Results in Immunology 5, no. : 37-42.
Carlo Riccardi; Graziella Migliorati; Antonio Giampietri; Emira Ayroldi; Lorenza Cannarile; Ronald B. Herberman. Regulation of Differentiation of Bone Marrow Precursors into Natural Killer Effector Cells1. Natural Immunity, Cancer and Biological Response Modification 2015, 34 -39.
AMA StyleCarlo Riccardi, Graziella Migliorati, Antonio Giampietri, Emira Ayroldi, Lorenza Cannarile, Ronald B. Herberman. Regulation of Differentiation of Bone Marrow Precursors into Natural Killer Effector Cells1. Natural Immunity, Cancer and Biological Response Modification. 2015; ():34-39.
Chicago/Turabian StyleCarlo Riccardi; Graziella Migliorati; Antonio Giampietri; Emira Ayroldi; Lorenza Cannarile; Ronald B. Herberman. 2015. "Regulation of Differentiation of Bone Marrow Precursors into Natural Killer Effector Cells1." Natural Immunity, Cancer and Biological Response Modification , no. : 34-39.
A recent report from our laboratory reveals how long glucocorticoid-induced leucine zipper (L-Gilz) protein binds to p53 and mouse double minute 2 homolog (Mdm2), thus dissociating the p53/Mdm2 complex and activating p53 with subsequent activation of downstream genes p21 and p53 upregulated modulator of apoptosis (Puma). p53 activation appears to be the mechanism by which both basal and glucocorticoid (GC)-induced L-Gilz inhibits proliferation and induces antioncogenic activity in human cancer.
Emira Ayroldi; Cristina Marchetti; Carlo Riccardi. The novel partnership of L-GILZ and p53: a new affair in cancer? Molecular & Cellular Oncology 2014, 2, e975087 .
AMA StyleEmira Ayroldi, Cristina Marchetti, Carlo Riccardi. The novel partnership of L-GILZ and p53: a new affair in cancer? Molecular & Cellular Oncology. 2014; 2 (2):e975087.
Chicago/Turabian StyleEmira Ayroldi; Cristina Marchetti; Carlo Riccardi. 2014. "The novel partnership of L-GILZ and p53: a new affair in cancer?" Molecular & Cellular Oncology 2, no. 2: e975087.
Glucocorticoids (GCs) are steroid hormones that are necessary for life and important in health and disease. They regulate crucial homeostatic functions, including metabolism, cell growth, and development. Although GCs are regulated by circadian rhythm, increased production is associated with stress. Synthetic GCs are a valuable resource for anti-inflammatory and immunosuppressive therapy. Natural and synthetic GCs transduce signals mainly through GC receptor (GR) activation. Extensive research has explored the downstream targets of the GR, and optimization of GC therapy has required collaborative efforts. One highly promising approach involves new dissociative GR modulators. Because transrepression and transactivation of GR genes induce beneficial and adverse effects, respectively, this approach favors transrepression. Another approach involves the use of GC-dependent genes to generate proteins to mediate therapeutic GC effects. In a third approach, drug discovery is used to identify agents that selectively target GR isoforms to obtain differential gene transcription and effects. In this review, we focus on mechanisms of GR function compatible with the use of dissociative drugs. We highlight GC-induced leucine zipper (GILZ), a gene cloned in our laboratory, as a mediator of GC anti-inflammatory and immunosuppressive effects, to outline our perspective on the future of GC therapy.—Ayroldi, E., Macchiarulo, A., Riccardi, C. Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid-induced leucine zipper? A perspective.
Emira Ayroldi; Antonio Macchiarulo; Carlo Riccardi. Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid‐induced leucine zipper? A perspective. The FASEB Journal 2014, 28, 5055 -5070.
AMA StyleEmira Ayroldi, Antonio Macchiarulo, Carlo Riccardi. Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid‐induced leucine zipper? A perspective. The FASEB Journal. 2014; 28 (12):5055-5070.
Chicago/Turabian StyleEmira Ayroldi; Antonio Macchiarulo; Carlo Riccardi. 2014. "Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid‐induced leucine zipper? A perspective." The FASEB Journal 28, no. 12: 5055-5070.
The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53+/+ HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53+/+ cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.
Emira Ayroldi; M G Petrillo; A Bastianelli; M C Marchetti; Simona Ronchetti; Giuseppe Nocentini; L Ricciotti; L Cannarile; Carlo Riccardi. L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells. Cell Death & Differentiation 2014, 22, 118 -130.
AMA StyleEmira Ayroldi, M G Petrillo, A Bastianelli, M C Marchetti, Simona Ronchetti, Giuseppe Nocentini, L Ricciotti, L Cannarile, Carlo Riccardi. L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells. Cell Death & Differentiation. 2014; 22 (1):118-130.
Chicago/Turabian StyleEmira Ayroldi; M G Petrillo; A Bastianelli; M C Marchetti; Simona Ronchetti; Giuseppe Nocentini; L Ricciotti; L Cannarile; Carlo Riccardi. 2014. "L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells." Cell Death & Differentiation 22, no. 1: 118-130.
The thymus is a lymphoid organ that governs the development of a diverse T-cell repertoire capable of defending against nonself-antigens and avoiding autoimmunity. However, the thymus can also succumb to different diseases. Hypertrophic diseases, such as thymomas, are typically associated with impairment of negative selection, which leads to autoimmune disease, or disruption of positive selection, which results in immunodeficiency. Hypotrophic diseases of the thymus can manifest during acute infections, cancer, allogeneic bone marrow transplantation, or with aging. This condition leads to decreased immune function and can be treated by either replacing lost thymic tissue or by preventing thymic tissue death. Studies have demonstrated the critical role of caspase-8 in regulating apoptosis in the thymus. In this review, we discuss how pharmacological activation and inhibition of caspase-8 can be used to treat hypertrophic and hypotrophic diseases of the thymus, respectively, to improve its function.
Nicola Pozzesi; Alessandra Fierabracci; Trinh Thy Thuy; Maria Paola Martelli; Anna Marina Liberati; Emira Ayroldi; Carlo Riccardi; Domenico V. Delfino. Pharmacological Modulation of Caspase-8 in Thymus-Related Medical Conditions. Journal of Pharmacology and Experimental Therapeutics 2014, 351, 18 -24.
AMA StyleNicola Pozzesi, Alessandra Fierabracci, Trinh Thy Thuy, Maria Paola Martelli, Anna Marina Liberati, Emira Ayroldi, Carlo Riccardi, Domenico V. Delfino. Pharmacological Modulation of Caspase-8 in Thymus-Related Medical Conditions. Journal of Pharmacology and Experimental Therapeutics. 2014; 351 (1):18-24.
Chicago/Turabian StyleNicola Pozzesi; Alessandra Fierabracci; Trinh Thy Thuy; Maria Paola Martelli; Anna Marina Liberati; Emira Ayroldi; Carlo Riccardi; Domenico V. Delfino. 2014. "Pharmacological Modulation of Caspase-8 in Thymus-Related Medical Conditions." Journal of Pharmacology and Experimental Therapeutics 351, no. 1: 18-24.
The thymus is the primary organ responsible for de novo generation of immunocompetent T cells that have a diverse repertoire of antigen recognition. During the developmental process, 98% of thymocytes die by apoptosis. Thus apoptosis is a dominant process in the thymus and occurs through either death by neglect or negative selection or through induction by stress/aging. Caspase activation is an essential part of the general apoptosis mechanism, and data suggest that caspases may have a role in negative selection; however, it seems more probable that caspase-8 activation is involved in death by neglect, particularly in glucocorticoid-induced thymocyte apoptosis. Caspase-8 is active in double-positive (DP) thymocytes in vivo and can be activated in vitro in DP thymocytes by T-cell receptor (TCR) crosslinking to induce apoptosis. Caspase-8 is a proapoptotic member of the caspase family and is considered an initiator caspase, which is activated upon stimulation of a death receptor (e.g., Fas), recruitment of the adaptor molecule FADD, and recruitment and subsequent processing of procaspase-8. The main role of caspase-8 seems to be pro-apoptotic and, in this review, we will discuss about the involvement of caspase-8 in (1) TCR-triggered thymic apoptosis; (2) death receptor-mediated thymic apoptosis; and (3) glucocorticoid-induced thymic apoptosis. Regarding TCR triggering, caspase-8 is active in medullary, semi-mature heat-stable antigenhi (HAShi SP) thymocytes as a consequence of strong TCR stimulation. The death receptors Fas, FADD, and FLIP are involved upstream of caspase-8 activation in apoptosis; whereas, Bid and HDAC7 are involved downstream of caspase-8. Finally, caspase-8 is involved in glucocortocoid-induced thymocyte apoptosis through an activation loop with the protein GILZ. GILZ activates caspase-8, promoting GILZ sumoylation and its protection from proteasomal degradation.
N Pozzesi; Alessandra Fierabracci; A M Liberati; M P Martelli; Emira Ayroldi; Carlo Riccardi; D V Delfino. Role of caspase-8 in thymus function. Cell Death & Differentiation 2013, 21, 226 -233.
AMA StyleN Pozzesi, Alessandra Fierabracci, A M Liberati, M P Martelli, Emira Ayroldi, Carlo Riccardi, D V Delfino. Role of caspase-8 in thymus function. Cell Death & Differentiation. 2013; 21 (2):226-233.
Chicago/Turabian StyleN Pozzesi; Alessandra Fierabracci; A M Liberati; M P Martelli; Emira Ayroldi; Carlo Riccardi; D V Delfino. 2013. "Role of caspase-8 in thymus function." Cell Death & Differentiation 21, no. 2: 226-233.
Cristiana Gambelunghe; Mauro Bacci; Kyriaki Aroni; Filomena De Falco; Emira Maria Ayroldi. Cocaine Addiction Treatment and Home Remedies: Use of the Scopolamine Transdermal Patch. Substance Use & Misuse 2013, 49, 1 -6.
AMA StyleCristiana Gambelunghe, Mauro Bacci, Kyriaki Aroni, Filomena De Falco, Emira Maria Ayroldi. Cocaine Addiction Treatment and Home Remedies: Use of the Scopolamine Transdermal Patch. Substance Use & Misuse. 2013; 49 (1-2):1-6.
Chicago/Turabian StyleCristiana Gambelunghe; Mauro Bacci; Kyriaki Aroni; Filomena De Falco; Emira Maria Ayroldi. 2013. "Cocaine Addiction Treatment and Home Remedies: Use of the Scopolamine Transdermal Patch." Substance Use & Misuse 49, no. 1-2: 1-6.
Long Glucocorticoid-Induced Leucine Zipper (L-GILZ) is a newly identified isoform of the better characterized GILZ, a glucocorticoid (GC)-induced gene, which plays an important role in GC-induced immunomodulation. GILZ interacts with many signaling proteins, such as NF-kB, Ras and Raf, inhibiting downstream signaling pathways and affecting cell cycle, apoptosis, and differentiation. L-GILZ interacts with Ras and contributes to cell differentiation control. The p53 transcription factor regulates the expression of genes crucial for biological processes such as apoptosis, cell proliferation, metabolism, senescence and cell repair. Activation of p53 can suppress neoplastic transformation, inhibiting the growth of mutated or damaged cells. Notably, p53 binding proteins, such as MDM2, limit p53 activity thus regulating p53 stress response. We here demonstrate that L-GILZ activates p53 and induces inhibition of cell proliferation and tumor cell growth. In particular, over-expression of L-GILZ in (p53+/+) HCT116 human colorectal carcinoma cells, results in inhibition of cell proliferation, induction of apoptosis and suppression of growth of xenograft in mice. Moreover, expression of p21 and PUMA is increased in L-GILZ-transfected (p53+/+) but not in (p53-/-) HCT116 cell line. A direct interaction of L-GILZ with both p53 and MDM2 appears to regulate p53 activation. In fact, we demonstrate that the binding affinity of L-GILZ for MDM2 is higher than that for p53 and that L-GILZ disturbs p53/MDM2 complex formation thus making p53 available for downstream gene activation. These findings reveal L-GILZ as a novel p53 regulator and as a candidate for new therapeutic anticancer strategies targeting p53.
Ayroldi Emira; Petrillo Grazia; Bastianelli Alessandra; Ronchetti Simona; Marchetti Cristina; Nocentini Giuseppe; Cannarile Lorenza; Riccardi Carlo. L-GILZ forms a complex with p53 and mdm2 and suppresses tumor growth through p53 activation. Frontiers in Immunology 2013, 4, 1 .
AMA StyleAyroldi Emira, Petrillo Grazia, Bastianelli Alessandra, Ronchetti Simona, Marchetti Cristina, Nocentini Giuseppe, Cannarile Lorenza, Riccardi Carlo. L-GILZ forms a complex with p53 and mdm2 and suppresses tumor growth through p53 activation. Frontiers in Immunology. 2013; 4 ():1.
Chicago/Turabian StyleAyroldi Emira; Petrillo Grazia; Bastianelli Alessandra; Ronchetti Simona; Marchetti Cristina; Nocentini Giuseppe; Cannarile Lorenza; Riccardi Carlo. 2013. "L-GILZ forms a complex with p53 and mdm2 and suppresses tumor growth through p53 activation." Frontiers in Immunology 4, no. : 1.