The Experts below are selected from a list of 732 Experts worldwide ranked by ideXlab platform

Monica Emanuelli - One of the best experts on this subject based on the ideXlab platform.

  • Nicotinamide N-Methyltransferase upregulation correlates with tumour differentiation in oral squamous cell carcinoma
    Histology and Histopathology, 2020
    Co-Authors: Monica Emanuelli, Davide Sartini, Valentina Pozzi, Corrado Rubini, Valentina Rossi, Andrea Santarelli, Domenico Ciavarella, Lorenzo Lo Muzio
    Abstract:

    We investigated expression levels of Nicotinamide N-Methyltransferase (NNMT), an enzyme involved in the biotransformation of many drugs and xenobiotic compounds, in oral squamous cell carcinoma (OSCC). Measurements were performed by immunohistochemistry and the relationship between tumour characteristics and NNMT levels in OSCC was studied to evaluate the effectiveness of NNMT as a prognostic marker in squamous cell carcinoma of the oral cavity. In conclusion, the present study suggests that NNMT may have potential as a biomarker and as a therapeutic target for OSCC.

  • Differential expression of Nicotinamide N-Methyltransferase in primary and recurrent ameloblastomas and odontogenic keratocysts.
    European Journal of Clinical Investigation, 2020
    Co-Authors: Marco Mascitti, Davide Sartini, Valentina Pozzi, Corrado Rubini, Andrea Santarelli, Lucrezia Togni, Monica Emanuelli
    Abstract:

    BACKGROUND: Odontogenic tumours are a group of rare heterogeneous diseases that range from hamartomatous tissue proliferations to benign and malignant neoplasms. Recurrences can occur after 10 years, so long-term clinical and radiological follow-up is required. The study of the molecular mechanisms involved in the development of these lesions is necessary to identify new prognostic markers. In this study, we evaluate the possible role of Nicotinamide N-Methyltransferase (NNMT) in ameloblastomas (AM) and odontogenic keratocysts (OKC). MATERIALS AND METHODS: A total of 105 surgical specimens of primary and recurrent lesions were obtained from 55 patients (25 AM, 30 OKC). In particular, 50 AMs (25 primary, 25 recurrences) and 55 OKCs (30 primary, 25 recurrences) were retrieved. We carried out immunohistochemical analyses to evaluate the cytoplasmic expression of NNMT, measuring the percentage of positive cells and the value of NNMT expression intensity. RESULTS: NNMT expression was significantly higher in recurrent than primary AMs (P = .0430). This result was confirmed by staining intensity, showing more cases with moderate/intense staining in recurrent AMs (P = .0470). NNMT expression was significantly lower in recurrent than primary OKC (P = .0014). Staining intensity showed more cases with moderate/intense staining in primary OKCs (P = .0276). CONCLUSIONS: This report is the first to evaluate NNMT expression in odontogenic lesions and to demonstrate a differential expression in recurrent AMs and OKCs, suggesting that there is potential for use of NNMT as prognostic marker.

  • Cancer stem cell enrichment is associated with enhancement of Nicotinamide N-Methyltransferase expression.
    Iubmb Life, 2020
    Co-Authors: Valentina Pozzi, Davide Sartini, Corrado Rubini, Roberto Campagna, Eleonora Salvolini, Guendalina Lucarini, Alessia Salvucci, Monica Emanuelli
    Abstract:

    The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self-renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo-2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic-activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC-enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme Nicotinamide N-Methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC-enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC-associated targets.

  • Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Matthijs J. Van Haren, Monica Emanuelli, Davide Sartini, Ed E. Moret, Johannes J.m. Rood, Alessia Salvucci, Pierrick Craveur, Nicolas Babault
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) catalyzes the methylation of Nicotinamide to form N-methylNicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme’s active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic Nicotinamide binding pocket via π–π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell prolifera...

  • Overexpression of Nicotinamide N-Methyltransferase in HSC-2 OSCC cell line: effect on apoptosis and cell proliferation.
    Clinical Oral Investigations, 2018
    Co-Authors: Riccardo Seta, Monia Cecati, Davide Sartini, Roberto Campagna, Andrea Santarelli, Lorenzo Lo Muzio, Marco Mascitti, Stefania Fumarola, M. Giuliani, Monica Emanuelli
    Abstract:

    Objectives Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cavity. Despite advances in therapeutic approaches, the 5-year survival rate for oral cancer has not improved in the last three decades. Therefore, new molecular targets for early diagnosis and treatment of OSCC are needed. In the present study, we focused on the enzyme Nicotinamide N-Methyltransferase (NNMT). We have previously shown that enzyme expression is upregulated in OSCC and NNMT knockdown in PE/CA PJ-15 cells significantly decreased cell growth in vitro and tumorigenicity in vivo.

Davide Sartini - One of the best experts on this subject based on the ideXlab platform.

  • Nicotinamide N-Methyltransferase upregulation correlates with tumour differentiation in oral squamous cell carcinoma
    Histology and Histopathology, 2020
    Co-Authors: Monica Emanuelli, Davide Sartini, Valentina Pozzi, Corrado Rubini, Valentina Rossi, Andrea Santarelli, Domenico Ciavarella, Lorenzo Lo Muzio
    Abstract:

    We investigated expression levels of Nicotinamide N-Methyltransferase (NNMT), an enzyme involved in the biotransformation of many drugs and xenobiotic compounds, in oral squamous cell carcinoma (OSCC). Measurements were performed by immunohistochemistry and the relationship between tumour characteristics and NNMT levels in OSCC was studied to evaluate the effectiveness of NNMT as a prognostic marker in squamous cell carcinoma of the oral cavity. In conclusion, the present study suggests that NNMT may have potential as a biomarker and as a therapeutic target for OSCC.

  • Differential expression of Nicotinamide N-Methyltransferase in primary and recurrent ameloblastomas and odontogenic keratocysts.
    European Journal of Clinical Investigation, 2020
    Co-Authors: Marco Mascitti, Davide Sartini, Valentina Pozzi, Corrado Rubini, Andrea Santarelli, Lucrezia Togni, Monica Emanuelli
    Abstract:

    BACKGROUND: Odontogenic tumours are a group of rare heterogeneous diseases that range from hamartomatous tissue proliferations to benign and malignant neoplasms. Recurrences can occur after 10 years, so long-term clinical and radiological follow-up is required. The study of the molecular mechanisms involved in the development of these lesions is necessary to identify new prognostic markers. In this study, we evaluate the possible role of Nicotinamide N-Methyltransferase (NNMT) in ameloblastomas (AM) and odontogenic keratocysts (OKC). MATERIALS AND METHODS: A total of 105 surgical specimens of primary and recurrent lesions were obtained from 55 patients (25 AM, 30 OKC). In particular, 50 AMs (25 primary, 25 recurrences) and 55 OKCs (30 primary, 25 recurrences) were retrieved. We carried out immunohistochemical analyses to evaluate the cytoplasmic expression of NNMT, measuring the percentage of positive cells and the value of NNMT expression intensity. RESULTS: NNMT expression was significantly higher in recurrent than primary AMs (P = .0430). This result was confirmed by staining intensity, showing more cases with moderate/intense staining in recurrent AMs (P = .0470). NNMT expression was significantly lower in recurrent than primary OKC (P = .0014). Staining intensity showed more cases with moderate/intense staining in primary OKCs (P = .0276). CONCLUSIONS: This report is the first to evaluate NNMT expression in odontogenic lesions and to demonstrate a differential expression in recurrent AMs and OKCs, suggesting that there is potential for use of NNMT as prognostic marker.

  • Cancer stem cell enrichment is associated with enhancement of Nicotinamide N-Methyltransferase expression.
    Iubmb Life, 2020
    Co-Authors: Valentina Pozzi, Davide Sartini, Corrado Rubini, Roberto Campagna, Eleonora Salvolini, Guendalina Lucarini, Alessia Salvucci, Monica Emanuelli
    Abstract:

    The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self-renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo-2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic-activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC-enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme Nicotinamide N-Methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC-enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC-associated targets.

  • Nicotinamide N-Methyltransferase in nonmelanoma skin cancers.
    European Journal of Clinical Investigation, 2019
    Co-Authors: Veronica Pompei, Davide Sartini, Valentina Pozzi, Anna Campanati, Corrado Rubini, E. Molinelli, Valerio Brisigotti, Eleonora Salvolini, Guendalina Lucarini, Annamaria Offidani
    Abstract:

    BACKGROUND: Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the most common forms of nonmelanoma skin cancers (NMSCs). Although successful treatment of these neoplasms is based on surgical excision, an increasing number of BCCs relapses and many SCCs display high rates of recurrence and metastasis. Nicotinamide N-Methyltransferase (NNMT) is a cytosolic enzyme, which was found to be upregulated in different solid tumours. However, there are no data regarding enzyme expression in NMSCs. The aim of this study was therefore to evaluate the potential involvement of NNMT in BCCs and SCCs. MATERIALS AND METHODS: Immunohistochemical analyses were carried out on 40 BCC cases and 39 SCC cases, to evaluate enzyme expression in tumour and surrounding healthy margins. Moreover, the relationship between NNMT intratumour levels and clinico-pathological parameters were explored. RESULTS: Nicotinamide N-Methyltransferase was found to be overexpressed in BCCs compared with control tissues, while a significant enzyme downregulation was detected in SCCs with respect to corresponding healthy margins. In addition, NNMT levels were negatively related to aggressiveness of both BCCs (distinguishing between infiltrative and nodular tumours) and SCCs (considering head and neck forms and tumours of the extremities and trunk). CONCLUSIONS: These evidences seem to demonstrate that the different NNMT dysregulation detected in BCC and SCC may be the result of important biological traits distinctively characterizing these two forms within NMSCs. In addition, enzyme levels seem to be inversely correlated with tumour aggressiveness, thus suggesting the potential suitability of the enzyme as a prognostic biomarker for both neoplasms.

  • Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Matthijs J. Van Haren, Monica Emanuelli, Davide Sartini, Ed E. Moret, Johannes J.m. Rood, Alessia Salvucci, Pierrick Craveur, Nicolas Babault
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) catalyzes the methylation of Nicotinamide to form N-methylNicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme’s active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic Nicotinamide binding pocket via π–π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell prolifera...

Valentina Pozzi - One of the best experts on this subject based on the ideXlab platform.

  • Nicotinamide N-Methyltransferase upregulation correlates with tumour differentiation in oral squamous cell carcinoma
    Histology and Histopathology, 2020
    Co-Authors: Monica Emanuelli, Davide Sartini, Valentina Pozzi, Corrado Rubini, Valentina Rossi, Andrea Santarelli, Domenico Ciavarella, Lorenzo Lo Muzio
    Abstract:

    We investigated expression levels of Nicotinamide N-Methyltransferase (NNMT), an enzyme involved in the biotransformation of many drugs and xenobiotic compounds, in oral squamous cell carcinoma (OSCC). Measurements were performed by immunohistochemistry and the relationship between tumour characteristics and NNMT levels in OSCC was studied to evaluate the effectiveness of NNMT as a prognostic marker in squamous cell carcinoma of the oral cavity. In conclusion, the present study suggests that NNMT may have potential as a biomarker and as a therapeutic target for OSCC.

  • Differential expression of Nicotinamide N-Methyltransferase in primary and recurrent ameloblastomas and odontogenic keratocysts.
    European Journal of Clinical Investigation, 2020
    Co-Authors: Marco Mascitti, Davide Sartini, Valentina Pozzi, Corrado Rubini, Andrea Santarelli, Lucrezia Togni, Monica Emanuelli
    Abstract:

    BACKGROUND: Odontogenic tumours are a group of rare heterogeneous diseases that range from hamartomatous tissue proliferations to benign and malignant neoplasms. Recurrences can occur after 10 years, so long-term clinical and radiological follow-up is required. The study of the molecular mechanisms involved in the development of these lesions is necessary to identify new prognostic markers. In this study, we evaluate the possible role of Nicotinamide N-Methyltransferase (NNMT) in ameloblastomas (AM) and odontogenic keratocysts (OKC). MATERIALS AND METHODS: A total of 105 surgical specimens of primary and recurrent lesions were obtained from 55 patients (25 AM, 30 OKC). In particular, 50 AMs (25 primary, 25 recurrences) and 55 OKCs (30 primary, 25 recurrences) were retrieved. We carried out immunohistochemical analyses to evaluate the cytoplasmic expression of NNMT, measuring the percentage of positive cells and the value of NNMT expression intensity. RESULTS: NNMT expression was significantly higher in recurrent than primary AMs (P = .0430). This result was confirmed by staining intensity, showing more cases with moderate/intense staining in recurrent AMs (P = .0470). NNMT expression was significantly lower in recurrent than primary OKC (P = .0014). Staining intensity showed more cases with moderate/intense staining in primary OKCs (P = .0276). CONCLUSIONS: This report is the first to evaluate NNMT expression in odontogenic lesions and to demonstrate a differential expression in recurrent AMs and OKCs, suggesting that there is potential for use of NNMT as prognostic marker.

  • Cancer stem cell enrichment is associated with enhancement of Nicotinamide N-Methyltransferase expression.
    Iubmb Life, 2020
    Co-Authors: Valentina Pozzi, Davide Sartini, Corrado Rubini, Roberto Campagna, Eleonora Salvolini, Guendalina Lucarini, Alessia Salvucci, Monica Emanuelli
    Abstract:

    The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self-renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo-2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic-activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC-enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme Nicotinamide N-Methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC-enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC-associated targets.

  • Nicotinamide N-Methyltransferase in nonmelanoma skin cancers.
    European Journal of Clinical Investigation, 2019
    Co-Authors: Veronica Pompei, Davide Sartini, Valentina Pozzi, Anna Campanati, Corrado Rubini, E. Molinelli, Valerio Brisigotti, Eleonora Salvolini, Guendalina Lucarini, Annamaria Offidani
    Abstract:

    BACKGROUND: Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the most common forms of nonmelanoma skin cancers (NMSCs). Although successful treatment of these neoplasms is based on surgical excision, an increasing number of BCCs relapses and many SCCs display high rates of recurrence and metastasis. Nicotinamide N-Methyltransferase (NNMT) is a cytosolic enzyme, which was found to be upregulated in different solid tumours. However, there are no data regarding enzyme expression in NMSCs. The aim of this study was therefore to evaluate the potential involvement of NNMT in BCCs and SCCs. MATERIALS AND METHODS: Immunohistochemical analyses were carried out on 40 BCC cases and 39 SCC cases, to evaluate enzyme expression in tumour and surrounding healthy margins. Moreover, the relationship between NNMT intratumour levels and clinico-pathological parameters were explored. RESULTS: Nicotinamide N-Methyltransferase was found to be overexpressed in BCCs compared with control tissues, while a significant enzyme downregulation was detected in SCCs with respect to corresponding healthy margins. In addition, NNMT levels were negatively related to aggressiveness of both BCCs (distinguishing between infiltrative and nodular tumours) and SCCs (considering head and neck forms and tumours of the extremities and trunk). CONCLUSIONS: These evidences seem to demonstrate that the different NNMT dysregulation detected in BCC and SCC may be the result of important biological traits distinctively characterizing these two forms within NMSCs. In addition, enzyme levels seem to be inversely correlated with tumour aggressiveness, thus suggesting the potential suitability of the enzyme as a prognostic biomarker for both neoplasms.

  • Involvement of transforming growth factor beta 1 in the transcriptional regulation of Nicotinamide N-Methyltransferase in clear cell renal cell carcinoma
    Cellular and Molecular Biology, 2018
    Co-Authors: Roberto Campagna, Monia Cecati, Davide Sartini, Valentina Pozzi, Giulio Milanese, Veronica Pompei, Stefania Fumarola, Andrea B. Galosi, Monica Emanuelli
    Abstract:

    Renal cell carcinoma (RCC) is the most common tumor of the kidney and its major histologic subtype is clear cell RCC (ccRCC). About 30% of diagnosed ccRCCs already have metastasis. Traditionally, localized ccRCC is treated with nephrectomy but the relapse rate is 30%. Thus, the discovery of effective biomarkers for early detection, as well as the identification of new targets for molecular-based therapy of ccRCC are urgently required. In this study, we focused on molecules that could modulate the trascription of the enzyme Nicotinamide N-Methyltransferase (NNMT) that is known to be up-regulated in ccRCC. Signal transducer and activator of transcription 3 (STAT3), interleukin 6 (IL-6), hepatocyte nuclear factor 1 beta (HNF-1β) and transforming growth factor beta 1 (TGF-β1) expression levels were determined in tumor and non tumor samples obtained from 30 patients with ccRCC, using Real-Time PCR. Results obtained showed that TGF-β1 is significantly (p

Richard M Weinshilboum - One of the best experts on this subject based on the ideXlab platform.

  • Human Nicotinamide N-Methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization.
    Pharmacogenetics, 1999
    Co-Authors: Diane M. Otterness, Richard M Weinshilboum
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) catalyses the N-methylation of Nicotinamide and structurally related pyridines. NNMT enzymatic activity in human liver varies over a five-fold range with a bimodal frequency distribution - raising the possibility of regulation by a genetic polymorphism. We set out to characterize molecular genetic mechanisms that might be involved in the regulation of individual variation in human liver NNMT activity. After Northern blot analysis confirmed that NNMT is highly expressed in the liver, eight human hepatic biopsy samples, four each with 'low' or 'high' levels of activity, were used to perform quantitative Western blot analysis. There was a highly significant correlation (r(s) = 0.96, P < 0.0001) between NNMT activity and immunoreactive protein in these samples. We next determined that a potent promoter was located within the initial 700 bp of the 5'-flanking region of the human NNMT gene. That gene consists of 3 exons, with an initial 1240 bp intron and a second intron that is approximately 14 kb in length. We subsequently isolated DNA from 27 human liver biopsy samples with low, intermediate or high levels of NNMT activity. The three exons, all 1240 bp of intron 1 and approximately 700 bp of the 5'-flanking region of the NNMT gene were amplified from each of these samples with the polymerase chain reaction, followed by DNA sequencing to identify genetic polymorphisms that might correlate with 'NNMT phenotype'. No single nucleotide polymorphisms (SNPs) or insertion/deletion events were detected within either the exons or 5'-flanking regions of NNMT for these 27 samples. Although there were eight SNPs within intron 1, none were systematically related to level of NNMT activity. These results indicate that the exons and 5'-flanking region of the NNMT gene display little or no sequence variation. Therefore, polymorphisms within these areas of the gene are unlikely to be related to wide individual variations in the level of this enzyme activity in the human liver.

  • Mouse Nicotinamide N-Methyltransferase gene: Molecular cloning, structural characterization, and chromosomal localization
    DNA and Cell Biology, 1998
    Co-Authors: Diane M. Otterness, Christine A. Kozak, Richard M Weinshilboum
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) catalyzes the N-methylation of Nicotinamide and structurally related compounds. There are large strain-dependent variations in the expression of NNMT activity in mouse liver during growth and development, raising the possibility of developmental regulation of the gene. Therefore, we set out to clone and structurally characterize the mouse NNMT gene, Nnmt. The gene spanned approximately 16 kb and consisted of three exons, 348 bp, 208 bp, and 487 bp in length, with an initial 1228-bp intron and a second intron that was approximately 14 kb in length. The locations of the splice junctions within the gene were highly conserved compared with those in genes for structurally related methyltransferase enzymes. The Nnmt gene contained no canonical TATA box sequences, but an "initiator" (Inr) sequence was located at the site of transcription initiation as determined by 5' rapid amplification of cDNAs ends. A promoter was located within the initial 750 bp of the 5' flanking region of the gene according to studies of the expression of a reporter gene in HepG2 cells. 5'-Flanking region sequences for mouse strains with high and low hepatic NNMT activity differed with regard to a series of nucleotide substitutions, insertions, and deletions, with the most striking difference being a 12-bp insertion/deletion. The Nnmt gene mapped to mouse chromosome 9 in an area of conserved synteny to human chromosome 11q, consistent with the localization of the human NNMT gene to 11q23. Cloning and structural characterization of the mouse Nnmt gene will make it possible to study molecular genetic mechanisms involved in the expression of this important methyltransferase.

  • Mouse Liver Nicotinamide N-Methyltransferase:: cDNA Cloning, Expression, and Nucleotide Sequence Polymorphisms
    Biochemical Pharmacology, 1997
    Co-Authors: Diane M. Otterness, Timothy L Craddock, Richard M Weinshilboum
    Abstract:

    Abstract Nicotinamide N -methyltransferase (NNMT) catalyzes the N-methylation of Nicotinamide and structurally related compounds. We cloned mouse liver NNMT cDNA to make it possible to test the hypothesis that large differences among strains in levels of hepatic NNMT activity might be associated with strain-dependent variation in NNMT amino acid sequence. Mouse liver NNMT cDNA was 1015 nucleotides in length with a 792 nucleotide open reading frame (ORF) that was 83% identical to the nucleotide sequence of the human liver NNMT cDNA ORF. The mouse liver cDNA encoded a 264 amino acid protein with a calculated M r value of 29.6 kDa. NNMT cDNA ORF sequences were then determined in five inbred strains of mice with very different levels of hepatic NNMT enzymatic activity. Although multiple differences among strains in nucleotide sequence were observed, none altered encoded amino acids. cDNA sequences for C57BL/6J and C3H/HeJ mice, prototypic strains with “high” and “low” levels of hepatic NNMT activity, respectively, were then expressed in COS-1 cells. Both expression constructs yielded comparable levels of enzyme activity, and biochemical properties of the expressed enzyme, including apparent K m values for substrates and ic 50 values for inhibition by N 1 -methylNicotinamide, were very similar to those of mouse liver NNMT. Growth and development experiments were then conducted, which demonstrated that, although at 8 weeks of age average hepatic NNMT activity in C57BL/6J mice was 5-fold higher than that in C3H/HeJ mice, activities in the two strains were comparable by 30 weeks of age—indicating strain-dependent variation in the developmental expression of NNMT in mouse liver. These observations will serve to focus future studies of strain-dependent differences in murine hepatic NNMT on the regulation of the enzyme activity during growth and development.

  • Mouse liver Nicotinamide N-Methyltransferase pharmacogenetics : biochemical properties and variation in activity among inbred strains
    Pharmacogenetics, 1996
    Co-Authors: Timo Scheller, Halina Orgacka, Carol L. Szumlanski, Richard M Weinshilboum
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) catalyses the N-methylation of Nicotinamide and other pyridines. Human liver NNMT activity shows large individual variations and a bimodal frequency distribution, raising the possibility that this activity, like those of many other methyltransferase enzymes, m

  • Human Nicotinamide N-Methyltransferase gene : molecular cloning, structural characterization and chromosomal localization
    Genomics, 1995
    Co-Authors: Saime Aksoy, B. F. Brandriff, Aviva Ward, Peter F.r. Little, Richard M Weinshilboum
    Abstract:

    Abstract Genomic DNA clones for Nicotinamide N -methyltransferase (NNMT), an enzyme that catalyzes drug and xenobiotic metabolism, were isolated from a human chromosome 11-specific DNA library. Study of one of those clones, when combined with PCR-based experiments performed with human genomic DNA, made it possible to determine the structure of the human NNMT gene. The gene was approximately 16.5 kb in length and consisted of 3 exons and 2 introns. Transcription initiation for the NNMT gene occurred 105–109 nucleotides 5′-upstream from the cDNA translation initiation codon on the basis of the results of both primer extension and 5′-rapid amplification of cDNA ends. NNMT mapped to chromosome band 11q23.1 by fluorescence in situ hybridization.

Corrado Rubini - One of the best experts on this subject based on the ideXlab platform.

  • Nicotinamide N-Methyltransferase upregulation correlates with tumour differentiation in oral squamous cell carcinoma
    Histology and Histopathology, 2020
    Co-Authors: Monica Emanuelli, Davide Sartini, Valentina Pozzi, Corrado Rubini, Valentina Rossi, Andrea Santarelli, Domenico Ciavarella, Lorenzo Lo Muzio
    Abstract:

    We investigated expression levels of Nicotinamide N-Methyltransferase (NNMT), an enzyme involved in the biotransformation of many drugs and xenobiotic compounds, in oral squamous cell carcinoma (OSCC). Measurements were performed by immunohistochemistry and the relationship between tumour characteristics and NNMT levels in OSCC was studied to evaluate the effectiveness of NNMT as a prognostic marker in squamous cell carcinoma of the oral cavity. In conclusion, the present study suggests that NNMT may have potential as a biomarker and as a therapeutic target for OSCC.

  • Differential expression of Nicotinamide N-Methyltransferase in primary and recurrent ameloblastomas and odontogenic keratocysts.
    European Journal of Clinical Investigation, 2020
    Co-Authors: Marco Mascitti, Davide Sartini, Valentina Pozzi, Corrado Rubini, Andrea Santarelli, Lucrezia Togni, Monica Emanuelli
    Abstract:

    BACKGROUND: Odontogenic tumours are a group of rare heterogeneous diseases that range from hamartomatous tissue proliferations to benign and malignant neoplasms. Recurrences can occur after 10 years, so long-term clinical and radiological follow-up is required. The study of the molecular mechanisms involved in the development of these lesions is necessary to identify new prognostic markers. In this study, we evaluate the possible role of Nicotinamide N-Methyltransferase (NNMT) in ameloblastomas (AM) and odontogenic keratocysts (OKC). MATERIALS AND METHODS: A total of 105 surgical specimens of primary and recurrent lesions were obtained from 55 patients (25 AM, 30 OKC). In particular, 50 AMs (25 primary, 25 recurrences) and 55 OKCs (30 primary, 25 recurrences) were retrieved. We carried out immunohistochemical analyses to evaluate the cytoplasmic expression of NNMT, measuring the percentage of positive cells and the value of NNMT expression intensity. RESULTS: NNMT expression was significantly higher in recurrent than primary AMs (P = .0430). This result was confirmed by staining intensity, showing more cases with moderate/intense staining in recurrent AMs (P = .0470). NNMT expression was significantly lower in recurrent than primary OKC (P = .0014). Staining intensity showed more cases with moderate/intense staining in primary OKCs (P = .0276). CONCLUSIONS: This report is the first to evaluate NNMT expression in odontogenic lesions and to demonstrate a differential expression in recurrent AMs and OKCs, suggesting that there is potential for use of NNMT as prognostic marker.

  • Cancer stem cell enrichment is associated with enhancement of Nicotinamide N-Methyltransferase expression.
    Iubmb Life, 2020
    Co-Authors: Valentina Pozzi, Davide Sartini, Corrado Rubini, Roberto Campagna, Eleonora Salvolini, Guendalina Lucarini, Alessia Salvucci, Monica Emanuelli
    Abstract:

    The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self-renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo-2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic-activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC-enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme Nicotinamide N-Methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC-enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC-associated targets.

  • Nicotinamide N-Methyltransferase in nonmelanoma skin cancers.
    European Journal of Clinical Investigation, 2019
    Co-Authors: Veronica Pompei, Davide Sartini, Valentina Pozzi, Anna Campanati, Corrado Rubini, E. Molinelli, Valerio Brisigotti, Eleonora Salvolini, Guendalina Lucarini, Annamaria Offidani
    Abstract:

    BACKGROUND: Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the most common forms of nonmelanoma skin cancers (NMSCs). Although successful treatment of these neoplasms is based on surgical excision, an increasing number of BCCs relapses and many SCCs display high rates of recurrence and metastasis. Nicotinamide N-Methyltransferase (NNMT) is a cytosolic enzyme, which was found to be upregulated in different solid tumours. However, there are no data regarding enzyme expression in NMSCs. The aim of this study was therefore to evaluate the potential involvement of NNMT in BCCs and SCCs. MATERIALS AND METHODS: Immunohistochemical analyses were carried out on 40 BCC cases and 39 SCC cases, to evaluate enzyme expression in tumour and surrounding healthy margins. Moreover, the relationship between NNMT intratumour levels and clinico-pathological parameters were explored. RESULTS: Nicotinamide N-Methyltransferase was found to be overexpressed in BCCs compared with control tissues, while a significant enzyme downregulation was detected in SCCs with respect to corresponding healthy margins. In addition, NNMT levels were negatively related to aggressiveness of both BCCs (distinguishing between infiltrative and nodular tumours) and SCCs (considering head and neck forms and tumours of the extremities and trunk). CONCLUSIONS: These evidences seem to demonstrate that the different NNMT dysregulation detected in BCC and SCC may be the result of important biological traits distinctively characterizing these two forms within NMSCs. In addition, enzyme levels seem to be inversely correlated with tumour aggressiveness, thus suggesting the potential suitability of the enzyme as a prognostic biomarker for both neoplasms.

  • Nicotinamide N-Methyltransferase: potential involvement in cutaneous malignant melanoma
    Melanoma Research, 2018
    Co-Authors: Giulia Ganzetti, Monia Cecati, Davide Sartini, Valentina Pozzi, Anna Campanati, Corrado Rubini, E. Molinelli, Valerio Brisigotti, Roberto Campagna, Annamaria Offidani
    Abstract:

    Nicotinamide N-Methyltransferase (NNMT) is an enzyme that catalyzes the N-methylation of Nicotinamide and pyridine compounds, participating in xenobiotic and drug metabolism. Data on literature have evidenced a possible role of NNMT in many solid cancers, but no data are currently available in cutan