Publications by authors named "Gennaro Bruno"

28 Publications

  • Page 1 of 1

Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells.

Cancers (Basel) 2021 Jul 15;13(14). Epub 2021 Jul 15.

Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.

Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination.
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http://dx.doi.org/10.3390/cancers13143551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305480PMC
July 2021

Thermodilatometric Study of the Decay of Zeolite-Bearing Building Materials.

Materials (Basel) 2021 Jun 25;14(13). Epub 2021 Jun 25.

ACSLabs-Applied Chemistry Labs, Department of Chemical, Materials Engineering and Industrial Production, University of Naples Federico II, P.le V. Tecchio 80, 80125 Naples, Italy.

Six zeolite-bearing rocks, often used as building materials, were analyzed by thermodilatometry, together with a rock not bearing zeolites and a plaster covering a containing wall made of zeolite-bearing dimension stones, up to 250 °C. The main results obtained were the following: (i) the zeolite-bearing rocks exhibited very small, if any, positive variation of ΔL/L (%) up to about 100 °C, whereas they more or less shrank in the temperature range 100-250 °C (final values ranging from -0.21 to -0.92%); (ii) the rock not bearing zeolites regularly expanded through the whole temperature range, attaining a final value of 0.19%; (iii) the plaster showed a thermodilatometric behavior strongly affected by its water content. Obtained results were interpreted based on plain thermal expansion, shrinkage by dehydration, cation migration and thermal collapse of the zeolitic structure. The decay of the zeolite-bearing building materials was essentially related to: (i) the large differences recorded in the thermodilatometric behavior of the various rocks and the plaster; (ii) the different minerogenetic processes that resulted in the deposition of the various zeolite-bearing rocks.
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http://dx.doi.org/10.3390/ma14133551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269499PMC
June 2021

Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain.

Cancer Res 2021 Jun 26;81(12):3387-3401. Epub 2021 Mar 26.

Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.

Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260461PMC
June 2021

Removal of non-steroidal anti-inflammatory drugs from water by zeolite-rich composites: The interference of inorganic anions on the ibuprofen and naproxen adsorption.

J Environ Manage 2021 May 23;286:112168. Epub 2021 Feb 23.

Department of Earth, Environment, and Resources Sciences, Federico II University, via Cinthia, 80126, Napoli, Italy.

Composites of two natural zeolites - clinoptilolite and phillipsite, and cationic surfactants (cetylpyridinium chloride and Arquad® 2HT-75) were tested for the removal of two emerging contaminants - ibuprofen and naproxen. For each zeolite-rich rock, two different modifications of the zeolitic surfaces were prepared (monolayer and bilayer surfactant coverage). The influence of the initial drug concentrations and contact time on adsorption of these drugs was followed in buffer solution. The Langmuir model showed the highest adsorption capacity for the composite characterized by a bilayered surfactant at the clinoptilolite surface: 19.7 mg/g and 16.1 mg/g for ibuprofen and naproxen, respectively. Also, to simulate real systems, drug adsorption isotherms were conducted in natural water (Grindstone creek water - Columbia, Missouri, USA) by using the best performing adsorbent; in this case, a slight decrease of drug adsorption was recorded. Kinetic runs were performed in distilled water as well as in the presence of ions such as sulfates and bicarbonates; also, in this case, the interfering agents defined an adsorption decrease for bilayer composites.
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http://dx.doi.org/10.1016/j.jenvman.2021.112168DOI Listing
May 2021

Beta-Blockers and Berberine: A Possible Dual Approach to Contrast Neuroblastoma Growth and Progression.

Oxid Med Cell Longev 2020 12;2020:7534693. Epub 2020 Aug 12.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

The use of nutraceuticals during cancer treatment is a long-lasting debate. Berberine (BBR) is an isoquinoline quaternary alkaloid extracted from a variety of medicinal plants. BBR has been shown to have therapeutic effects in different pathologies, particularly in cancer, where it affects pathways involved in tumor progression. In neuroblastoma, the most common extracranial childhood solid tumor, BBR, reduces tumor growth by regulating both stemness and differentiation features and by inducing apoptosis. At the same time, the inhibition of -adrenergic signaling leads to a reduction in growth and increase of differentiation of neuroblastoma. In this review, we summarize the possible beneficial effects of BBR in counteracting tumor growth and progression in various types of cancer and, in particular, in neuroblastoma. However, BBR administration, besides its numerous beneficial effects, presents a few side effects due to inhibition of MAO A enzyme in neuroblastoma cells. Therefore, herein, we proposed a novel therapeutic strategy to overcome side effects of BBR administration consisting of concomitant administration of BBR together with -blockers in neuroblastoma.
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http://dx.doi.org/10.1155/2020/7534693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443044PMC
May 2021

Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P receptor axis.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 09 19;1865(9):158759. Epub 2020 Jun 19.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.
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http://dx.doi.org/10.1016/j.bbalip.2020.158759DOI Listing
September 2020

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance.

Int J Mol Sci 2020 Jun 12;21(12). Epub 2020 Jun 12.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.
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http://dx.doi.org/10.3390/ijms21124210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352890PMC
June 2020

Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor.

Cancers (Basel) 2020 May 30;12(6). Epub 2020 May 30.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, 50139 Florence, Italy.

Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.
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http://dx.doi.org/10.3390/cancers12061415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352170PMC
May 2020

The WD40 repeat protein, WDR36, orchestrates sphingosine kinase-1 recruitment and phospholipase C-β activation by G-coupled receptors.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 07 31;1865(7):158704. Epub 2020 Mar 31.

Institut für Allgemeine Pharmakologie und Toxikologie, Universitätsklinikum, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address:

Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that G-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed G regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Gα to phospholipase C (PLC)-β and the thromboxane A receptor-β (TPβ receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPβ receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M and bradykinin B receptors. In agreement with its effect on PLCβ, WDR36 augmented TPβ receptor-induced [Ca] increases. Surprisingly, WDR36 also augmented M receptor-induced [Ca] increases, which was due to increased Ca mobilization while the Ca content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by G-coupled M, B and H receptors in HEK-293 cells, while TPβ receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B receptors. It is concluded that WDR36 reduces signalling of G-coupled receptors other than TPβ towards PLC and SphK1, most likely by scavenging Gα and PLCβ. Our results support a role of WDR36 in orchestration of G signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
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http://dx.doi.org/10.1016/j.bbalip.2020.158704DOI Listing
July 2020

β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Hematology-Oncology Department, "Anna Meyer Children's Hospital", 50139 Florence, Italy.

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.
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http://dx.doi.org/10.3390/ijms21041420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073111PMC
February 2020

Pozzolanic Activity of Zeolites: The Role of Si/Al Ratio.

Materials (Basel) 2019 Dec 17;12(24). Epub 2019 Dec 17.

Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, Università Federico II di Napoli, Piazzale V. Tecchio 80, 80125 Naples, Italy.

A great challenge of research is the utilization of natural or synthetic zeolites, in place of natural pozzolans, for manufacturing blended cements. The difficulties of interpretation of the pozzolanic behavior of natural zeolite-rich materials and the role played by their nature and composition can be overcome by studying more simple systems, such as pure synthetic zeolites. This study aims at investigating the pozzolanic ability of isostructural zeolites with different framework compositions, such as three sodium zeolites of the faujasite (FAU) framework type: LSX, X, and Y. The pozzolanic activity has been estimated by thermogravimetry and X-ray diffraction analysis. The overall outcome of the investigation is that the zeolite structure affects its pozzolanic activity, as zeolites with similar framework densities exhibit distinct abilities to fix lime. Moreover, the framework composition is effective either from a kinetic point of view or on the total amount of fixed lime. Zeolite X appears to possess the best average features.
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http://dx.doi.org/10.3390/ma12244231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947560PMC
December 2019

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P modulation.

Oncogene 2020 01 2;39(2):368-384. Epub 2019 Sep 2.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P signaling.
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http://dx.doi.org/10.1038/s41388-019-0993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949192PMC
January 2020

Surface modified natural zeolites (SMNZs) as nanocomposite versatile materials for health and environment.

Colloids Surf B Biointerfaces 2019 Oct 18;182:110380. Epub 2019 Jul 18.

Department of Science and Technology, University of Sannio, Via De Sanctis snc, 82100 Benevento, Italy.

The present research deals with the evaluation of a clinoptilolite-rich rock, occurring in the Nižný Hrabovec deposit (Slovakia), for high-value technological applications based on sorption and in vitro release of nonsteroidal anti-inflammatory drugs (i.e., ibuprofen sodium salt). This georesource was surface modified (SMNZ) using four cationic surfactants. Results demonstrate that ibuprofen sorption is very fast and SMZNs can sorb up to ˜26 mg/g of drug as a function of the type of counterion and morphology of surfactant, as well as the hydrophobicity and molecular structure of the drug. Maximum sorption capacities observed for all SMNZs are fully comparable to other adsorbent carriers usually used for removal of contaminants in wastewaters. Sorption of ibuprofen is controlled by a dual mechanism: external anionic exchange and partition into the hydrophobic portion of the patchy bilayer. A prompt drug release in simulated intestinal fluid (SIF) was also observed, making this natural material also suitable to provide rapid soothing effects in potential pharmacological applications. Comparing the results of this study with other recent investigations, a good technological performance of clinoptilolite-rich rock can be inferred despite the relatively low zeolite content (˜56 wt.%).
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http://dx.doi.org/10.1016/j.colsurfb.2019.110380DOI Listing
October 2019

Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1.

FEBS Open Bio 2019 06 20;9(6):1082-1096. Epub 2019 Apr 20.

Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', University of Florence, Italy.

Oxidative stress and abnormal osteocyte apoptosis are often related to dysregulation of bone turnover and chronic bone loss, and so fruit and vegetables with high antioxidant potential may play an important role in the prevention and/or management of osteoporosis. Osteocytes are the main regulators of bone remodelling. For the first time, we demonstrate here that blueberry juice (BJ), obtained from Vaccinium myrtillus, rich in polyphenols, shows antioxidant and antiosteoclastogenic properties in MLO-Y4 osteocytes. We report that BJ prevents oxidative stress-induced apoptosis and reverses the increase in receptor activator of nuclear factor κB ligand and sclerostin expression, crucial factors for osteoclast activation and bone resorption. BJ is also able to prevent oxidative stress-induced cell cytotoxicity in bone marrow mesenchymal stromal cells (MSCs), which are considered to be an important tool for cell therapy in bone disorders. No significant difference in preventing these events was observed between BJ and blueberry dry extract containing equal amounts of total soluble polyphenols. We have also shown that blueberry acts as both an antioxidant and an activator of sirtuin type 1, a class III histone deacetylase involved in cell death regulation and considered a molecular target for blocking bone resorption without affecting osteoclast survival. Overall, these novel data obtained in osteocytes and MSCs may help us clarify the mechanisms by which blueberry counteracts oxidative stress-induced damage in bone remodelling and osteogenesis at the cellular and molecular level. Our findings are consistent with the reported beneficial effects of blueberry on bone tissue reported in animal studies, which suggest that blueberry may be a useful supplement for the prevention and/or management of osteoporosis and osteogenic process.
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http://dx.doi.org/10.1002/2211-5463.12634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551492PMC
June 2019

β -Adrenoceptor as a potential immuno-suppressor agent in melanoma.

Br J Pharmacol 2019 07 9;176(14):2509-2524. Epub 2019 May 9.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer University Children's Hospital, Florence, Italy.

Background And Purpose: Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β -adrenoceptors have been identified as new targets in treating melanoma. Recently, β -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β -adrenoceptors in immune-tolerance regulation.

Experimental Approach: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β - or β -adrenoceptors were used.

Key Results: Only β -, but not β -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes.

Conclusions And Implications: Our data suggest that β -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth.

Linked Articles: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592854PMC
July 2019

3-Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells.

Oxid Med Cell Longev 2018 13;2018:6816508. Epub 2018 Nov 13.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, A. Meyer Children's University Hospital, Florence, Italy.

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that 3-adrenergic receptor (3-AR) is involved in tumor progression, playing an important role in metastasis. Among -adrenergic receptors, 3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. 3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, 3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that 3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The 3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific 3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of 3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
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http://dx.doi.org/10.1155/2018/6816508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258109PMC
January 2019

Bradykinin mediates myogenic differentiation in murine myoblasts through the involvement of SK1/Spns2/S1P axis.

Cell Signal 2018 05 3;45:110-121. Epub 2018 Feb 3.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale GB Morgagni 50, 50134 Firenze, Italy; Istituto interuniversitario di Miologia, IIM, Padova, Italy.

Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration. Growth factors exploit sphingosine kinase (SK), the enzyme that catalyzes the production of sphingosine 1-phosphate (S1P), to exert their biological effects in skeletal muscle. In this paper we show for the first time that bradykinin (BK), the leading member of kinin/kallikrein system, is able to induce myogenic differentiation in C2C12 myoblasts. Moreover, evidence is provided that SK1, the specific S1P-transporter spinster homolog 2 (Spns2) and S1P receptor are involved in the action exerted by BK, since pharmacological inhibition/antagonism or specific down-regulation significantly alter BK-induced myogenic differentiation. Moreover, the molecular mechanism initiated by BK involves a rapid translocation of SK1 to plasma membrane, analyzed by time-lapse immunofluorescence analysis. The present study highlights the role of SK1/Spns2/S1P receptor 2 signaling axis in BK-induced myogenic differentiation, thus confirming the crucial involvement of this pathway in skeletal muscle cell biology.
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http://dx.doi.org/10.1016/j.cellsig.2018.02.001DOI Listing
May 2018

On the Use of Nonsteroidal Anti-Inflammatory Drugs as Rheology Modifiers for Surfactant Solutions.

J Pharm Sci 2017 11 13;106(11):3410-3412. Epub 2017 Jul 13.

DICMaPI, Università degli Studi di Napoli Federico II, Napoli, Italy.

Surfactant molecules can give rise to different morphological structures, depending on numerous parameters such as temperature, surfactant concentration, and salinity. Specifically, the salt content can be easily tuned in a way to induce morphological transitions and modulate the rheological response. It is shown that nonsteroidal anti-inflammatory drugs can be used in the same way as classical binding salts in changing the rheological properties of the resulting gel-like system. On the one hand, the experimental results show that by tuning small details in the molecular conformation of the drug and its concentration in the micellar solution, it is possible to obtain the desired mechanical response. On the other hand, the results prove that rheology can be considered as a powerful tool to detect the drug release content, with obvious consequences on possible applications.
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http://dx.doi.org/10.1016/j.xphs.2017.07.002DOI Listing
November 2017

Adsorption of the mycotoxin zearalenone by clinoptilolite and phillipsite zeolites treated with cetylpyridinium surfactant.

Colloids Surf B Biointerfaces 2017 Mar 23;151:324-332. Epub 2016 Dec 23.

Department of Chemical, Materials and Industrial Production Engineering, Federico II University, Piazzale V. Tecchio, 80, 80125 Naples, Italy.

In this study, organozeolites were prepared by treatment of the natural zeolites (clinoptilolite and phillipsite) with cetylpyridinium chloride (CP) equivalent to 50 and 100% of their external cation exchange capacities (ECEC). Organoclinoptilolites (ZCPs) and organophillipsites (PCPs) were characterized by FTIR spectroscopy, thermal analysis, determination of the point of zero charge and zeta potential. Adsorption of zearalenone (ZEN) by ZCPs and PCPs at pH 3 and 7 was investigated. Results showed that adsorption of ZEN increases with increasing amounts of CP at the zeolitic surfaces for both ZCPs and PCPs but the adsorption mechanism was different. Adsorption of ZEN by ZCPs followed a linear type of isotherm at pH 3 and 7 while ZEN adsorption by PCPs showed non linear (Langmuir and Freundlich) type of isotherm at both pH values. Different interactions between the ZEN molecule (or ion) and ZCPs and PCPs occurred: partition (linear isotherms) and adsorption in addition to partition (non linear isotherms), respectively. For the highest level of organic phase at the zeolitic surfaces, the maximum adsorbed amount of ZEN was 5.73mg/g for organoclinoptilolite and 6.86mg/g for organophillipsite at pH 3. Slightly higher adsorption: 6.98mg/g for organoclinoptilolite and 7.54mg/g for organophillipsite was achieved at pH 7. The results confirmed that CP ions at both zeolitic surfaces are responsible for ZEN adsorption and that organophillipsites are as effective in ZEN adsorption as organoclinoptilolites.
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http://dx.doi.org/10.1016/j.colsurfb.2016.12.033DOI Listing
March 2017

Surface modified zeolite-based granulates for the sustained release of diclofenac sodium.

Eur J Pharm Sci 2017 Mar 22;99:202-208. Epub 2016 Dec 22.

Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano 49, Napoli, Italy; Interdisciplinary Research Centre on Biomaterials - CRIB - Università di Napoli Federico II, P.le Tecchio, 80, Napoli, Italy.

In this study, a granulate for the oral controlled delivery of diclofenac sodium (DS), an anionic sparingly soluble nonsteroidal anti-inflammatory drug, has been realized by wet granulation, using a surface modified natural zeolite (SMNZ) as an excipient. The surface modification of the zeolite has been achieved by means of a cationic surfactant, so as to allow the loading of DS through ionic interaction and bestow a control over the drug release mechanism. The granules possessed a satisfactory dosage uniformity, a flowability suitable for an oral dosage form manufacturing, along with a sustained drug release up to 9h, driven by both ion exchange and transport kinetics. Furthermore, the obtained granulate did not elicit a significant cytotoxicity and could also induce a prolonged anti-inflammatory effect on RAW264.7 cells. Taking also into account that natural zeolites are generally abundant and economic, SMNZ can be considered as an attracting alternative excipient for the production of granules with sustained release features.
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http://dx.doi.org/10.1016/j.ejps.2016.12.019DOI Listing
March 2017

Endothelial sphingosine kinase/SPNS2 axis is critical for vessel-like formation by human mesoangioblasts.

J Mol Med (Berl) 2015 Oct 9;93(10):1145-57. Epub 2015 May 9.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università di Firenze, Viale G.B. Morgagni 50, 50134, Florence, Italy.

Unlabelled: The interaction between endothelial cells and pericytes is crucial for the stabilization of newly formed vessels in angiogenesis. The comprehension of the mechanisms regulating pericyte recruitment might open therapeutical perspectives on vascular-related pathologies. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that derives from sphingomyelin catabolism and regulates biological functions in cell survival, proliferation, and differentiation. In this study, we aimed to identify the role of S1P axis in the intercellular communication between human mesenchymal progenitor mesoangioblasts (MAB) and endothelial cells (human microvascular endothelial cells (H-MVEC)) in the formation of capillary-like structures. We demonstrated that the S1P biosynthetic pathway brought about by sphingosine kinases (SK) SK1 and SK2 as well as spinster homolog 2 (SPNS2) transporter in H-MVEC is crucial for MAB migration measured by Boyden chambers and for the formation and stabilization of capillary-like structures in a 3D Matrigel culture. Moreover, the conditioned medium (CM) harvested from H-MVEC, where SK1, SK2, and SPNS2 were down-regulated, exerted a significantly diminished effect on MAB capillary morphogenesis and migration. Notably, we demonstrated that S1P1 and S1P3 receptors were positively involved in CM-induced capillary-like formation and migration, while S1P2 exerted a negative role on CM-induced migratory action of MAB. Finally, SK inhibition as well as MAB S1P1 and S1P3 down-regulation impaired H-MVEC-MAB cross-talk significantly reducing in vivo angiogenesis evaluated by Matrigel plug assay. These findings individuate novel targets for the employment of MAB in vascular-related pathologic conditions.

Key Message: • Down-regulation of SK1/2 in H-MVEC impaired vessel formation when cultured with MAB. • H-MVEC SPNS2 is critical for morphogenesis and migration induced by H-MVEC CM of MAB. • CM from SK1- and SK2-siRNA H-MVEC impaired morphogenesis and migration of MAB. • S1P1/3 were involved on CM-induced morphogenesis and migration of MAB. • Matrigel plug assay showed the role of S1P axis in MAB-endothelial cell interaction.
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http://dx.doi.org/10.1007/s00109-015-1292-0DOI Listing
October 2015

Surface modified natural zeolite as a carrier for sustained diclofenac release: A preliminary feasibility study.

Colloids Surf B Biointerfaces 2015 Jun 3;130:101-9. Epub 2015 Apr 3.

Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy; Interdisciplinary Research Centre on Biomaterials - CRIB - Università di Napoli Federico II, P.le Tecchio 80, Napoli, Italy. Electronic address:

In view of zeolite potentiality as a carrier for sustained drug release, a clinoptilolite-rich rock from California (CLI_CA) was superficially modified with cetylpyridinium chloride and loaded with diclofenac sodium (DS). The obtained surface modified natural zeolites (SMNZ) were characterized by confocal scanning laser microscopy (CLSM), powder X-ray diffraction (XRPD) and laser light scattering (LS). Their flowability properties, drug adsorption and in vitro release kinetics in simulated intestinal fluid (SIF) were also investigated. CLI_CA is a Na- and K-rich clinoptilolite with a cationic exchange ability that fits well with its zeolite content (clinoptilolite=80 wt%); the external cationic exchange capacity is independent of the cationic surfactant used. LS and CLSM analyses have shown a wide distribution of volume diameters of SMNZ particles that, along with their irregular shape, make them cohesive with scarce flow properties. CLSM observation has revealed the localization of different molecules in/on SMNZ by virtue of their chemical nature. In particular, cationic and polar probes prevalently localize in SMNZ bulk, whereas anionic probes preferentially arrange themselves on SMNZ surface and the loading of a nonpolar molecule in/on SMNZ is discouraged. The adsorption rate of DS onto SMNZ was shown by different kinetic models highlighting the fact that DS adsorption is a pseudo-second order reaction and that the diffusion through the boundary layer is the rate-controlling step of the process. DS release in an ionic medium, such as SIF, can be sustained for about 5h through a mechanism prevalently governed by anionic exchange with a rapid final phase.
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http://dx.doi.org/10.1016/j.colsurfb.2015.03.052DOI Listing
June 2015

CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFβ.

Biochim Biophys Acta 2015 Feb 29;1851(2):194-202. Epub 2014 Nov 29.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio," Università di Firenze, Viale G.B. Morgagni 50, Firenze 50134, Italy; Istituto Interuniversitario di Miologia, Italy. Electronic address:

The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGFβ) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins α-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P3 signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P3 became the S1P receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGFβ-dependent up-regulation of SK1/S1P3 signaling axis and strongly reduced the profibrotic effect exerted by TGFβ, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGFβ challenge in the transmission of at least part of its profibrotic effect. These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P3 axis plays a critical role in the onset of fibrotic cell phenotype.
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http://dx.doi.org/10.1016/j.bbalip.2014.11.011DOI Listing
February 2015

Lysophosphatidic acid stimulates cell migration of satellite cells. A role for the sphingosine kinase/sphingosine 1-phosphate axis.

FEBS J 2014 Oct 25;281(19):4467-78. Epub 2014 Aug 25.

Dipartimento di Scienze Biomediche Sperimentali e Cliniche 'Mario Serio', Università di Firenze, Italy; Istituto Interuniversitario di Miologia, Italy.

Regulation of the motility of skeletal muscle precursor cells, such as satellite cells, is critically important for their proper recruitment at the site of tissue damage, and ultimately for its correct repair. Here we show that lysophosphatidic acid (LPA), which is well-recognized as a powerful bioactive agent, strongly stimulates cell migration of activated murine satellite cells. The biological effect exerted by LPA was found to be induced via activation of LPA1 and LPA3 , being abolished by cell treatment with the antagonist Ki16425, and severely impaired by siRNA-mediated down-regulation of the two receptor isoforms. In contrast, silencing of LPA2 potentiated the stimulation of cell motility by LPA, suggesting that it is negatively coupled to cell migration. Pharmacological inhibition of both sphingosine kinase (SK) isoforms using VPC96047, or the selective blocking of SK1 using VPC96091, abolished cell responsiveness to LPA; in agreement, gene silencing of SK1 or SK2 significantly reduced the biological effect of LPA. Moreover, the LPA-dependent stimulation of cell chemotaxis was found to be impaired by down-regulation of the sphingosine 1-phosphate (S1P) receptors S1P1 or S1P4 by specific siRNAs. In summary, the results obtained support the notion that the sphingosine kinase/sphingosine 1-phosphate (SK/S1P) axis is critically involved in the mechanism by which LPA elicits its pro-migratory action. This study provides compelling new information on the regulatory mechanisms of satellite cell motility, and reinforces the view that the SK/S1P signaling pathway plays a crucial role in the control of skeletal muscle precursor cell biology.
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http://dx.doi.org/10.1111/febs.12955DOI Listing
October 2014

Anion exchange selectivity of surfactant modified clinoptilolite-rich tuff for environmental remediation.

J Colloid Interface Sci 2014 Sep 2;430:178-83. Epub 2014 Jun 2.

Dipartimento di Scienze e Tecnologie, Università del Sannio, Via dei Mulini 59/A, 82100 Benevento, Italy. Electronic address:

Lately, the functionalization of industrial minerals with high technological properties, such as natural zeolites, is shaping as a promising approach in environmental sphere. In fact, under the specific conditions, the surface functionalization via adsorption of cationic surfactants reverses the surface charge of the mineral, enabling zeolites to simultaneously interact either with organic contaminants or inorganic anions. This aspect allows zeolites to be used in the remediation of contaminated fluids. The present research shed new light on some still not fully understood aspects concerning exchange kinetics such as anion-exchange mechanisms and selectivity of surface modified minerals. For this purpose the mineralogical characterization and the surface properties evaluation (X Ray Powder Diffraction, chemical analysis, thermal analysis, ECEC and AEC) of a clinoptilolite-rich tuff were performed, and the anion exchange isotherms of the sample, modified with hexadecyltrimethylammonium chloride or bromide (HDTMA-Cl/-Br), were determined. Ion-exchange equilibrium data of uni-uni valent reaction were obtained by solutions containing Br(-), Cl(-), NO3(-) or ClO4(-). Liquid phase was analysed via high performance liquid chromatography. Thermodynamic quantities (Ka and ΔG(0)) were determined and compared with the Hofmeister series. The value of the ECEC, calculated in batch conditions, was about 137 mmol/kg, in good agreement with that evaluated in dynamic conditions, while the AEC data were different for the SMNZ-Br and -Cl samples, amounting to 137 and 106 mmol/kg, respectively, thus indicating a different compactness of the bilayer formed in the two cases. Moreover, the anion isotherm results and the mathematical evaluation of the thermodynamic parameters, demonstrated the good affinity of SMNZ-Br towards chloride, nitrate and perchlorate, and of SMNZ-Cl for nitrate and perchlorate, also endorsing the possibility of using the same thermodynamic approach developed to describe cation exchange selectivity in zeolites. Finally, it was also verified that the zeolite modified with HDTMA-Cl is able to better exploit its anion exchange capacity compared to the same zeolite modified with HDTMA-Br.
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http://dx.doi.org/10.1016/j.jcis.2014.05.037DOI Listing
September 2014

Ethical and deontological issues in Transfusion Medicine.

Blood Transfus 2013 Jan 19;11(1):14-25. Epub 2012 Sep 19.

Institute of Bioethics, A Gemelli School of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.2450/2012.0087-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557472PMC
January 2013

Solidification of Cd-bearing zeolitic tuff by reaction with lime.

J Environ Sci Health A Tox Hazard Subst Environ Eng 2012 ;47(2):228-36

Dipartimento di Scienze della Terra, Università Federico II, Naples, Italy.

This article aims to find a reliable procedure by which to remove Cd(2+) from water and store it safely. The proposed procedure includes Cd(2+) uptake by a zeolitic tuff, a natural cation exchanger, followed by stabilization of the contaminated solid in a hardened lime matrix. Several tuff-lime pastes were examined and their safety tested by cation leaching and mechanical strength measurement. It was demonstrated that a very cheap mixture, containing only 10% lime, is able to safely retain the harmful cation and may be disposed of in a segregated landfill.
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http://dx.doi.org/10.1080/10934529.2012.640894DOI Listing
May 2012

An unconventional method for the recovery of caustic soda from spent Al-rich pickling solutions.

J Environ Manage 2011 Jul 1;92(7):1821-7. Epub 2011 Apr 1.

Dipartimento d'Ingegneria dei Materiali e della Produzione, Università Federico II, Piazzale V. Tecchio 80, 80125 Naples, Italy.

This work presents an unconventional procedure for the recovery of spent Al-rich caustic soda solutions from the pickling of dies for the production of aluminium extrusions. Caustic soda was regenerated at roughly 70%, by precipitating aluminate, after addition of a silica source, in the form of zeolite A, a microporous material that is widely used in many technological sectors. It was shown that the process is reliable and can be repeated for several cycles, provided the concentration of the caustic soda solution is suitably restored. The by-product obtained, zeolite A, proved to be a high-grade material with performance as a cation exchanger and physical sorbent that is certainly comparable to that reported in literature (e.g., cation exchange capacity equal to 5.14 meq g(-1) vs. 5.48 meq g(-1) and water vapour adsorption capacity of 26.5% vs. 27.6% at 16 torr and 298 K). The economics of the process, although not examined yet, would appear generally favourable, considering that zeolite A is a valuable by-product which widely covers the costs for the recovery of the spent solutions. There are, therefore, significant prospects for the use of zeolite A, particularly as a builder in detergent formulation.
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http://dx.doi.org/10.1016/j.jenvman.2011.03.012DOI Listing
July 2011
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