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Dr. Massimo Bortolotti
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Italy

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0 Immunotherapy
0 ricin
0 Immunotoxins
0 plant toxins
0 ribosome-inactivating proteins

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Review
Published: 08 August 2021 in Biomedicines
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Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.

ACS Style

Letizia Polito; Giulia Calafato; Massimo Bortolotti; Cecilia Chiarelli Olivari; Stefania Maiello; Andrea Bolognesi. Antibody Conjugates for Sarcoma Therapy: How Far along Are We? Biomedicines 2021, 9, 978 .

AMA Style

Letizia Polito, Giulia Calafato, Massimo Bortolotti, Cecilia Chiarelli Olivari, Stefania Maiello, Andrea Bolognesi. Antibody Conjugates for Sarcoma Therapy: How Far along Are We? Biomedicines. 2021; 9 (8):978.

Chicago/Turabian Style

Letizia Polito; Giulia Calafato; Massimo Bortolotti; Cecilia Chiarelli Olivari; Stefania Maiello; Andrea Bolognesi. 2021. "Antibody Conjugates for Sarcoma Therapy: How Far along Are We?" Biomedicines 9, no. 8: 978.

Review article
Published: 27 January 2021 in Redox Biology
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Human xanthine oxidoreductase (XOR) is a multiple-level regulated enzyme, resulting from a complicated evolutionary process that assigned it many physiological roles. The main XOR activities are: (i) xanthine dehydrogenase (XDH) activity that performs the last two steps of purine catabolism, from hypoxanthine to uric acid; (ii) xanthine oxidase (XO) activity that, besides purine catabolism, produces reactive oxygen species (ROS); (iii) nitrite reductase activity that generates nitric oxide, contributing to vasodilation and regulation of blood pressure; (iv) NADH oxidase activity that produces ROS. All these XOR activities contribute also to metabolize various endogenous and exogenous compounds, including some drugs. About XOR products, it should be considered that (i) uric acid is not only a proinflammatory agent, but also a fundamental antioxidant molecule in serum and (ii) XOR-derived ROS are essential to the inflammatory defensive response. Although XOR has been the object of a large number of studies, most of them were focused on the pathological consequences of its activity and there is not a clear and schematic picture of XOR physiological roles. In this review, we try to fill this gap, reporting and graphically schematizing the main roles of XOR and its products.

ACS Style

Massimo Bortolotti; Letizia Polito; Maria Giulia Battelli; Andrea Bolognesi. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biology 2021, 41, 101882 .

AMA Style

Massimo Bortolotti, Letizia Polito, Maria Giulia Battelli, Andrea Bolognesi. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biology. 2021; 41 ():101882.

Chicago/Turabian Style

Massimo Bortolotti; Letizia Polito; Maria Giulia Battelli; Andrea Bolognesi. 2021. "Xanthine oxidoreductase: One enzyme for multiple physiological tasks." Redox Biology 41, no. : 101882.

Journal article
Published: 22 January 2021 in Toxins
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Ribosome-inactivating proteins (RIPs) are plant toxins that irreversibly damage ribosomes and other substrates, thus causing cell death. RIPs are classified in type 1 RIPs, single-chain enzymatic proteins, and type 2 RIPs, consisting of active A chains, similar to type 1 RIPs, linked to lectin B chains, which enable the rapid internalization of the toxin into the cell. For this reason, many type 2 RIPs are very cytotoxic, ricin, volkensin and stenodactylin being the most toxic ones. From the caudex of Adenia kirkii (Mast.) Engl., a new type 2 RIP, named kirkiin, was purified by affinity chromatography on acid-treated Sepharose CL-6B and gel filtration. The lectin, with molecular weight of about 58 kDa, agglutinated erythrocytes and inhibited protein synthesis in a cell-free system at very low concentrations. Moreover, kirkiin was able to depurinate mammalian and yeast ribosomes, but it showed little or no activity on other nucleotide substrates. In neuroblastoma cells, kirkiin inhibited protein synthesis and induced apoptosis at doses in the pM range. The biological characteristics of kirkiin make this protein a potential candidate for several experimental pharmacological applications both alone for local treatments and as component of immunoconjugates for systemic targeting in neurodegenerative studies and cancer therapy.

ACS Style

Massimo Bortolotti; Stefania Maiello; José Ferreras; Rosario Iglesias; Letizia Polito; Andrea Bolognesi. Kirkiin: A New Toxic Type 2 Ribosome-Inactivating Protein from the Caudex of Adenia kirkii. Toxins 2021, 13, 81 .

AMA Style

Massimo Bortolotti, Stefania Maiello, José Ferreras, Rosario Iglesias, Letizia Polito, Andrea Bolognesi. Kirkiin: A New Toxic Type 2 Ribosome-Inactivating Protein from the Caudex of Adenia kirkii. Toxins. 2021; 13 (2):81.

Chicago/Turabian Style

Massimo Bortolotti; Stefania Maiello; José Ferreras; Rosario Iglesias; Letizia Polito; Andrea Bolognesi. 2021. "Kirkiin: A New Toxic Type 2 Ribosome-Inactivating Protein from the Caudex of Adenia kirkii." Toxins 13, no. 2: 81.

Review
Published: 08 September 2020 in Antioxidants
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The senescence process is the result of a series of factors that start from the genetic constitution interacting with epigenetic modifications induced by endogenous and environmental causes and that lead to a progressive deterioration at the cellular and functional levels. One of the main causes of aging is oxidative stress deriving from the imbalance between the production of reactive oxygen (ROS) and nitrogen (RNS) species and their scavenging through antioxidants. Xanthine oxidoreductase (XOR) activities produce uric acid, as well as reactive oxygen and nitrogen species, which all may be relevant to such equilibrium. This review analyzes XOR activity through in vitro experiments, animal studies and clinical reports, which highlight the pro-aging effects of XOR products. However, XOR activity contributes to a regular level of ROS and RNS, which appears essential for the proper functioning of many physiological pathways. This discourages the use of therapies with XOR inhibitors, unless symptomatic hyperuricemia is present.

ACS Style

Maria Giulia Battelli; Massimo Bortolotti; Andrea Bolognesi; Letizia Polito. Pro-Aging Effects of Xanthine Oxidoreductase Products. Antioxidants 2020, 9, 839 .

AMA Style

Maria Giulia Battelli, Massimo Bortolotti, Andrea Bolognesi, Letizia Polito. Pro-Aging Effects of Xanthine Oxidoreductase Products. Antioxidants. 2020; 9 (9):839.

Chicago/Turabian Style

Maria Giulia Battelli; Massimo Bortolotti; Andrea Bolognesi; Letizia Polito. 2020. "Pro-Aging Effects of Xanthine Oxidoreductase Products." Antioxidants 9, no. 9: 839.

Journal article
Published: 21 August 2020 in Toxins
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Stenodactylin is one of the most potent type 2 ribosome-inactivating proteins (RIPs); its high toxicity has been demonstrated in several models both in vitro and in vivo. Due to its peculiarities, stenodactylin could have several medical and biotechnological applications in neuroscience and cancer treatment. In this work, we report the complete amino acid sequence of stenodactylin and 3D structure prediction. The comparison between the primary sequence of stenodactylin and other RIPs allowed us to identify homologies/differences and the amino acids involved in RIP toxic activity. Stenodactylin RNA was isolated from plant caudex, reverse transcribed through PCR and the cDNA was amplificated and cloned into a plasmid vector and further analyzed by sequencing. Nucleotide sequence analysis showed that stenodactylin A and B chains contain 251 and 258 amino acids, respectively. The key amino acids of the active site described for ricin and most other RIPs are also conserved in the stenodactylin A chain. Stenodactylin amino acid sequence shows a high identity degree with volkensin (81.7% for A chain, 90.3% for B chain), whilst when compared with other type 2 RIPs the identity degree ranges from 27.7 to 33.0% for the A chain and from 42.1 to 47.7% for the B chain.

ACS Style

Rosario Iglesias; Letizia Polito; Massimo Bortolotti; Manuela Pedrazzi; Lucía Citores; José M. Ferreras; Andrea Bolognesi. Primary Sequence and 3D Structure Prediction of the Plant Toxin Stenodactylin. Toxins 2020, 12, 538 .

AMA Style

Rosario Iglesias, Letizia Polito, Massimo Bortolotti, Manuela Pedrazzi, Lucía Citores, José M. Ferreras, Andrea Bolognesi. Primary Sequence and 3D Structure Prediction of the Plant Toxin Stenodactylin. Toxins. 2020; 12 (9):538.

Chicago/Turabian Style

Rosario Iglesias; Letizia Polito; Massimo Bortolotti; Manuela Pedrazzi; Lucía Citores; José M. Ferreras; Andrea Bolognesi. 2020. "Primary Sequence and 3D Structure Prediction of the Plant Toxin Stenodactylin." Toxins 12, no. 9: 538.

Journal article
Published: 25 June 2020 in Toxicology
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Gene-regulatory networks reconstruction has become a very popular approach in applied biology to infer and dissect functional interactions of Transcription Factors (TFs) driving a defined phenotypic state, termed as Master Regulators (MRs). In the present work, cutting-edge bioinformatic methods were applied to re-analyze experimental data on leukemia cells (human myelogenous leukemia cell line THP-1 and acute myeloid leukemia MOLM-13 cells) treated for 6 h with two different Ribosome-Inactivating Proteins (RIPs), namely Shiga toxin type 1 (400 ng/mL) produced by Escherichia coli strains and the plant toxin stenodactylin (60 ng/mL), purified from the caudex of Adenia stenodactyla Harms. This analysis allowed us to identify the common early transcriptional response to 28S rRNA damage based on gene-regulatory network inference and Master Regulator Analysis (MRA). Both toxins induce a common response at 6 h which involves inflammatory mediators triggered by AP-1 family transcriptional factors and ATF3 in leukemia cells. We describe for the first time the involvement of MAFF, KLF2 and KLF6 in regulating RIP-induced apoptotic cell death, while receptor-mediated downstream signaling through ANXA1 and TLR4 is suggested for both toxins.

ACS Style

Daniele Mercatelli; Massimo Bortolotti; Federico M. Giorgi. Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells. Toxicology 2020, 441, 152531 .

AMA Style

Daniele Mercatelli, Massimo Bortolotti, Federico M. Giorgi. Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells. Toxicology. 2020; 441 ():152531.

Chicago/Turabian Style

Daniele Mercatelli; Massimo Bortolotti; Federico M. Giorgi. 2020. "Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells." Toxicology 441, no. : 152531.

Original research article
Published: 08 May 2020 in Frontiers in Pharmacology
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Stenodactylin, a highly toxic type 2 ribosome-inactivating protein purified from the caudex of Adenia stenodactyla Harms, is a potential anticancer drug candidate. Previous studies demonstrated that stenodactylin induces apoptosis and necroptosis in treated cells, involving the production of reactive oxygen species. We analyzed the effect of stenodactylin on Raji and Ramos (Human Burkitt’s lymphoma cells) and MOLM-13 (acute myeloid leukemia cells). Moreover, we focused on the early events in MOLM-13 cells that characterize the cellular response to the toxin by whole-genome microarray analysis of gene expression. Treatment with stenodactylin induced the depurination of 28S rRNA within 4 h and increased the phosphorylation of p38 and JNK. A time-dependent activation of caspase 1, 2, 8, 9, 3/7 was also observed. Genome-wide gene expression microarray analysis revealed early changes in the expression of genes involved in the regulation of cell death, inflammation and stress response. After 4 h, a significant increase of transcript level was detectable for ATF3, BTG2, DUSP1, EGR1, and JUN. Increased upstream JUN signaling was also confirmed at protein level. The early response to stenodactylin treatment involves inflammatory and apoptotic signaling compatible with the activation of multiple cell death pathways. Because of the above described properties toward acute myeloid leukemia cells, stenodactylin may be a promising candidate for the design of new immunoconjugates for experimental cancer treatment.

ACS Style

Daniele Mercatelli; Massimo Bortolotti; Vibeke Andresen; André Sulen; Letizia Polito; Bjørn Tore Gjertsen; Andrea Bolognesi. Early Response to the Plant Toxin Stenodactylin in Acute Myeloid Leukemia Cells Involves Inflammatory and Apoptotic Signaling. Frontiers in Pharmacology 2020, 11, 630 .

AMA Style

Daniele Mercatelli, Massimo Bortolotti, Vibeke Andresen, André Sulen, Letizia Polito, Bjørn Tore Gjertsen, Andrea Bolognesi. Early Response to the Plant Toxin Stenodactylin in Acute Myeloid Leukemia Cells Involves Inflammatory and Apoptotic Signaling. Frontiers in Pharmacology. 2020; 11 ():630.

Chicago/Turabian Style

Daniele Mercatelli; Massimo Bortolotti; Vibeke Andresen; André Sulen; Letizia Polito; Bjørn Tore Gjertsen; Andrea Bolognesi. 2020. "Early Response to the Plant Toxin Stenodactylin in Acute Myeloid Leukemia Cells Involves Inflammatory and Apoptotic Signaling." Frontiers in Pharmacology 11, no. : 630.

Journal article
Published: 01 February 2020 in Microbial Pathogenesis
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Chlamydia persistence is a viable, but non-cultivable, growth stage, resulting in a long-term relationship with the infected host cell. In vitro, this condition can be induced by different stressor agents, including beta-lactam antibiotics, as penicillin. The aim of this study was to get new insights into the interactions between Chlamydia trachomatis (serovars D and L2) and the epithelial host cells (HeLa) during persistence condition. In particular, we evaluated the following aspects, by comparing the normal chlamydial development cycle with penicillin-induced persistence: (i) cell survival/death, (ii) externalization of phosphatidylserine, (iii) caspase 1 and caspase 3/7 activation, and (iv) reactive oxygen species (ROS) production by the infected cells. At 72 h post-infection, the cytotoxic effect displayed by CT was completely abolished for both serovars and for all levels of multiplicity of infection only in the cells with aberrant CT inclusions. At the same time, CT was able to switch off the exposure of the lipid phosphatidylserine on the surface of epithelial cells and to strongly inhibit the activation of caspase 1 and caspase 3/7 only in penicillin-treated cells. Forty-eight hours post-infection, CT elicited a significant ROS expression both in case of a normal cycle and in case of persistence. However, serovar L and penicillin-free infection activated a higher ROS production compared to serovar D and to penicillin-induced persistence, respectively. In conclusion, we added knowledge to the cellular dynamics taking place during chlamydial persistence, demonstrating that CT creates a suitable niche to survive, switching off signals able to activate phagocytes/leukocytes recruitment. Nevertheless, persistent CT elicits ROS production by the infected cells, potentially contributing to the onset of chronic inflammation and tissue damages.

ACS Style

Claudio Foschi; Massimo Bortolotti; Letizia Polito; Antonella Marangoni; Chiara Zalambani; Irene Liparulo; Romana Fato; Andrea Bolognesi. Insights into penicillin-induced Chlamydia trachomatis persistence. Microbial Pathogenesis 2020, 142, 104035 .

AMA Style

Claudio Foschi, Massimo Bortolotti, Letizia Polito, Antonella Marangoni, Chiara Zalambani, Irene Liparulo, Romana Fato, Andrea Bolognesi. Insights into penicillin-induced Chlamydia trachomatis persistence. Microbial Pathogenesis. 2020; 142 ():104035.

Chicago/Turabian Style

Claudio Foschi; Massimo Bortolotti; Letizia Polito; Antonella Marangoni; Chiara Zalambani; Irene Liparulo; Romana Fato; Andrea Bolognesi. 2020. "Insights into penicillin-induced Chlamydia trachomatis persistence." Microbial Pathogenesis 142, no. : 104035.

Review
Published: 06 June 2019 in Toxins
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The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for several biocrimes. This manuscript intends to give the reader an overview of ricin, focusing on the historical path to the current knowledge on this protein. The main steps of ricin research are here reported, with particular regard to its enzymatic activity, structure, and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation between bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been used to develop immunotoxins for the elimination of unwanted cells, mainly cancer cells; some of these immunoconjugates gave promising results in clinical trials but also showed critical limitation.

ACS Style

Letizia Polito; Massimo Bortolotti; Maria Battelli; Giulia Calafato; Andrea Bolognesi. Ricin: An Ancient Story for a Timeless Plant Toxin. Toxins 2019, 11, 324 .

AMA Style

Letizia Polito, Massimo Bortolotti, Maria Battelli, Giulia Calafato, Andrea Bolognesi. Ricin: An Ancient Story for a Timeless Plant Toxin. Toxins. 2019; 11 (6):324.

Chicago/Turabian Style

Letizia Polito; Massimo Bortolotti; Maria Battelli; Giulia Calafato; Andrea Bolognesi. 2019. "Ricin: An Ancient Story for a Timeless Plant Toxin." Toxins 11, no. 6: 324.

Preprint
Published: 28 May 2019
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The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for biocrimes in several cases. Here, the main steps of ricin research are reported with particular regards to its enzymatic activity, structure and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation amongst bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been of great utility to develop a number of immunotoxins specific for the elimination of unwanted cells, mainly cancer cells; some of these immunotoxins gave promising results also in clinical trials.

ACS Style

Letizia Polito; Massimo Bortolotti; Maria Giulia Battelli; Giulia Calafato; Andrea Bolognesi. Ricin: An Ancient Story for a Timeless Plant Toxin. 2019, 1 .

AMA Style

Letizia Polito, Massimo Bortolotti, Maria Giulia Battelli, Giulia Calafato, Andrea Bolognesi. Ricin: An Ancient Story for a Timeless Plant Toxin. . 2019; ():1.

Chicago/Turabian Style

Letizia Polito; Massimo Bortolotti; Maria Giulia Battelli; Giulia Calafato; Andrea Bolognesi. 2019. "Ricin: An Ancient Story for a Timeless Plant Toxin." , no. : 1.

Mini review article
Published: 08 May 2019 in Frontiers in Pharmacology
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Momordica charantia, commonly called bitter melon, is a plant belonging to Cucurbitaceae family known for centuries for its pharmacological activities, and nutritional properties. Due to the presence of many bioactive compounds, some of which possess potent biological actions, this plant is used in folk medicine all over the world for the treatment of different pathologies, mainly diabetes, but also cancer, and other inflammation-associated diseases. It is widely demonstrated that M. charantia extracts contribute in lowering glycaemia in patients affected by type 2 diabetes. However, the majority of existing studies on M. charantia bioactive compounds were performed only on cell lines and in animal models. Therefore, because the real impact of bitter melon on human health has not been thoroughly demonstrated, systematic clinical studies are needed to establish its efficacy and safety in patients. Besides, both in vitro and in vivo studies have demonstrated that bitter melon may also elicit toxic or adverse effects under different conditions. The aim of this review is to provide an overview of anti-inflammatory and anti-neoplastic properties of bitter melon, discussing its pharmacological activity as well as the potential adverse effects. Even if a lot of literature is available about bitter melon as antidiabetic drug, few papers discuss the anti-inflammatory and anti-cancer properties of this plant.

ACS Style

Massimo Bortolotti; Daniele Mercatelli; Letizia Polito. Momordica charantia, a Nutraceutical Approach for Inflammatory Related Diseases. Frontiers in Pharmacology 2019, 10, 486 .

AMA Style

Massimo Bortolotti, Daniele Mercatelli, Letizia Polito. Momordica charantia, a Nutraceutical Approach for Inflammatory Related Diseases. Frontiers in Pharmacology. 2019; 10 ():486.

Chicago/Turabian Style

Massimo Bortolotti; Daniele Mercatelli; Letizia Polito. 2019. "Momordica charantia, a Nutraceutical Approach for Inflammatory Related Diseases." Frontiers in Pharmacology 10, no. : 486.

Research article
Published: 26 April 2019 in PLOS ONE
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The sexually transmitted pathogen Chlamydia trachomatis (CT) is able to replicate and survive in human intestinal epithelial cells, being the gastro-intestinal tract a suitable site of residence for this microorganism. In this context, no detailed information about the mechanisms of cell death in intestinal cell lines after a chlamydial infection is available. The aim of this study was to compare the effect of two different CT serovars (D and L2) on the survival/death of different intestinal cell lines (Caco-2 and COLO-205), using endocervical cells (HeLa) as a reference model of genital infection. Seventy two hours after chlamydial infection at different multiplicity of infection (MOI) levels, the viability of HeLa, Caco-2 and COLO 205 cells was evaluated through dose-response experiments by means of a MTS-based assay. To get deeper insights in the mechanisms of cell death induced by CT, cell viability was assessed in presence of different inhibitors (i.e. pan-caspase inhibitor Z-VAD, necroptosis inhibitor Necrostatin-1, hydrogen peroxide scavenger catalase, caspase-1 inhibitor Ac-YVAD-cmk). Moreover, the activation of effector caspases and the presence of cellular apoptotic/necrotic changes were evaluated at different time points after CT infection. Our results demonstrated that, for both chlamydial serovars, intestinal cell lines are more resistant to CT-induced cell death compared to HeLa, thus representing a suitable 'niche' for chlamydial residence and replication. In literature, apoptosis has been widely described to be the main cell death mechanism elicited by chlamydia infection. However, our data demonstrate that necroptosis plays a relevant role, proceeding in parallel with apoptosis. The protective effect of catalase suggests the involvement of oxidative stress in triggering both cell death pathways. Moreover, we demonstrated that caspase-1 is involved in CT-induced cell death, potentially contributing to host inflammatory response and tissue damage. Cells infected by L2 serovar displayed a higher activation of effector caspases compared to cells infected with serovar D, suggesting a serovar-specific activation of apoptotic pathways and potentially explaining the greater virulence of L serovars. Finally, we found that Chlamydia elicits the early externalization of phosphatidylserine on the external leaflet of plasma membrane independently of caspase activation.

ACS Style

Claudio Foschi; Massimo Bortolotti; Giacomo Marziali; Letizia Polito; Antonella Marangoni; Andrea Bolognesi. Survival and death of intestinal cells infected by Chlamydia trachomatis. PLOS ONE 2019, 14, e0215956 .

AMA Style

Claudio Foschi, Massimo Bortolotti, Giacomo Marziali, Letizia Polito, Antonella Marangoni, Andrea Bolognesi. Survival and death of intestinal cells infected by Chlamydia trachomatis. PLOS ONE. 2019; 14 (4):e0215956.

Chicago/Turabian Style

Claudio Foschi; Massimo Bortolotti; Giacomo Marziali; Letizia Polito; Antonella Marangoni; Andrea Bolognesi. 2019. "Survival and death of intestinal cells infected by Chlamydia trachomatis." PLOS ONE 14, no. 4: e0215956.

Journal article
Published: 15 February 2019 in International Journal of Molecular Sciences
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Palmitic acid metabolism involves delta-9 and delta-6 desaturase enzymes forming palmitoleic acid (9cis-16:1; n-7 series) and sapienic acid (6cis-16:1; n-10 series), respectively. The corresponding biological consequences and lipidomic research on these positional monounsaturated fatty acid (MUFA) isomers are under development. Furthermore, sapienic acid can bring to the de novo synthesis of the n-10 polyunsaturated fatty acid (PUFA) sebaleic acid (5cis,8cis-18:2), but such transformations in cancer cells are not known. The model of Caco-2 cell line was used to monitor sapienic acid supplementation (150 and 300 μM) and provide evidence of the formation of n-10 fatty acids as well as their incorporation at levels of membrane phospholipids and triglycerides. Comparison with palmitoleic and palmitic acids evidenced that lipid remodelling was influenced by the type of fatty acid and positional isomer, with an increase of 8cis-18:1, n-10 PUFA and a decrease of saturated fats in case of sapienic acid. Cholesteryl esters were formed only in cases with sapienic acid. Sapienic acid was the less toxic among the tested fatty acids, showing the highest EC50s and inducing death only in 75% of cells at the highest concentration tested. Two-photon fluorescent microscopy with Laurdan as a fluorescent dye provided information on membrane fluidity, highlighting that sapienic acid increases the distribution of fluid regions, probably connected with the formation of 8cis-18:1 and the n-10 PUFA in cell lipidome. Our results bring evidence for MUFA positional isomers and de novo PUFA synthesis for developing lipidomic analysis and cancer research.

ACS Style

Roberta Scanferlato; Massimo Bortolotti; Anna Sansone; Chryssostomos Chatgilialoglu; Letizia Polito; Marco De Spirito; Giuseppe Maulucci; Andrea Bolognesi; Carla Ferreri. Hexadecenoic Fatty Acid Positional Isomers and De Novo PUFA Synthesis in Colon Cancer Cells. International Journal of Molecular Sciences 2019, 20, 832 .

AMA Style

Roberta Scanferlato, Massimo Bortolotti, Anna Sansone, Chryssostomos Chatgilialoglu, Letizia Polito, Marco De Spirito, Giuseppe Maulucci, Andrea Bolognesi, Carla Ferreri. Hexadecenoic Fatty Acid Positional Isomers and De Novo PUFA Synthesis in Colon Cancer Cells. International Journal of Molecular Sciences. 2019; 20 (4):832.

Chicago/Turabian Style

Roberta Scanferlato; Massimo Bortolotti; Anna Sansone; Chryssostomos Chatgilialoglu; Letizia Polito; Marco De Spirito; Giuseppe Maulucci; Andrea Bolognesi; Carla Ferreri. 2019. "Hexadecenoic Fatty Acid Positional Isomers and De Novo PUFA Synthesis in Colon Cancer Cells." International Journal of Molecular Sciences 20, no. 4: 832.

Preprint
Published: 08 February 2019
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Palmitic acid metabolism involves delta-9 and delta-6 desaturase enzymes forming palmitoleic acid (9cis-16:1; n-7 series) and sapienic acid (6cis-16:1; n-10 series), respectively. The corresponding biological consequences and lipidomic research on these positional MUFA isomers are under development. Furthermore, sapienic acid can bring to the de novo synthesis of the n-10 polyunsaturated fatty acid (PUFA) sebaleic acid (5cis,8cis-18:2), but such transformations in cancer cells are not known. The model of Caco-2 cell line was used to monitor sapienic acid supplementation (150 and 300 μM) and evidence the formation of n-10 fatty acids as well as their incorporation at levels of membrane phospholipids and triglycerides. Comparison with palmitoleic and palmitic acids evidenced that lipid remodeling was influenced by the type of fatty acid and positional isomer, with increase of 8cis-18:1, n-10 PUFA and decrease of saturated fats in case of sapienic acid. Cholesteryl esters were formed only in case of sapienic acid. EC50 of sapienic acid (232.3 μM at 96 hrs) was the highest found among the tested fatty acids, thus influencing cell viability that was only reduced at 25% at 300 μM, whereas palmitoleic acid induced cell death. Two-photon fluorescent microscopy with Laurdan as a fluorescent dye provided information on membrane fluidity, highlighting that sapienic acid increases the distribution of fluid regions, probably connected with the formation of 8cis-18:1 and the n-10 PUFA in cell lipidome. Our results bring evidence for MUFA positional isomers and de novo PUFA synthesis for developing lipidomic analysis and cancer research.

ACS Style

Roberta Scanferlato; Massimo Bortolotti; Anna Sansone; Chryssostomos Chatgilialoglu; Letizia Polito; Marco De Spirito; Giuseppe Maulucci; Andrea Bolognesi; Carla Ferreri. Hexadecenoic Fatty Acid Positional Isomers and de Novo PUFA Synthesis in Colon Cancer Cells. 2019, 1 .

AMA Style

Roberta Scanferlato, Massimo Bortolotti, Anna Sansone, Chryssostomos Chatgilialoglu, Letizia Polito, Marco De Spirito, Giuseppe Maulucci, Andrea Bolognesi, Carla Ferreri. Hexadecenoic Fatty Acid Positional Isomers and de Novo PUFA Synthesis in Colon Cancer Cells. . 2019; ():1.

Chicago/Turabian Style

Roberta Scanferlato; Massimo Bortolotti; Anna Sansone; Chryssostomos Chatgilialoglu; Letizia Polito; Marco De Spirito; Giuseppe Maulucci; Andrea Bolognesi; Carla Ferreri. 2019. "Hexadecenoic Fatty Acid Positional Isomers and de Novo PUFA Synthesis in Colon Cancer Cells." , no. : 1.

Review article
Published: 07 December 2018 in Redox Biology
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Obesity and related pathologies such as diabetes and metabolic syndrome are associated with chronic inflammation and cancer. The serum level of xanthine oxidoreductase (XOR) is correlated to obesity-associated metabolic disorders. XOR can play a role in the pathogenesis of both metabolic syndrome and cancer through the inflammatory response and the oxidative stress elicited by the products of its activity. The reactive oxygen and nitrogen species and the uric acid derived from XOR concur to the development of hypertension, dyslipidemia and insulin resistance and participate in both cell transformation and proliferation, as well as in the progression and metastasis process. Despite the availability of different drugs to inhibit in vivo XOR activity, the complexity of XOR inhibition effects should be carefully considered before clinical application, save in the case of symptomatic hyperuricemia.

ACS Style

Maria Giulia Battelli; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi. Metabolic syndrome and cancer risk: The role of xanthine oxidoreductase. Redox Biology 2018, 21, 101070 .

AMA Style

Maria Giulia Battelli, Massimo Bortolotti, Letizia Polito, Andrea Bolognesi. Metabolic syndrome and cancer risk: The role of xanthine oxidoreductase. Redox Biology. 2018; 21 ():101070.

Chicago/Turabian Style

Maria Giulia Battelli; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi. 2018. "Metabolic syndrome and cancer risk: The role of xanthine oxidoreductase." Redox Biology 21, no. : 101070.

Research article
Published: 27 November 2018 in ACS Omega
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The use of copper complexes for redox and oxidative-based mechanisms in therapeutic strategies is an important field of multidisciplinary research. Here, a novel Cu(II) complex [Cu(TPMA)(Phen)](ClO4)2 (Cu-TPMA-Phen, where TPMA = tris-(2-pyridylmethyl)amine and Phen = 1,10-phenanthroline) was studied using both the free and encapsulated forms. A hollow pH-sensitive drug-delivery system was synthesized, characterized, and used to encapsulate and release the copper complex, thus allowing for the comparison with the free drug. The human neuroblastoma-derived cell line NB100 was treated with 5 μM Cu-PMA-Phen for 24 h, pointing to the consequences on mono- and polyunsaturated fatty acids (MUFA and PUFA) present in the membrane lipidome, coupled with cell viability and death pathways (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium viability assay, flow cytometry, microscopy, caspase activation). In parallel, the Cu-TPMA-Phen reactivity with the fatty acid moieties of phospholipids was studied using the liposome model to work in a biomimetic environment. The main results concerned: (i) the membrane lipidome in treated cells, involving remodeling with a specific increase of saturated fatty acids (SFAs) and a decrease of MUFA, but not PUFA; (ii) cytotoxic events and lipidome changes did not occur for the encapsulated Cu-TPMA-Phen, showing the influence of such nanocarriers on drug activity; and (iii) the liposome behavior confirmed that MUFA and PUFA fatty acid moieties in membranes are not affected by oxidative and isomerization reactions, proving the different reactivities of thiyl radicals generated from amphiphilic and hydrophilic thiols and Cu-TPMA-Phen. This study gives preliminary but important elements of copper(II) complex reactivity in cellular and biomimetic models, pointing mainly to the effects on membrane reactivity and remodeling based on the balance between SFA and MUFA in cell membranes that are subjects of strong interest for chemotherapeutic activities as well as connected to nutritional strategies.

ACS Style

Gianluca Toniolo; Maria Louka; Georgia Menounou; Nicolo Zuin Fantoni; George Mitrikas; Eleni K. Efthimiadou; Annalisa Masi; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi; Andrew Kellett; Carla Ferreri; Chryssostomos Chatgilialoglu. [Cu(TPMA)(Phen)](ClO4)2: Metallodrug Nanocontainer Delivery and Membrane Lipidomics of a Neuroblastoma Cell Line Coupled with a Liposome Biomimetic Model Focusing on Fatty Acid Reactivity. ACS Omega 2018, 3, 15952 -15965.

AMA Style

Gianluca Toniolo, Maria Louka, Georgia Menounou, Nicolo Zuin Fantoni, George Mitrikas, Eleni K. Efthimiadou, Annalisa Masi, Massimo Bortolotti, Letizia Polito, Andrea Bolognesi, Andrew Kellett, Carla Ferreri, Chryssostomos Chatgilialoglu. [Cu(TPMA)(Phen)](ClO4)2: Metallodrug Nanocontainer Delivery and Membrane Lipidomics of a Neuroblastoma Cell Line Coupled with a Liposome Biomimetic Model Focusing on Fatty Acid Reactivity. ACS Omega. 2018; 3 (11):15952-15965.

Chicago/Turabian Style

Gianluca Toniolo; Maria Louka; Georgia Menounou; Nicolo Zuin Fantoni; George Mitrikas; Eleni K. Efthimiadou; Annalisa Masi; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi; Andrew Kellett; Carla Ferreri; Chryssostomos Chatgilialoglu. 2018. "[Cu(TPMA)(Phen)](ClO4)2: Metallodrug Nanocontainer Delivery and Membrane Lipidomics of a Neuroblastoma Cell Line Coupled with a Liposome Biomimetic Model Focusing on Fatty Acid Reactivity." ACS Omega 3, no. 11: 15952-15965.

Review
Published: 08 August 2018 in Toxins
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Bougainvillea (Bougainvillea spectabilis Willd.) is a plant widely used in folk medicine and many extracts from different tissues of this plant have been employed against several pathologies. The observation that leaf extracts of Bougainvillea possess antiviral properties led to the purification and characterization of a protein, named bouganin, which exhibits typical characteristics of type 1 ribosome-inactivating proteins (RIPs). Beyond that, bouganin has some peculiarities, such as a higher activity on DNA with respect to ribosomal RNA, low systemic toxicity, and immunological properties quite different than other RIPs. The sequencing of bouganin and the knowledge of its three-dimensional structure allowed to obtain a not immunogenic mutant of bouganin. These features make bouganin a very attractive tool as a component of immunotoxins (ITs), chimeric proteins obtained by linking a toxin to a carrier molecule. Bouganin-containing ITs showed very promising results in the experimental treatment of both hematological and solid tumors, and one bouganin-containing IT has entered Phase I clinical trial. In this review, we summarize the milestones of the research on bouganin such as bouganin chemico-physical characteristics, the structural properties and de-immunization studies. In addition, the in vitro and in vivo results obtained with bouganin-containing ITs are summarized.

ACS Style

Massimo Bortolotti; Andrea Bolognesi; Letizia Polito. Bouganin, an Attractive Weapon for Immunotoxins. Toxins 2018, 10, 323 .

AMA Style

Massimo Bortolotti, Andrea Bolognesi, Letizia Polito. Bouganin, an Attractive Weapon for Immunotoxins. Toxins. 2018; 10 (8):323.

Chicago/Turabian Style

Massimo Bortolotti; Andrea Bolognesi; Letizia Polito. 2018. "Bouganin, an Attractive Weapon for Immunotoxins." Toxins 10, no. 8: 323.

Review article
Published: 05 May 2018 in Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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Xanthine oxidoreductase (XOR) could contribute to the pathogenesis of metabolic syndrome through the oxidative stress and the inflammatory response induced by XOR-derived reactive oxygen species and uric acid. Hyperuricemia is strongly linked to hypertension, insulin resistance, obesity and hypertriglyceridemia. The serum level of XOR is correlated to triglyceride/high density lipoprotein cholesterol ratio, fasting glycemia, fasting insulinemia and insulin resistance index. Increased activity of endothelium-linked XOR may promote hypertension. In addition, XOR is implicated in pre-adipocyte differentiation and adipogenesis. XOR and uric acid play a role in cell transformation and proliferation as well as in the progression and metastatic process. Collected evidences confirm the contribution of XOR and uric acid in metabolic syndrome. However, in some circumstances XOR and uric acid may have anti-oxidant protective outcomes. The dual-face role of both XOR and uric acid explains the contradictory results obtained with XOR inhibitors and suggests caution in their therapeutic use.

ACS Style

Maria Giulia Battelli; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi. The role of xanthine oxidoreductase and uric acid in metabolic syndrome. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018, 1864, 2557 -2565.

AMA Style

Maria Giulia Battelli, Massimo Bortolotti, Letizia Polito, Andrea Bolognesi. The role of xanthine oxidoreductase and uric acid in metabolic syndrome. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2018; 1864 (8):2557-2565.

Chicago/Turabian Style

Maria Giulia Battelli; Massimo Bortolotti; Letizia Polito; Andrea Bolognesi. 2018. "The role of xanthine oxidoreductase and uric acid in metabolic syndrome." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1864, no. 8: 2557-2565.

Review
Published: 10 February 2018 in Biomedicines
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Osteosarcoma (OS) is an aggressive osteoid-producing tumor of mesenchymal origin, which represents the most common primary bone malignancy. It is characterized by a complex and frequently uncertain etiology. The current standard care for high-grade OS treatment is neoadjuvant chemotherapy, followed by surgery and post-operative chemotherapy. In order to ameliorate survival rates of patients, new therapeutic approaches have been evaluated, mainly immunotherapy with antibody-drug conjugates or immunoconjugates. These molecules consist of a carrier (frequently an antibody) joined by a linker to a toxic moiety (drug, radionuclide, or toxin). Although several clinical trials with immunoconjugates have been conducted, mainly in hematological tumors, their potential as therapeutic agents is relatively under-explored in many types of cancer. In this review, we report the immunoconjugates directed against OS surface antigens, considering the in vitro and in vivo studies. To date, several attempts have been made in preclinical settings, reporting encouraging results and demonstrating the validity of the idea. The clinical experience with glembatumumab vedotin may provide new insights into the real efficacy of antibody-drug conjugates for OS therapy, possibly giving more information about patient selection. Moreover, new opportunities could arise from the ongoing clinical trials in OS patients with unconjugated antibodies that could represent future candidates as carrier moieties of immunoconjugates.

ACS Style

Daniele Mercatelli; Massimo Bortolotti; Alberto Bazzocchi; Andrea Bolognesi; Letizia Polito. Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives. Biomedicines 2018, 6, 19 .

AMA Style

Daniele Mercatelli, Massimo Bortolotti, Alberto Bazzocchi, Andrea Bolognesi, Letizia Polito. Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives. Biomedicines. 2018; 6 (1):19.

Chicago/Turabian Style

Daniele Mercatelli; Massimo Bortolotti; Alberto Bazzocchi; Andrea Bolognesi; Letizia Polito. 2018. "Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives." Biomedicines 6, no. 1: 19.

Journal article
Published: 30 May 2017 in Toxins
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Immunotoxins (ITs) are hybrid proteins combining the binding specificity of antibodies with the cytocidal properties of toxins. They represent a promising approach to lymphoma therapy. The cytotoxicity of two immunotoxins obtained by chemical conjugation of the plant toxin saporin-S6 with the anti-CD20 chimeric antibody rituximab and the anti-CD22 murine antibody OM124 were evaluated on the CD20-/CD22-positive cell line Raji. Both ITs showed strong cytotoxicity for Raji cells, but the anti-CD22 IT was two logs more efficient in killing, probably because of its faster internalization. The anti-CD22 IT gave slower but greater caspase activation than the anti-CD20 IT. The cytotoxic effect of both immunotoxins can be partially prevented by either the pan-caspase inhibitor Z-VAD or the necroptosis inhibitor necrostatin-1. Oxidative stress seems to be involved in the cell killing activity of anti-CD20 IT, as demonstrated by the protective role of the H2O2 scavenger catalase, but not in that of anti-CD22 IT. Moreover, the IT toxicity can be augmented by the contemporary administration of other chemotherapeutic drugs, such as PS-341, MG-132, and fludarabine. These results contribute to the understanding of the immunotoxin mechanism of action that is required for their clinical use, either alone or in combination with other drugs.

ACS Style

Letizia Polito; Daniele Mercatelli; Massimo Bortolotti; Stefania Maiello; Alice Djemil; Maria Giulia Battelli; Andrea Bolognesi. Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells. Toxins 2017, 9, 182 .

AMA Style

Letizia Polito, Daniele Mercatelli, Massimo Bortolotti, Stefania Maiello, Alice Djemil, Maria Giulia Battelli, Andrea Bolognesi. Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells. Toxins. 2017; 9 (6):182.

Chicago/Turabian Style

Letizia Polito; Daniele Mercatelli; Massimo Bortolotti; Stefania Maiello; Alice Djemil; Maria Giulia Battelli; Andrea Bolognesi. 2017. "Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells." Toxins 9, no. 6: 182.