Search

Introduction: Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H2O2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome. Objectives: To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli. Methods: A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism. Results: AgNP have an effective ability to decompose endogenous H2O2 in cells. The decomposed endogenous H2O2 generates several different types of reactive species (•OH, O2•−) including peroxynitrite (ONOO−) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO). Conclusion: This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis.

The changes in macrophyte biodiversity and cover from the soft bottoms of 87 stations spread in the entire Venice Lagoon in 2011, 2014, 2018 and 2021 have been analyzed. Results showed a strong macrophyte resilience with an increase in the spread of sensitive macroalgae and aquatic angiosperms, especially Z. noltei and R. cirrhosa, which were not affected by the increase of non-indigenous species (NIS) introduction.The simultaneous analysis of macrophyte variables and the main water and sediment parameters carried out in 2021 highlighted the key role of water transparency and salinity to regulate the vegetation, especially the presence/absence of aquatic angiosperms and sensitive macroalgae. Vice versa, high chlorophyll-a, total suspended solids, nitrogen and silicate concentrations in the water column, and high moisture, low grain-size and phosphorus concentrations in surface sediments favored the presence of opportunistic species, especially Ulva rigida, Gracilariopsis longissima, Agardhiella subulata and Solieria filiformis. The distribution of the aquatic angiosperms and the 41 most widespread macroalgae in association with the main environmental parameters allowed us to highlight their different ecological value, their possible presence/absence and abundance; indeed, their spatial and temporal changes can be excellent tools to determine and predict the ecological status of transitional water systems (TWS).These results carried out in a polyhedric basin such as the Venice Lagoon, composed by a complex of very different microhabitats, can be considered representative of most environmental conditions present in the main TWS of the Italian coastline, and spatial and temporal macrophyte changes can be excellent tools to determine and predict their ecological status evolution.

Programmed cell death 1 ligand 1 (PD-L1) expressed in non-immune cells is involved in immune-mediated tissue damage in the context of inflammatory conditions and tumor immune escape. Emerging evidence suggests soluble (s)PD-L1 as a marker of inflammation. Based on well-established sex-specific differences in immunity, we tested the novel hypotheses that (i) endothelial cell PD-L1 is modulated by inflammatory cytokines and vascular endothelial growth factor (VEGF) in a sex-specific fashion, and (ii) the endothelium is a source of sPD-L1. After exposure of human umbilical vein endothelial cells (HUVECs) to lipopolysaccharide, interleukin (IL)1β or VEGF for 24 h, total PD-L1 levels were upregulated solely in cells from female donors, while being unchanged in those from male donors. Accordingly, exposure to synovial fluids from patients with inflammatory arthritis upregulated PD-L1 levels in HUVECs from female donors only. Membrane PD-L1 expression as measured by flow cytometry was unchanged in response to inflammatory stimuli. However, exposure to 2 ng/mL IL-1β or 50 ng/mL VEGF time-dependently increased sPD-L1 release by HUVECs from female donors. Treatment with the metalloproteinase (MMP) inhibitor GM6001 (10 μM) prevented IL-1β-induced sPD-L1 release and enhanced membrane PD-L1 levels. The anti-VEGF agents bevacizumab and sunitinib reduced both VEGF-induced PD-L1 accumulation and sPD-L1 secretion. Thus, inflammatory agents and VEGF rapidly increased endothelial PD-L1 levels in a sex-specific fashion. Furthermore, the vascular endothelium may be a sPD-L1 source, whose production is MMP-dependent and modulated by anti-VEGF agents. These findings may have implications for sex-specific immunity, vascular inflammation and response to anti-angiogenic therapy.

Microplastic contamination of the benthic invertebrate fauna in Terra Nova Bay (Ross Sea, Antarctica) was determined. Twelve macrobenthic species, characterized by different feeding strategies, were selected at 3 sampling sites at increasing distance from the Italian Scientific Base (Mario Zucchelli, Camp Icarus, Adelie Cove). The 83% of the analyzed macrobenthic species contained microplastics (0.01–3.29 items mg−1). The size of the particles, measured by Feret diameter, ranged from 33 to 1000 µm with the highest relative abundance between 50 and 100 µm. Filter-feeders and grazers displayed values of microplastic contamination from 3 to 5 times higher than omnivores and predators, leading to the hypothesis that there is no evident bioaccumulation through the food web. The prevalent polymers identified by micro-FTIR were nylon (86%) and polyethylene (5%); other polymers identified in Antarctic benthos were polytetrafluoroethylene, polyoxymethylene, phenolic resin, polypropylene, polystyrene resin and XT polymer. Keywords: Antarctica, Benthos, Microplastics, Food web, FTIR, Nile red

The acute toxicity of citrate capped silver nanoparticles (AgNP) and silver nitrate was evaluated on the marine macroalga Ulva rigida C. Agardh (1823). Silver bioaccumulation, ultrastructural chloroplast damages verified by TEM microscopy, inhibition of primary production, neutral lipid production and oxidative stress were observed after 24 h of exposure to AgNP. The toxic effects of silver nitrate in artificial seawater started from a concentration of 0.05 ppm and was more toxic than AgNP that produced effects from a concentration of 0.1 ppm. However only AgNP induced lipid peroxidation in U. rigida. The addition of natural organic and inorganic ligands, represented by transparent exopolymer particles (TEP) and clay, drastically reduced AgNP acute toxicity in a ratio AgNP:ligand of 1:100 and 1:200, respectively. The findings suggest a marked toxicity of Ag on marine macroalgae which however should be mitigated by the high natural ligand concentrations of the transitional environments.

We performed a comprehensive systematic targeted literature review and used the Delphi method to formulate expert consensus statements to guide the treatment of adult-onset Still's disease (AOSD) to achieve an early and long-term remission. Seven candidate statements were generated and reached consensus in the first round of voting by the panel of experts. We postulate: (i) In patients with AOSD with predominant arthritis at onset who achieved no disease control with glucocorticoids (GCs), the use of methotrexate can be considered, whereas the use of cyclosporin A and low-dose GCs should not (Statements 1-3); (ii) In patients with AOSD with poor prognostic factors at diagnosis, an IL-1 inhibitor (IL-1i) in addition to GCs should be taken into consideration as early as possible (Statement 4); (iii) A switch to an IL-6 inhibitor (IL-6i) may be considered in patients with AOSD with prevalent joint involvement, who are unresponsive or intolerant to IL-1i (Statement 5); (iv) Drug tapering or discontinuation may be considered in patients who achieved a sustained clinical and laboratory remission with IL-1i (Statement 6); (v) In patients with AOSD who failed to attain a good clinical response with an IL-1i, switching to an IL-6i may be considered in alternative to a different IL-1i. TNF-inhibitors may be considered as a further choice in patients with a prominent joint involvement (Statement 7). These statements will help clinicians in treatment decision making in patients with AOSD., Competing Interests: Declaration of Competing Interest RP received fees from Novartis; RC received speaker's and paid consultation fees from Abbvie, BMS, Lilly. Pfizer, Galapagos, Novartis, MSD. Janssen, Fresenius-Kabi, Sandoz, UCB. The remaining authors have nothing to declare., (Copyright © 2023. Published by Elsevier B.V.)

The interleukin (IL) 1 family of cytokines is noteworthy to have pleiotropic functions in inflammation and acquired immunity. Over the last decades, several progresses have been made in understanding the function and regulation of the prototypical inflammatory cytokine (IL-1) in human diseases. IL-1α and IL-1β deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. In this review, we examine and compare the key aspects of IL-1α and IL-1β biology and regulation and discuss their importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases. We also report the current and ongoing inhibitors of IL-1 signaling, targeting IL-1α, IL-1β, their receptor or other molecular compounds as effective strategies to prevent or treat the onset and progression of various inflammatory disorders., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Systemic vasculitis (SV) are uncommon diseases that rarely affect women during their reproductive age; little data, mainly retrospective, is available on this topic. The aim of our study was to evaluate maternal/neonatal outcome and disease course before, during and after pregnancy., Methods: Sixty-five pregnancies in 50 women with SV were followed by a multispecialistic team in 8 institutions between 1995 and 2014. Clinical data on pregnancy, 1year before and 1year after delivery was retrospectively collected. The rate of pregnancy complications was compared to that of a General Obstetric Population (GOP) of 3939 women., Results: In 2 patients the diagnosis of SV was done during pregnancy; 59 out of the remaining 63 started when maternal disease was quiescent. We recorded 56 deliveries with 59 live births, 8 miscarriages and 1 fetal death. In SV, preterm, particularly early preterm (<34weeks) deliveries and cesarean sections appeared significantly more frequent than in GOP (11.3% vs 5.0%, p=0.049 and 48.2% vs 31.0%, p=0.009). Vasculitis-related complications occurred in 23 pregnancies (35.4%), with 5 severe events (7.7%) including 3 cases of transient ischemic attack (TIA). Data about the post-partum period were available for 56 pregnancies: 12 flares (21.4%) occurred, with 1 severe event (1.8%)., Conclusion: SV patients can have successful pregnancies (especially during a disease remission phase) despite an increased rate of preterm delivery. Severe flares were limited, but the occurrence of 3 TIA suggests that particular attention should be given to possible thrombotic complications in SV patients during pregnancy and puerperium., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS. In some cases the presence of fever is also observed; atypical cases of BS have been reported with cardiovascular, neurological, renal, intestinal and other organ involvement. The rarity and the variations in the severity and evolution of its expressions do not permit sufficient data about optimal treatment for patients with BS. The first step of therapy is represented by the use of corticosteroids and successively, in case of unsatisfactory response, by additional treatment with immunosuppressive agents. The results with biologic anti-cytokine agents, such as anti-TNFα and anti-IL1β, are different, particularly with regard to ocular morbidity. Clinical and genetic aspects of the familial and the sporadic form of BS will be discussed and focused on. A description of a case study of an Italian family is also included., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Unlabelled: The aim of this study was to investigate apolipoprotein (apo) A-I, apo B, lipoprotein (Lp) (a), HDL-cholesterol (C), LDL-C, triglycerides (TG) and total cholesterol (TC) values in the serum and synovial fluid (SF) of untreated rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) patients., Methods: Paired SF and serum samples were collected simultaneously from 14 patients with RA, 14 with PsA, and 16 with OA and tested for apo A-I, apo B, HDL-C, LDL-C, Lp(a), TC and TG. Serum C reactive protein (CRP) and amyloid A (SAA) levels were also determined., Results: The inflammatory arthritis patients had higher SF lipid levels with the exception of HDL. Reflecting increased synovial permeability, the lipid SF/serum ratio was always higher in RA and PsA with respect to OA patients. The positive correlation between serum and SF apo A-I, apo B, HDL-C, TG, and Lp(a) levels confirmed that there is lipoprotein diffusion into the SF. RA and PsA patients had lower concentrations of all serum lipids except for Lp(a) with respect to OA patients. The levels in the RA patients were similar to those in healthy matched controls, while the PsA patients had significantly lower apo A-I and HDL levels and higher apo B and LDL values., Conclusions: Lipid diffusion into the joint cavity, which largely depends on the degree of inflammation, may contribute to modulating local inflammatory processes., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Blau syndrome (BS) is a rare dominantly inherited, inflammatory syndrome characterised by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis. The caspase recruitment domain gene CARD15/NOD2 has been identified as the gene responsible for BS. In the majority of patients, the disease is characterised by early onset, usually before 3-4 years of age. Onset is most often articular and cutaneous. Eye symptoms usually start later; however, eye involvement is the most relevant morbidity of BS. Atypical cases of BS have been reported with involvement of organs other than skin, joint and eyes. Due to its rarity and the variations in the severity and evolution of its expressions, there have been no studies on the optimal treatment for patients with BS. If the therapeutic response to corticosteroids is unsatisfactory, additional treatment with immunosuppressive agents should be tried. The results with biologic anti-cytokine agents, such as infliximab and anakinra, are variable, particularly with regard to ocular morbidity. This review will focus on the clinical and genetics aspects of the familial and the sporadic form of BS. Further, we will describe an Italian family followed by us over the past 25 years., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Diffuse-type tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, are unique mesenchymal lesions that arise from the synovial tissue of the joints. They are predominantly intraarticular, aggressive, infiltrative processes, characterized by both inflammatory or neoplastic properties and local destructive progression. The pattern of synovial gene and protein expressions in pigmented villonodular synovitis, similar to those in activated macrophages in rheumatoid arthritis, and the phenotype of multinucleated giant cells, characteristic of osteoclasts, suggest that there is a common autocrine mechanism in osteoclast differentiation in both diseases and indicate the potential utility of tumor necrosis factor (TNF)-alpha blockade. High synovial colony stimulating factor 1 (CSF1) messenger RNA (m RNA) expression in pigmented villonodular synovitis, unrelated to a chromosomal translocation involving CSF1 locus, may indicate that there is a synergic paracrine loop mediated by TNF-alpha and CSF1, as shown in both inflammatory and neoplastic conditions. The effects of a new therapeutic approach consisting in intraarticular TNF-alpha blockade were studied in four pigmented villonodular synovitis knees. Knee injections produced a rapid reduction in clinical and sonographic indexes and immunohistological alterations, confirmed by arthroscopic synovectomy. A delayed relapse in one of the four knees and unaltered synovial CSF1 expression were other important findings. In the light of these observations, CSF1/CSF1R interaction probably represents a more sensible therapeutic target than TNF-alpha blockade in the diffuse form of pigmented villonodular synovitis., (Copyright 2010 Elsevier B.V. All rights reserved.)

The aim of the treatment in rheumatoid arthritis (RA) is to prevent articular damage and functional loss by decreasing the activity of the disease. The overall goal is the full suppression of the activity of the disease, also called clinical remission. The most reliable indices to assess RA activity were defined by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) and the International League Against Rheumatism (ILAR) and are habitually used for the evaluation of remission. The Food and Drug Administration (FDA) established three increasingly restrictive categories of disease remission: complete clinical response, major clinical response, and remission. Then, OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) advanced the concept of low disease activity state (LDAS) or minimal disease activity (MDA). Thus, those reported by FDA are the only criteria for remission which consider radiographic arrest of the disease. This review aims to describe the criteria for RA remission and to discuss their advantages and limitations., (Copyright 2009 Elsevier B.V. All rights reserved.)

Associations between rheumatoid arthritis (RA) susceptibility and polymorphism in multiple immunoregulatory genes suggest a role of altered T cell function in the disease. The growing relevance of the oxidative stress in RA synovitis, which results in a number of T cell signalling abnormalities, is reinforced by the demonstration of a direct NO inducing activity through the shared epitope of the HLA class II molecules HLA-DRbeta1, with secondary lymphocytes oxidative damage. Direct T cell/macrophage contact-dependent activation, one of the driving mechanisms of synovitis, is mediated by co-stimulatory molecules as well as cell membrane cytokines and may also result in an impaired suppressive function of T regulatory cells (Treg) in RA joints. The fusion of CTLA4 extracellular binding domain to the Fcgamma1 allows to obtain a soluble CTLA4 receptor, the dimeric recombinant human fusion protein abatacept (CTLA4-Ig). The improved knowledge of the CTLA4-B7 co-stimulation regulatory mechanisms by signals delivered into DCs and Tregs provides multiple potential targets for the abatacept treatment. CTLA4-Ig shows the capacity, either ex vivo or in vivo, to interrupt at multiple steps the ongoing inflammatory and destructive process, and to concur in restoring the immunoregulatory balance in RA.

The classical definition of psoriatic arthritis (PsA) as an inflammatory arthritis associated with psoriasis reflects only in part the large spectrum of musculoskeletal disorders found in patients with psoriasis. In particular, enthesopathy, dactilytis, osteitis and axial involvement are frequently neglected and probably account for the unsatisfactory response of PsA to traditional drugs, such as NSAIDs, steroids and DMARDs. Furthermore, these drugs showed only a partial ability to influence radiographic progression and psoriasis. The new anti-TNF agents, in particular etanercept but also infliximab and adalimumab, have demonstrated a comprehensive effectiveness on the multiple aspects of the PsA disease, including quality of life and slowing of radiographic progression. Despite this clear efficacy, the actual mechanisms by which TNF-blocking agents are able to obtain all these effects are still incompletely understood. However, the success of this therapy suggested one of the best ways for further research in the field of PsA. In this new fashion, the most stimulating hypotheses involving TNF are those regarding genetic predisposition, angiogenesis and osteoclastogenesis.

Erosive osteoarthritis (EOA) is believed to be a clinically uncommon subset of generalized osteoarthritis (OA) characterized by a clinical course, which is frequently aggressive. The diagnosis of EOA is accepted only for patients meeting American College of Rheumatology clinical criteria for OA of the hand and showing radiographic aspects of articular surface erosions. Conditions to be considered in the differential diagnosis include primarily nodal generalized OA, psoriatic arthritis and rheumatoid arthritis. It is possible to find erosive changes resembling EOA in endocrine diseases, microcrystal-induced diseases, chronic renal diseases, autoimmune diseases and others. Despite the absence of a clear etiology, immunogenetic studies are useful in identifying a possible predisposition to developing EOA in some subjects. No definitive therapeutic approach to EOA has been reported. It is reasonable to assume that in the presence of a symptomatic EOA our therapeutic approach should differ from that used for common, nodal, non-EOA.