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Herein, we report the synthesis of a new hybrid compound based on a 2′-deoxyuridine nucleoside conjugated with a NO photo-donor moiety (dU-t-NO) via CuAAC click chemistry. Hybrid dU-t-NO, as well as two previously reported 2′-deoxyadenosine based hybrids (dAdo-S-NO and dAdo-t-NO), were evaluated for their cytotoxic and cytostatic activities in selected cancer cell lines. dAdo-S-NO and dAdo-t-NO hybrids displayed higher activity with respect to dU-t-NO. All hybrids showed effective release of NO in the micromolar range. The photochemical behavior of the newly reported hybrid, dU-t-NO, was studied in the RKO colon carcinoma cell line, whereas the dAdo-t-NO hybrid was tested in both colon carcinoma RKO and hepatocarcinoma Hep 3B2.1-7 cell lines to evaluate the potential effect of NO released upon irradiation on cell viability. A customized irradiation apparatus for in vitro experiments was also designed. [ABSTRACT FROM AUTHOR]

Research progresses have led to the development of different kinds of nanoplatforms to deliver drugs through different biological membranes. Particularly, nanocarriers represent a precious means to treat skin pathologies, due to their capability to solubilize lipophilic and hydrophilic drugs, to control their release, and to promote their permeation through the stratum corneum barrier. A crucial point in the development of nano-delivery systems relies on their characterization, as well as in the assessment of their interaction with tissues, in order to predict their fate under in vivo administration. The size of nanoparticles, their shape, and the type of matrix can influence their biodistribution inside the skin strata and their cellular uptake. In this respect, an overview of some characterization methods employed to investigate nanoparticles intended for topical administration is presented here, namely dynamic light scattering, zeta potential, scanning and transmission electron microscopy, X-ray diffraction, atomic force microscopy, Fourier transform infrared and Raman spectroscopy. In addition, the main fluorescence methods employed to detect the in vitro nanoparticles interaction with skin cell lines, such as fluorescence-activated cell sorting or confocal imaging, are described, considering different examples of applications. Finally, recent studies on the techniques employed to determine the nanoparticle presence in the skin by ex vivo and in vivo models are reported. [ABSTRACT FROM AUTHOR]

Convolvulus pluricaulis (CP) is a common Indian herb, largely employed in Ayurvedic medicine and known for its neuroprotective and neuroinflammatory action. Its effectiveness against several pathologic/sub-pathologic conditions is widely accepted, but it is not yet completely chemically characterized. In recent years, several researchers have pointed out the involvement of CP and other Convolvulaceae in lipidic and glucidic metabolism, particularly in the control of hyperlipidaemia and diabetic conditions. In this scenario, the aim of the study was to chemically characterize the medium polarity part of the CP whole plant and its fractions and to shed light on their biological activity in adipocyte differentiation using the 3T3-L1 cell model. Our results demonstrated that the CP extract and fractions could upregulate the adipocyte differentiation through the modulation of the nuclear receptor PPARγ (Peroxisome Proliferator-Activated Receptor γ), broadly recognized as a key regulator of adipocyte differentiation, and the glucose transporter GLUT-4, which is fundamental for cellular glucose uptake and for metabolism control. CP also showed the ability to exert an anti-inflammatory effect, downregulating cytokines such as Rantes, MCP-1, KC, eotaxin, and GM-CSF, which are deeply involved in insulin resistance and glucose intolerance. Taken together, these data suggest that CP could exert a potential beneficial effect on glycemia and could be employed as an anti-diabetic adjuvant or, in any case, a means to better control glucose homeostasis. [ABSTRACT FROM AUTHOR]

Hyperglycaemia and increased circulating saturated fatty acids are key metabolic features of type 2 diabetes mellitus (T2DM) that contribute to diabetic retinopathy pathogenesis. Contrarily, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to improve or prevent T2DM. This study aimed at investigating the effect of TRAIL in an in vitro model of human retinal pigment epithelium: the ARPE-19 cell line, treated with palmitic acid (PA) in the presence of high glucose concentration. PA caused a drop in cellular metabolic activity and cell viability as well as an increase in apoptosis rates, which were paralleled by an upregulation of reactive oxygen species (ROS) generation as well as mitochondrial fragmentation. Despite ARPE-19 cells expressing TRAIL-R2 at the cell surface, TRAIL failed to counteract the cytotoxic effects of PA. However, when TRAIL was used alongside PA and then removed or used alone following PA challenge, it partially attenuated PA-induced lipotoxicity. This effect of TRAIL appeared to rely upon the modulation of inflammation and ROS production. Thus, TRAIL exerted a trophic effect on ARPE-19 cells, which became evident only when the lipotoxic insult was removed. Nevertheless, whether recombinant TRAIL might have a therapeutic potential for the treatment of diabetic retinopathy requires further investigation. [ABSTRACT FROM AUTHOR]

Early post-transplant is the critical phase for the success of hematopoietic stem cell transplantation (HSCT). New viral infections and the reactivations associated with complete ablation of the recipient's T-cell immunity and inefficient reconstitution of the donor-derived system represent the main risks of HSCT. To date, the pharmacological treatments for post-HSCT viral infection-related complications have many limitations. Adoptive cell therapy (ACT) represents a new pharmacological strategy, allowing us to reconstitute the immune response to infectious agents in the post-HSC period. To demonstrate the potential advantage of this novel immunotherapy strategy, we report three cases of pediatric patients and the respective central nervous system complications after donor lymphocyte infusion. [ABSTRACT FROM AUTHOR]

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK–STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies. [ABSTRACT FROM AUTHOR]

In B-chronic lymphocytic leukemia (B-CLL), the interaction between leukemic cells and the microenvironment promotes tumor cell survival. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is one of the first-in-class molecules for the treatment of B-CLL patients; however, the emerging mechanisms of resistance to ibrutinib call for new therapeutic strategies. The purpose of the current study was to investigate the ability of ibrutinib plus the MDM2-inhibitor nutlin-3 to counteract the tumor microenvironment protective effect. We observed that primary B-CLL cells cultivated in microenvironment mimicking conditions were protected from apoptosis by the upregulation of c-MYC and of p53. In the same setting, combined treatments with ibrutinib plus nutlin-3 led to significantly higher levels of apoptosis compared to the single treatments, counteracting the c-MYC up-regulation. Moreover, the combination induced high p53 levels and a significant dissipation of the mitochondrial membrane potential, together with BAX cleavage in the more active p18 form and phospho-BAD down-regulation, that are key components of the mitochondrial apoptotic pathway, enhancing the apoptosis level. Our findings propose a new therapeutic strategy to overcome the tumor microenvironment protection involved in B-CLL resistance to drugs, with possible clinical implications also for other hematologic and solid tumors for which ibrutinib is considered a therapeutic option. [ABSTRACT FROM AUTHOR]

Eosinophils are major effector cells against parasites, fungi, bacteria, and viruses. However, these cells also take part in local and systemic inflammation, which are central to eczema, atopy, rhinitis, asthma, and autoimmune diseases. A role for eosinophils has been also shown in vascular thrombotic disorders and in cancer. Many, if not all, above-mentioned conditions involve the release of intracellular nucleotides (ATP, ADP, UTP, etc.) and nucleosides (adenosine) in the extracellular environment. Simultaneously, eosinophils further release ATP, which in autocrine and paracrine manners, stimulates P2 receptors. Purinergic signaling in eosinophils mediates a variety of responses including CD11b induction, ROI production, release of granule contents and enzymes, as well as cytokines. Exposure to extracellular ATP also modulates the expression of endothelial adhesion molecules, thereby favoring eosinophil extravasation and accumulation. In addition, eosinophils express the immunosuppressive adenosine P1 receptors, which regulate degranulation and migration. However, pro-inflammatory responses induced by extracellular ATP predominate. Due to their important role in innate immunity and tissue damage, pharmacological targeting of nucleotide- and nucleoside-mediated signaling in eosinophils could represent a novel approach to alleviate eosinophilic acute and chronic inflammatory diseases. These innovative approaches might also have salutary effects, particularly in host defense against parasites and in cancer. [ABSTRACT FROM AUTHOR]

Ligands and receptors of the tumor necrosis factor (TNF) superfamily regulate immune responses and homeostatic functions with potential diagnostic and therapeutic implications. Kidney disease represents a global public health problem, whose prevalence is rising worldwide, due to the aging of the population and the increasing prevalence of diabetes, hypertension, obesity, and immune disorders. In addition, chronic kidney disease is an independent risk factor for the development of cardiovascular disease, which further increases kidney-related morbidity and mortality. Recently, it has been shown that some TNF superfamily members are actively implicated in renal pathophysiology. These members include TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin (OPG), and TNF-like weaker inducer of apoptosis (TWEAK). All of them have shown the ability to activate crucial pathways involved in kidney disease development and progression (e.g. canonical and non-canonical pathways of the transcription factor nuclear factor-kappa B), as well as the ability to regulate cell proliferation, differentiation, apoptosis, necrosis, inflammation, angiogenesis, and fibrosis with double-edged effects depending on the type and stage of kidney injury. Here we will review the actions of TRAIL, OPG, and TWEAK on diabetic and non-diabetic kidney disease, in order to provide insights into their full clinical potential as biomarkers and/or therapeutic options against kidney disease. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Methods: Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. Results: The lowest levels of TRAIL at baseline were significantly (p<0.05) associated with the appearance, after 24 months of follow-up, of at least two new atheromatous plaques in all territories and of one new plaque in the carotid artery, even after adjusting for CV risk factors. In addition, the patients with low levels of TRAIL at baseline were characterized by the presence of at least one hypoechoic plaque in the carotid artery. This association was significant (p<0.05) even after adjusting for CKD stage. Conclusions: Overall, the results of our study suggest TRAIL as an assertable independent prognostic biomarker for atheromatosis plaque formation in CKD patients. This observation further supports the potential role of TRAIL for the prevention/treatment of CV disease. [ABSTRACT FROM AUTHOR]

Objective. “Oxinflammation” is a recently coined term that defines the deleterious crosstalk between inflammatory and redox systemic processes, which underlie several diseases. Oxinflammation could be latently responsible for the predisposition of certain healthy individuals to disease development. The oxinflammatory pathway has been recently suggested to play a crucial role in regulating the activity of TNF-related apoptosis-inducing ligand (TRAIL), a TNF superfamily member that can mediate multiple signals in physiological and pathological processes. Therefore, we investigated the associations between TRAIL and key players of vascular redox homeostasis. Methods. We measured circulating TRAIL levels relative to praoxonas-1, lipoprotein phospholipase-A2, and ceruloplasmin levels in a cohort of healthy subjects (n=209). Results. Multivariate analysis revealed that ceruloplasmin levels were significantly inversely associated with TRAIL levels (r=−0.431, p<0.001). The observed association retained statistical significance after adjustment for additional confounding factors. After stratification for high-sensitivity C-reactive protein levels, the inverse association between TRAIL and ceruloplasmin levels remained strong and significant (r=−0.508, p<0.001, R2=0.260) only in the presence of inflammation, confirming the role of inflammation as emerged in in vitro experiments where recombinant TRAIL decreased ceruloplasmin expression levels in TNF-treated PBMC cultures. Conclusion. The results indicated that in an inflammatory milieu, TRAIL downregulates ceruloplasmin expression, highlighting a signaling axis involving TRAIL and ceruloplasmin that are linked via inflammation and providing important insights with potential clinical implications. [ABSTRACT FROM AUTHOR]

Photorefractive keratectomy (PRK) represents a therapeutic option to remodel corneal stroma and to compensate refractive errors, which involves inflammatory and/or regenerative processes. In this context, the modulation of cytokines/chemokines in the conjunctival sac fluid and their role in the maintenance of the corneal microenvironment during the healing process upon refractive procedures has not been deeply investigated. In this study, serial samples of conjunctival sac fluid of patients (n=25) undergoing PRK were harvested before and at different time points after surgery. The levels of 29 cytokines/chemokines/growth factors involved in inflammatory/immune processes were measured with a multiplex array system. The results have firstly highlighted the different pattern of cytokine expression between the microenvironment at the anterior surface of the eye and the systemic circulation. More importantly, the kinetic of modulation of cytokines/chemokines at the conjunctival level following PRK revealed that while the majority of cytokines/chemokines showed a significant decrease, MCP-1 emerged in light of its pronounced and significant increase soon after PRK and during the follow-up. This methodological approach has highlighted the role of MCP-1 in the healing process following PRK and has shown a potential for the identification of expression/modulation of soluble factors for biomarker profiling in ocular surface diseases. [ABSTRACT FROM AUTHOR]

Besides its well-established oncosuppressor activity, a key function of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the role of p53 with respect to diabetes mellitus (DM) appears highly controversial. To address this issue, we have used the cis-imidazoline compound Nutlin-3, an inhibitor of MDM2/p53 interaction, which represents a potent and selective non-genotoxic activator of the p53 pathway both in in vivo and in vitro experimental settings. Experimental DM was induced by intraperitoneal injections of low concentrations of streptozotocin (STZ) in C57BL/6N mice ( n = 20). A group of control vehicle-injected mice ( n = 10) and of STZ-treated mice ( n = 10) was co-injected with Nutlin-3. Mice co-injected with STZ + Nutlin-3 exhibited attenuated features of DM with respect to animals treated with STZ alone. Indeed, STZ + Nutlin-3-treated mice were characterized by significantly ( p < 0.05) lower levels of hyperglycemia, reduced weight loss, and increased spleen weight. In addition, STZ alone promoted a marked decrease in the levels of several circulating cytokines, including interleukin-12 (IL-12)p40. On the other hand, co-injection of STZ + Nutlin-3 significantly ( p < 0.01) counteracted IL-12p40 down-modulation. In vitro experiments performed on the RAW264.7 macrophagic cell line model, used as cellular source of IL-12p40, demonstrated that Nutlin-3 treatment increased IL-12p40 release, strongly suggesting a direct effect of Nutlin-3 on the immune system. Overall, these data demonstrate that systemic administration of Nutlin-3 ameliorates the severity of STZ-induced DM and increases the levels of circulating IL-12p40. [ABSTRACT FROM AUTHOR]

The article analyzes the role of myeloid leukemia cell differentiation protein (MCL1) down-regulation in the different anti-leukaemic activity of the multi-kinase inhibitor Sorafenib with respect to Dasatinib in Acute myeloid leukaemia (AML) cell lines. Sorafenib plays higher cytotoxicity with respect to Dasatinib in all cell lines. It is also mentioned that Sorafenib potently down-regulates MCL1 in all leukaemic cell lines, while Dasatinib increases MCL1 expression in OCI and HL60 cells.

Background: Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL. Methodology/Principal Findings: The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV2 Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV+ B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC:lymphoma ratio of 1:10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures. Conclusions/Significance: Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL. [ABSTRACT FROM AUTHOR]

The article presents a research according to which combination of perifosine and nutlin-3 shows a synergistic anti-leukaemic activity. According to the researchers, use of the combination induced a significant increase of cytotoxicity in all leukaemic cell lines as compared to the cytotoxicity when perifosine alone is given.

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line. [ABSTRACT FROM AUTHOR]

Little is known on the ability of different epithelia to release soluble TNF-related apoptosis-inducing ligand (TRAIL) and the relevance of TRAIL secretion by epithelial cells is still incompletely understood. On these bases, we have measured the concentration of soluble TRAIL by ELISA in the conjunctival sac fluid. It was the highest ever detected in a biological fluid (mean value of 26,800 pg/ml), being approximately 20-fold greater than that found in human saliva and >200-fold greater than that detected in human serum. On the other hand, osteoprotegerin, the soluble decoy receptor of TRAIL, was almost undetectable in the conjunctival sac fluid. Of note, the levels of soluble TRAIL measured in conjunctival sac fluid were in the range able to induce in vitro apoptosis of lymphoma cells. By in situ immunohistochemistry, TRAIL protein expression was predominantly detected in the corneal epithelium and, to a less extent, in the conjunctival epithelium. By flow cytometry analysis, membrane-associated TRAIL was documented in isolated corneal epithelial cells obtained from patients undergoing photorefractive keratectomy (PRK). The key contribution provided by corneal epithelium to the production of soluble TRAIL was underscored in time-course experiments, in which a marked decrease of the levels of soluble TRAIL in the conjunctival sac fluid was demonstrated 1 day after PRK followed by a progressive recovery at days 5–30 after PRK. Taken together, our findings strongly support a major role of soluble TRAIL in protecting cornea and conjunctiva from tumor formation and/or invasion. J. Cell. Physiol. 218: 199–204, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Adult multipotent stromal cells (MSCs), also known as mesenchymal stem cells, represent an important source of cells for the repair of a number of damaged tissues. Both bone marrow (BM)-derived and amniotic MSCs expressed detectable surface levels of two (tumor necrosis factor-related apoptosis-inducing ligand receptor 2 [TRAIL-R2] and TRAIL-R4) of four transmembrane TRAIL receptors. Although the best-characterized activity of TRAIL-R2 is the transduction of apoptotic signals, neither recombinant TRAIL (rTRAIL) nor infection with an adenovirus-expressing TRAIL induced cytotoxic effects on MSCs. Moreover, whereas rTRAIL did not affect proliferation or differentiation of MSCs along the osteogenic and adipogenic lineages, it significantly promoted the migration of human MSCs in range of concentrations comparable to that of soluble TRAIL in human plasma (100 pg/ml). Since rTRAIL induced the rapid phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in MSC cultures and pretreatment with pharmacological inhibitors of the ERK1/2 pathway efficiently counteracted the rTRAIL-induced human MSC migration, these data indicate that ERK1/2 is involved in mediating the ability of rTRAIL to stimulate MSC migration. Taking into consideration that the soluble factors able to induce MSC migration have not been extensively characterized, our current data indicate that the TRAIL/TRAIL-R system might play an important role in the biology of MSCs. [ABSTRACT FROM AUTHOR]

Among 14 peripheral blood samples obtained from patients affected by B chronic lymphocytic leukemia (B-CLL) at initial stages (Rai 0–1) of the disease, 6 showed intermediate/high levels of Zap-70 while 8 displayed low/absent levels of Zap-70. Although Zap-70high and Zap-70low B-CLL samples displayed similar levels of surface death receptor TRAIL-R2, recombinant TRAIL induced cytotoxicity only in a subset of Zap-70low B-CLL samples while Zap-70high were completely resistant to TRAIL. The gene expression profiling was next analyzed in all B-CLL samples treated with either chlorambucil or recombinant TRAIL. While chlorambucil up-regulated the steady-state mRNA levels of known p53 target genes, such as PUMA, Fas/CD95 and MDM2 in all B-CLL samples examined, it significantly down-regulated survivin in Zap-70low but not in Zap-70high. On the other hand, recombinant TRAIL up-regulated the expression of several cytokines (IL-1β, IL-1α, IL-8), which have been involved in promoting B-CLL cell survival. In particular, TRAIL selectively up-regulated IL-1β in Zap-70low B-CLL samples, while it markedly and selectively up-regulated its own mRNA and that of cyclooxigenase-2 (COX-2) in Zap-70high. Taken together, our findings suggest that a significant expression of Zap-70 modulate the response of B-CLL to TRAIL, which might represents an initial step in the pathogenesis of B-CLL. J. Cell. Physiol. 213: 229–236, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

B chronic lymphocytic leukemia (B-CLL) cells express several members of the tumor necrosis factor (TNF) family, such as CD40L, CD30L, and TRAIL. By using the cDNA microarray technology, B-CLL samples were found to overexpress receptor activator of nuclear factor kB (NF-kB) ligand (RANKL), as compared to normal CD19+ B cells. These findings were validated at the protein level by Western blot and flow cytometry analyses. Moreover, unlike primary normal B cells, leukemic B-CLL cells showed surface expression of RANK, the cognate transmembrane receptor of RANKL. When added in vitro to B-CLL cultures, either alone or in association with chlorambucil or fludarabine, recombinant RANKL did not significantly modulate cell viability, and it minimally affected the IL-8 expression/release. On the other hand, treatment with RANK-Fc chimera potently upregulated the release of IL-8 in the B-CLL culture supernatants, suggesting involvement of reverse signaling through transmembrane RANKL in IL-8 induction. In turn, exposure of B-CLL cells to recombinant IL-8 significantly decreased spontaneous apoptosis as well as chlorambucil- and fludarabine-mediated cytoxicity in B-CLL cells. Since IL-8 has been implicated in progression of B-CLL disease, our findings suggest that, by upregulating IL-8, the RANKL/RANK system may contribute to the pathogenesis of B-CLL. J. Cell. Physiol. 207: 158–164, 2006. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The regulatory human immunodeficiency virus-1 (HIV-1) Tat protein shows pleiotropic effects on the survival and growth of both HIV-1-infected and uninfected CD4+ T lymphocytes. In this study, we have demonstrated that low concentrations (10 ng/ml) of extracellular Tat protein induce the expression of both c-fos mRNA and protein in serum-starved Jurkat CD4+ lymphoblastoid T cells. Using deletion mutants, we demonstrates that the SRE, CRE and, to a lesser extent, also the SIE domains (all placed in the first 356 bp of c-fos promoter) play a key role in mediating the response to extracellular Tat. Moreover, the ability of Tat to activate the transcriptional activity of c-fos promoter was consistently decreased by pretreatment with the ERK/MAPK kinase inhibitor PD98058. Activation of c-fos is functional as demonstrated by induction of the AP-1 transcription factor, which is involved in the regulation of critical genes for the activation of T lymphocytes, such as interleukin 2. The Tat-mediated induction of c-fos and AP-1 in uninfected lymphoid T cells may contribute to explain the immune hyperactivation that characterizes the progression to autoimmuno deficiency syndrome and constitutes the optimal environment for HIV-1 replication, occurring predominantly in activated/proliferating CD4+ T cells. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms. [ABSTRACT FROM AUTHOR]

Mitoquinone (MitoQ) is a mitochondrial reactive oxygen species scavenger that is characterized by high bioavailability. Prior studies have demonstrated its neuroprotective potential. Indeed, the release of reactive oxygen species due to damage to mitochondrial components plays a pivotal role in the pathogenesis of several neurodegenerative diseases. The present study aimed to examine the impact of the inflammation platform activation on the neuronal cell line (DAOY) treated with specific inflammatory stimuli and whether MitoQ addition can modulate these deregulations. DAOY cells were pre-treated with MitoQ and then stimulated by a blockade of the cholesterol pathway, also called mevalonate pathway, using a statin, mimicking cholesterol deregulation, a common parameter present in some neurodegenerative and autoinflammatory diseases. To verify the role played by MitoQ, we examined the expression of genes involved in the inflammation mechanism and the mitochondrial activity at different time points. In this experimental design, MitoQ showed a protective effect against the blockade of the mevalonate pathway in a short period (12 h) but did not persist for a long time (24 and 48 h). The results obtained highlight the anti-inflammatory properties of MitoQ and open the question about its application as an effective adjuvant for the treatment of the autoinflammatory disease characterized by a cholesterol deregulation pathway that involves mitochondrial homeostasis. [ABSTRACT FROM AUTHOR]

Despite the great progress in screening techniques and medical treatments, colorectal cancer remains one of the most widespread cancers in both sexes, with a high death rate. In this work, the volatile compounds released from human colon cancer tissues were detected by a set of four different chemoresistive sensors, made with a nanostructured powder of metal-oxide materials, inserted into an innovative patented device. The sensor responses to the exhalation of a primary cancer sample and of a healthy sample (both of the same weight, collected during colorectal surgery from the intestine of the same patient) were statistically analyzed. The sensors gave reversible, reproducible, and fast responses for at least one year of continuous use, making them quite superior in respect to the existing diagnostic methods. Preliminary results obtained using principal component analysis of the sensor responses to samples removed from 13 patients indicate that the nanostructured sensors employed in this study were able to distinguish between healthy and tumor tissue samples with coherent responses (the discrimination power of the most sensitive sensor was about 17%), highlighting a strong potential for clinical practice. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated protein that endows its carrier with (lipo-)lactonase-dependent antioxidative features. Low levels of PON1 activity have been observed in association with obesity, a major risk factor for cardiovascular disease (CVD). Considering the well-recognized atheroprotective role of PON1, exogenous/endogenous factors that might modulate its levels/activity are raising great interest. Since adipokines represent a molecular link between obesity and CVD, we here explored the possible impact of these substances on PON1 activity/expression. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, resistin, leptin, and adiponectin were measured along with arylesterase, paraoxonase, and lactonase activities of PON1 in 107 postmenopausal women. Moreover, the direct effect of resistin on PON1 expression was evaluated in vitro. Multivariate analysis revealed that only resistin was significantly and inversely correlated with PON1-lactonase activities (r = −0.346, p < 0.001) regardless of confounding factors such as age or HDL-cholesterol. It is worth noting that no statistical link was found between adipokine and arylesterase or paraoxonase, the two promiscuous activities of PON1. Notably, resistin down-regulated PON1 expression occurred in hepatocellular carcinoma cultures. Our study suggests that resistin might be a negative modulator of PON1 expression and anti-oxidative activity. [ABSTRACT FROM AUTHOR]

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure. [ABSTRACT FROM AUTHOR]