PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis.

The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated signaling.

Effect of PTX3 and voriconazole combination in a rat model of invasive pulmonary aspergillosis.

This study evaluated the pharmacological activity of PTX3, administered in combination with voriconazole, in a rat model of pulmonary aspergillosis. The data indicated additive therapeutic activities of these compounds, as demonstrated by the amelioration of respiratory function changes, reduction of lung fungal burden, and increased survival. Overall, we provide clear evidence that the combination of PTX3 with a suboptimal dose of voriconazole might represent a therapeutic option under those clinical conditions where the use of voriconazole alone is not warranted for efficacy and tolerability reasons.

Current understanding of PTX3 protective activity on Aspergillus fumigatus infection.

Infection caused by Aspergillus fumigatus remains a major therapeutic challenge in immunocompromised individuals. Innate immunity represents the first line of defense against pathogens. In the last 20 years, several proteins belonging to this arm of the immune system have been characterized as being endowed with antifungal activity.

Efficacy of PTX3 in a rat model of invasive aspergillosis.

Pentraxin 3 (PTX3) is an acute-phase glycoprotein with a nonredundant function in the host resistance to Aspergillus fumigatus. PTX3 activity was evaluated against pulmonary aspergillosis in rats immunosuppressed with cortisone acetate. PTX3 enhanced the survival rate and reduced the lung fungal burden of infected rats in both therapeutic and prophylactic modalities.

Anti-proliferative effect of a triazole derivative (ST1959) on LNCaP human prostate cancer cells through down-regulation of cyclin and androgen receptor expression.

Background: Previous studies demonstrated that ST1959, a triazole derivative endowed with immunomodulatory activities, also exerts inhibitory effects on proliferation and survival of a panel of tumor cells. In this study, we sought to ascertain the effects of ST1959 on the growth of androgen-dependent and androgen-independent prostate cancer (PCa) cells.

Methods: The growth of androgen-dependent (LNCaP) and androgen-independent (PC3, DU-145) cells was analyzed in vitro both in the presence and absence of ST1959.

Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening bacterial and fungal infections and hyperinflammation. The susceptibility to aspergillosis in experimental CGD (p47(phox-/-) mice) is associated with the failure to control the inherent inflammatory response to the fungus and to restrict the activation of inflammatory Th17 cells. We assessed whether pentraxin (PTX)3, a member of a family of multimeric pattern-recognition proteins with potent anti-Aspergillus activity, could limit pathogenic inflammation in p47(phox-/-) mice by curbing the IL-23/Th17 inflammatory axis in response to the fungus.

Efficacy of a nanocochleate-encapsulated 3,5-diaryl-s-triazole derivative in a murine model of graft-versus-host disease.

We have previously demonstrated that the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole exerts immunosuppressive effects in several experimental models of autoimmunity. These results were achieved by subcutaneously administering ST1959 after dissolution in an oily vehicle, because of its poor water solubility. To circumvent this problem, we sought to determine whether nanocochleate technology could be successfully exploited to deliver ST1959 and protect mice undergoing lethal acute graft-versus-host disease (GVHD).

Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound.

MyD88 is an adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R and several TLRs. Central to its function is the ability of its Toll/IL-1R translation initiation region (TIR) domain to heterodimerize with the receptor and to homodimerize with another MyD88 molecule to favor the recruitment of downstream signaling molecules such as the serine/threonine kinases IL-1R-associated kinase 1 (IRAK1) and IRAK4. Herein, we have synthesized and tested the activity of a synthetic peptido-mimetic compound (ST2825) modeled after the structure of a heptapeptide in the BB-loop of the MyD88-TIR domain, which interferes with MyD88 signaling.

Dissecting drug and vehicle metabolic effects in rats by a metabonomic approach.

A combined application of high resolution (1)H NMR spectroscopy and multivariate statistical techniques focused on establishing a consistent statistical approach to metabonomic studies was tested. The data reduction, which is preliminary to the application of multivariate analysis to NMR spectra, was carried out by means of two complementary methods: pure Pattern Recognition (PR) and Assigned Signal Analysis (ASA). The simultaneous use of both approaches allowed us to obtain additional information in the analysis of metabonomic data, compared to the use of PR alone.

Low and high tenascin-expressing tumors are efficiently targeted by ST2146 monoclonal antibody.

ST2146biot is a biotinylated anti-tenascin monoclonal antibody (mAb) to be used for Pretargeted Antibody Guided Radioimmunotherapy (PAGRIT) of solid tumors. In vivo biodistribution studies of (125)I-labeled ST2146biot were done in nude mice transplanted with human HT-29 colon carcinoma and/or human U-118MG glioblastoma cells characterized for low and high tenascin expression, respectively. In vitro results show that ST2146 retains immunoreactivity upon biotinylation, in contrast to other anti-tenascin mAbs.

Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma.

Interleukin-6 (IL-6) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases as well as B-cell lymphoproliferative disorders. This work describes the effects of the recombinant or adenovirally-delivered IL-6 superantagonist Sant7, anti-IL-6 and IL-6 receptor monoclonal antibodies in a severe murine model of human B-cell lymphoma induced in SCID mice by transplantation of an LCL-41 cell line variant (isotype-switched IgM>IgG). Survival of 60% of the animals treated with anti-gp130 was observed up to day 33, while about 20% of the animals survived with anti-gp80 and Sant7 treatment.

In vivo and in vitro cytokine modulatory activity of newly synthesised 2-aminotetraline derivatives.

In the present study, the protective effect of newly synthesised 2-aminotetralines was investigated in murine models of toxic shock. A few derivatives protected mice against lethality induced by lipopolysaccharide from different bacterial strains and shock induced by staphylococcal enterotoxin B in mice sensitized by D-Galactosamine (D-Galn). Notably, one derivative, S(-)-2-amino-6-fluoro-7-methoxy-1,2,3,4 tetrahydronaphthalene hydrochloride (ST1214), was also effective when administered orally (30 mg kg-1) in a therapeutic regimen.