1,721,167 research outputs found
The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology
No full textTRAIL is a member of the tumor necrosis factor superfamily that interacts with an unusually complex receptor system, comprising transmembrane (TRAIL-R1, -R2, -R3 and -R4) and soluble (osteoprotegerin) receptors. TRAIL has received considerable attention because of the finding that many cancer cell types are sensitive to TRAIL-induced apoptosis. However, increasing experimental evidence shows that TRAIL exhibits regulatory roles in various normal tissues, as well. Although the best-characterized biological activity of TRAIL is in the homeostatic regulation of the immune system, in this review we have summarized and discussed the physiological function of TRAIL and its receptors, in normal hematopoiesis and vascular physiopathology
Rationale for Considering Oral Idasanutlin as a Therapeutic Option for COVID-19 Patients
No full textThe spread of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), firstly
detected in Wuhan (China) at the end of 2019, has rapidly reached pandemic status. At the present
time, under the “pressure” of the infection the need of effective and innovative treatments is
becoming crucial. In particular, new insights into potential innovative therapeutic interventions,
including the repositioning of pharmaceutical compounds already available that may be useful to
control and contrast coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 are needed, also
in the view of potential second waves of infection. With this aim, we here describe the rationale for
the use of Idasanutlin, an orally available, potent and selective small-molecule antagonist of MDM2
acting as non-genotoxic p53 activator to treat COVID-19 patients and support its clinical evaluation
Linfociti T memoria ricircolanti dalla cute nelle comorbidità associate a psoriasi: prospettive prognostiche e terapeutiche
No full text“Questa ricerca ha lo scopo di definire e confermare il legame causale tra le risposte mediate da particolari cellule del
sistema immunitario (i linfociti T, che si attivano ed amplificano nella cosiddetta “placca psoriasica”) e l’infiammazione sistemica ed articolare che si sviluppa in una frazione di pazienti con psoriasi. L’ipotesi dello studio è che una frazione di cellule T possano migrare dalla cute attraverso il circolo sanguigno e raggiungere altri distretti dell’organismo, tra cui
le articolazioni, dove potrebbero attivare e ricreare il “network” pro-infiammatorio, causando complicanze cliniche. Verranno analizzate specifiche popolazioni cellulari nel circolo sanguigno e nei tessuti infiammati di pazienti con malattia psoriasica, al fine di identificare le sottopopolazioni che possono propagare l’infiammazione. Le popolazioni cellulari che verranno identificate e validate potrebbero rappresentare biomarcatori precoci di manifestazioni extracutanee in pazienti con psoriasi.
Dexamethasone counteracts the anti-osteoclastic, but not the anti-leukemic, activity of TNF-related apoptosis inducing ligand (TRAIL).
No full textWe have analyzed the effect of the synthetic glucocorticoid dexamethasone, used alone or in combination with recombinant TRAIL, on in vitro osteoclastic differentiation of peripheral blood-derived macrophages cultured in the presence of macrophage-colony stimulating factor (M-CSF) + RANKL for 12-14 days. Dexamethasone exhibited different effects based on the concentration used. Indeed, while at 10(-7) M dexamethasone reduced the number of mature osteoclasts, at 10(-8) M showed no significant effects and at 10(-9) M significantly increased the number of mature osteoclasts, with respect to cells cultured with only M-CSF + RANKL. On the other hand, the addition in culture of recombinant TRAIL inhibited the output of mature osteoclasts induced by M-CSF + RANKL. However, the presence of dexamethasone (10(-8) or 10(-9) M) into the culture medium significantly counteracted the anti-osteoclastic activity of TRAIL. In order to ascertain whether dexamethasone, might also interfere with the anti-leukemic activity of TRAIL, the degree of apoptosis induced by TRAIL was evaluated in several myeloid (OCI, MOLM, HL-60) and lymphoid (SKW6.4, MAVER, BJAB) leukemic cell lines. The levels of TRAIL-triggered apoptosis were not significantly different between leukemic cells cultured in the absence or presence of dexamethasone. Concerning the molecular mechanism mediating the dexamethasone-suppression of the TRAIL activity in pre-osteoclasts, but not in leukemic cells, we found that dexamethasone induced a significant down-regulation of the surface levels of TRAIL-R2 in cells of the osteoclastic lineage but not in leukemic cells. The ability of dexamethasone to counteract the TRAIL pathway envisions a novel mechanism mediating the pro-osteoclastic activity of dexamethasone in vivo
Purinergic signaling and inflammasome activation in psoriasis pathogenesis
No full textPsoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques’ formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes’ inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments
Actively targeted nanocarriers for drug delivery to cancer cells
No full textIntroduction: Progressive breakthroughs in nanomedicine have been instrumental for the clinical translation of actively targeted drug-delivery approaches. Besides storing large payloads of drugs within the nanoparticle core, the conjugation of targeting moieties confers specific targeting ability to the nanoplatforms. In this respect, clinical results suggest that actively targeted nanocarriers can exhibit an overall improved antitumor efficacy, minimizing off-target toxicity. Areas covered: This review article summarizes the advances in active targeting of nanocarriers to cancer cells. Specifically, we discuss the various types of nanocarriers, describe the receptors that are frequently overexpressed in solid tumors, and discuss how this approach can be used to improve clinical outcomes. We particularly focus on ongoing clinical trials of actively targeted nanoparticles that are yet to be clinically approved. Expert opinion: Further investment in active targeting will likely pose clinical benefits. We envisage a future requiring the use of longitudinal measures in the clinical setting to profile the patients that are likely to benefit from actively targeted nanocarriers. At the preclinical stage, a complete picture of intratumoral barriers combined with a quantitative approach of the intratumoral fate of nanomaterials will be instrumental in defining more effective strategies to improve their clinical translation
Reduced expression of cell cycle-associated genes in B lymphocytes purified from the peripheral blood of early-stage B chronic lymphocytic leukaemia patients.
No full text
Receptor activator of nuclear factor kappa B ligand(RANKL) modulates the expression of genes involved in apoptosis and cell cycle in human osteoclasts.
No full textABSTRACTIt has been clearly established that receptor activator of nuclear factor kappa B ligand (RANKL) is a key cytokine involved in the differentiation of osteoclastic precursors of momocytic/macrophagic lineage. However relatively little information is available on the ability of RANKLE to modulate the expression of genes controlling cell survival/apoptosis and proliferation in human osteoclastic cells in comparison to macrophages. For this purpose, CD14+ human periferal blood mononuclear cells, which express the cognate high affinity receptor activator of nuclear factor kappa B (RANK), were differentiated alog the macrophagic or osteoclastic lineage by adding macrophage- colony stimulating factor (M-CSF) or M-CSF plus RANKL in culture for 12 days. RANKL up-regulated the expression of chemokine MIP1 alpha, which potentiates osteoclasic differentiation and simultaneously activated both antiapoptotic (Bcl-2) and pro-apoptotic (CIDEB, PYCARD, and BAK-1) genes. Moreover, RANKL markedl
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