Biomedical subjects

Yaara Ben-Yosef

Publications and source records attributed to Yaara Ben-Yosef.

4 recordsLinked to original sources

PubMed2006

Chronotherapy using corticosteroids for multiple sclerosis relapses.

BACKGROUND: The activity of the immune system displays a circadian rhythm. In diseases characterised by aberrant immune activity, chronotherapy (a treatment regimen tailored to diurnal body rhythms) may increase the efficiency, safety and tolerability of drugs. AIM: To compare the outcomes of intravenous corticosteroid administration during the day or night, for treatment of acute multiple sclerosis relapses. METHODS: 17 patients with multiple sclerosis were included in the study. Clinical assessment of disability was performed at trial entry, and at days 7 and 30 from the initiation of treatment. Adverse events and preference of night-time versus daytime treatment were assessed at the end of the treatment course. RESULTS: After night-time treatment, clinical recovery was significantly (p<0.001) enhanced and the mean number of side effects was significantly (p = 0.007) lower. Furthermore, most patients expressed a preference for night-time versus daytime treatment. CONCLUSIONS: The study suggests a potential benefit for implementation of chronotherapy using steroid treatment for acute multiple sclerosis relapse, with implications for other immune-mediated disorders.

Acute Disease↗

PubMed2006

Cytokine-mediated modulation of MMPs and TIMPs in multipotential neural precursor cells.

Recent studies have implicated the inflammatory process during experimental allergic encephalomyelitis (EAE) in triggering migration and differentiation of transplanted neural precursors cells (NPCs) into the inflamed white matter. The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma are key factors in the pathogenesis of brain inflammation in EAE and were shown to enhance NPCs migration in vitro. As cell migration is dependent on extracellular matrix remodeling, involving proteolytic enzyme members of the matrix metalloproteinase (MMPs) family, we characterized the profile of expression of MMPs and their endogenous inhibitors (TIMPs) in rat NPCs, and evaluated the effects of TNF-alpha, IFN-gamma and IFN-beta, a clinically proven modulator of brain inflammation, on the expression of these molecules. Newborn rat striatal NPCs were expanded in spheres as nestin+, PSA-NCAM+ and NG2(-) cells, which can differentiate into astrocytes, oligodendrocytes and neurons. NPCs' gelatinase activities of MMP-2 and MMP-9, as determined by zymography, were increased by TNF-alpha, and to a lesser extent by IFN-gamma. Semi-quantitative RT-PCR indicated that TNF-alpha also upregulated MMP-9 mRNA levels. IFN-beta suppressed the TNF-alpha-induced levels of secreted MMP-9 and MMP-2, while enhancing the expression of TIMP-1 and TIMP-2 mRNA. These results suggest that MMPs activity is induced in NPCs by pro-inflammatory cytokines to mobilize them for promoting reparative processes. IFN-beta, on the other hand, appears to have an anti-proteolytic influence that may attenuate such NPC-mediated repair processes.

Animals↗

PubMed2005

Hypoxia of endothelial cells leads to MMP-2-dependent survival and death.

Exposure of endothelial cells (ECs) to hypoxia has separately been shown to induce their angiogenesis or death. Matrix metalloproteinase (MMP)-2 is associated with EC angiogenesis, although recent studies also implicate this molecule in EC death. We studied the effect of hypoxia in the absence or presence of TNF-alpha (characteristic of the inflammatory microenvironment accompanying hypoxia) on MMP-2 expression and its role in angiogenesis (proliferation, migration, and tube formation) and in the death of primary human umbilical vein endothelial cells (HUVECs). Hypoxia alone (24-48 h in 0.3% O(2) in the hypoxic chamber) and furthermore, when combined with TNF-alpha, significantly enhanced MMP-2 expression and activity. Hypoxia also led to a reduction in membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 mRNA and protein while enhancing the expression of alpha(v)beta(3) integrin and the cytoskeletal protein phosphopaxillin. Moreover, hypoxia led to colocalization of alpha(v)beta(3) and MMP-2, but not MT1-MMP, with phosphopaxillin in ECs. These results suggest MT1-MMP-independent activation of MMP-2 during hypoxia and support interactions between the ECM, integrins, and the cytoskeleton in hypoxia-induced MMP-2-related functions. Hypoxia enhanced EC migration in an MMP-2-dependent manner while leading to a reduction of cell number via their apoptosis, which was also dependent on MMP-2. In addition, hypoxia caused an aberrant tubelike formation on Matrigel that appeared to be unaffected by MMP-2. The hypoxia-induced, MMP-2-dependent migration of ECs is in accordance with the proangiogenic role ascribed to MMP-2, while the involvement of this protease in the hypoxia-related death of ECs supports an additional apoptotic role for this protease. Hence, in the hypoxic microenvironment, MMP-2 appears to have a dual autocrine role in determining the fate of ECs.

Cell Death↗

PubMed2002

Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation.

Among the consequences resulting from the exposure of endothelial cells (ECs) to ischemia/reperfusion is angiogenesis, involving degradation of vascular basement membrane and extracellular matrix. Matrix metalloproteinase (MMP)-2, a member of the MMP family, partakes in this process. MMP-2, secreted as a proenzyme, undergoes activation through interaction with membrane type (MT)1-MMP and the endogenous tissue inhibitor of MMPs (TIMP)-2. Although hypoxia and reoxygenation (H/R) are major constituents of ischemia/reperfusion processes, their direct effects on endothelial MMP-2 have been scarcely investigated. This study examined the in vitro effects of H/R on human macrovascular ECs (EAhy 926). The level of MMP-2 mRNA (Northern blot) and protein (zymography, ELISA) and the mRNA of its activator (MT1-MMP) and inhibitor (TIMP-2) were analyzed. Short (6-hour) hypoxia inhibited the mRNA expression of MMP-2, MT1-MMP, and TIMP-2, culminating in reduced latent and active MMP-2 protein. Prolonged (24-hour) hypoxia further suppressed MT1-MMP and TIMP-2 mRNA, whereas it enhanced MMP-2 mRNA and enzyme secretion (after 48-hour hypoxia). Reoxygenation did not influence the inhibited TIMP-2 but upregulated MMP-2 and MT1-MMP mRNA expression, leading to enhanced secretion of active MMP-2 protein. These results demonstrate H/R-mediated modulation of EC MMP-2 at both transcriptional and posttranscriptional levels. Prolonged hypoxia of ECs appears to enhance MMP-2 production and secretion, whereas reoxygenation further increases its level. These H/R-mediated effects on MMPs have the potential of enabling EC migration and possible angiogenesis.

Blotting, Northern↗