Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

Memos, Nikolaos; Betrosian, Alex P.; Messaris, Evangelos; Boutsikou, Maria; Kataki, Agapi; Chatzigianni, Emmy; Nikolopoulou, Μarilena; Leandros, Emmanuel; Konstadoulakis, Manousos M.

doi:10.1016/j.brainres.2009.01.053

Cited by 13 publications

(7 citation statements)

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“…The direct cleavage of 14‐3‐3 θ by caspases‐7, −8, and −3 can also lead to bax disassociation (Nomura et al,2003). In our previous study, bax protein levels were elevated as early as 6 hr post‐CLP together with the levels of active caspase‐3 and cytochrome c, while Bcl‐2 levels were decreased, suggesting that the mitochondrial pathway of apoptosis is activated in the hyperdynamic phase of sepsis (Messaris et al,2004; Memos et al,2009). In fact, the basal protein levels of 14‐3‐3 θ isoform up to 24 hr post‐CLP in association with the levels of bax, bcl‐2, cytochrome c, and active caspase‐3 appear to provide a probable positive feedback mechanism for the elevated apoptosis observed during the hyperdynamic phase of sepsis.…”

Section: Discussionmentioning

confidence: 90%

“…CSF levels of 14‐3‐3 ζ but not 14‐3‐3 β showed a secondary increase at 48 hr and declined thereafter (Siman et al,2004). The time‐dependent regulation of 14‐3‐3 isoforms at translational levels during sepsis prompted us to investigate further their relation with apoptosis, because apoptotic neurons or astrocytes were described as following a biphasic pattern in sepsis as well (Messaris et al,2004; Memos et al,2009). It is known that apoptosis is involved in brain dysfunction occurring during sepsis and systemic inflammatory response syndrome (SIRS; septic encephalopathy), probably as a result of inflammatory signals that induce neuronal and glial apoptosis (Sharshar et al, 2005; Jacob et al,2007).…”

Section: Discussionmentioning

confidence: 99%

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Alternations of 14‐3‐3 θ and β protein levels in brain during experimental sepsis

Memos

Kataki

Chatziganni

et al. 2011

J of Neuroscience Research

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The 14-3-3 family members play a crucial role in the determination of cell fate, exerting their antiapoptotic activity through directly interfering with the critical function of the mitochondrial core proapoptotic machinery. Dimerization of 14-3-3 is vital for the interaction with many of its client proteins and is regulated by phosphorylation. In a previous study, we observed time-dependent neuronal apoptosis during sepsis. Therefore, in the present study, we sought to evaluate the expression of 14-3-3 θ and β isoforms in septic brain and their association with apoptosis. Sepsis was induced by a CLP model in Wistar rats that were sacrificed at predefined time points. Flow cytometric analysis showed a sepsis-induced, time-dependent alteration of 14-3-3 θ and β isoforms in both Neun(+) and GFAP(+) cells. 14-3-3 θ was linearly correlated with apoptosis, and stratified analysis for alive and apoptotic neuronal cells demonstrated a gradual down-regulation of θ isoform in alive neurons and astrocytes. The phospho-P38 (pP38) MAP kinase levels were altered in a time-dependent manner during sepsis, presenting a peak at 6 hr post-CLP. A significant correlation between the two isoforms of 14-3-3 was observed in septic rats, with the θ isoform predominant at all time points. The hippocampus, Purkinje cells, and glia-like cells showed intense immunohistochemical reactivity for 14-3-3 θ isoform, whereas the choroid plexus showed constantly increased β isoform expression. Our results showed that sepsis alters the expression of both 14-3-3 θ and β isoforms in a time-, cell-, and topography-dependent manner.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Alternations of 14‐3‐3 θ and β protein levels in brain during experimental sepsis

Memos

Kataki

Chatziganni

et al. 2011

J of Neuroscience Research

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“…Guo et al reported that APC strongly inhibits astrocyte differentiation in vitro in human neuroprogenitor cell populations (Guo et al, 2013a). Furthermore, administration of protein C (PC) zymogen in a sepsis model protected against astrocyte cell death (Memos et al, 2009). Consistent with this theme of APC mediating neuroprotection, our data show that in the hypoxic CNS, APC plays a key role in promoting physiological remodeling of cerebral blood vessels in response to CMH.…”

Section: Discussionmentioning

confidence: 99%

Physiological cerebrovascular remodeling in response to chronic mild hypoxia: A role for activated protein C

Burnier

Boroujerdi

Fernández

et al. 2016

Experimental Neurology

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Activated protein C (APC) is a serine protease that promotes favorable changes in vascular barrier integrity and post-ischemic angiogenic remodeling in animal models of ischemic stroke, and its efficacy is currently being investigated in clinical ischemic stroke trials. Interestingly, application of sub-clinical chronic mild hypoxia (CMH) (8% O2) also promotes angiogenic remodeling and increased tight junction protein expression, suggestive of enhanced blood-brain barrier (BBB) integrity, though the role of APC in mediating the influence of CMH has not been investigated. To examine this potential link, we studied CMH-induced cerebrovascular remodeling after treating mice with two different reagents: (i) a function-blocking antibody that neutralizes APC activity, and (ii) exogenous recombinant murine APC. While CMH promoted endothelial proliferation, increased vascular density, and upregulated the angiogenic endothelial integrins α5β1 and αvβ3, these events were almost completely abolished by functional blockade of APC. Consistent with these findings, addition of exogenous recombinant APC enhanced CMH-induced endothelial proliferation, expansion of total vascular area and further enhanced the CMH-induced right-shift in vessel size distribution. Taken together, our findings support a key role for APC in mediating physiological remodeling of cerebral blood vessels in response to CMH.

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“…foram desidratadas e montadas para posterior leitura em microscópio óptico (GOBE, 2009;MEMOS et al, 2009). …”

Section: 2-ensaios Imuno-histoquímicosunclassified

Avaliação da interferência do efeito antioxidante do carvedilol, um potencial agente nefroprotetor, na atividade antitumoral da cisplatina

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Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

Cited by 13 publications

References 30 publications

Alternations of 14‐3‐3 θ and β protein levels in brain during experimental sepsis

Alternations of 14‐3‐3 θ and β protein levels in brain during experimental sepsis

Physiological cerebrovascular remodeling in response to chronic mild hypoxia: A role for activated protein C

Avaliação da interferência do efeito antioxidante do carvedilol, um potencial agente nefroprotetor, na atividade antitumoral da cisplatina

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