Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro

Busciglio, Jorge; Yankner, Bruce A.

doi:10.1038/378776a0

Cited by 698 publications

(426 citation statements)

References 24 publications

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“…Alterations in chromosome number, particularly trisomy 21, have been associated with elevated mitochondrial ROS, oxidative damage, diminished metabolism, and compromised resilience (Busciglio & Yankner, 1995; Coskun et al, 2016; Slonim et al, 2009; Zis et al, 2012) Here, we show that human DS HF and mouse Dp16 MEF display compromised mitochondrial function, oxidative stress, and activated Nrf2 antioxidant response. Furthermore, our results demonstrate that sustained Nrf2 stabilization is vital to maintain cell function in both DS and Dp16.…”

Section: Discussionmentioning

confidence: 48%

“…An expanding number of studies have reported the presence of chronic oxidative stress and mitochondrial dysfunction in DS at both the cellular and organismal levels (Annerén & Epstein, 1987; Busciglio & Yankner, 1995; Antonarakis et al, 2004; Lott & Dierssen, 2012; Campos et al, 2011). Recently, we reported that decreased mitochondrial activity, increased ROS and mitochondrial fragmentation in DS cells are associated with transcriptional activation of the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) signaling pathway (Helguera et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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“…ROS-mediated cell death may be important in the pathogenesis of several neurodegenerative disorders (Coyle and Puttfarrcken, 1993;Busciglio and Yankner, 1995). Moreover, oxidative tissue injury has been observed to be central in reperfusion injury of ischaemic tissues in myocardium, kidney and brain (Bulkley, 1983).…”

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confidence: 99%

Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells

Miyajima

Nakashima²,

Yoshioka³

et al. 1997

Br J Cancer

162

101

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Summary This study was undertaken to investigate the intracellular induction of reactive oxygen species (ROS) by cis-dichlorodiammineplatinum (CDDP) and the augmentation of their cytotoxicity in bladder cancer cells (KU7) by enhancement of ROS generation by the glutathione (GSH) depletors buthionine sulphoximine (BSO) and diethylmaleate (DEM). CDDP-induced cytotoxicity in KU7 cells and its modulation by GSH depletors were determined using spectrophotometric measurement with crystal violet staining. The effects of GSH depletors on intracellular GSH levels were confirmed using the GSH reductase-DTNB recycling method. Intracellular ROS generation induced by CDDP with or without GSH depletors was estimated from the amount of intracellular dichlorofluorescein (DCF), an oxidized product of dichlorofluorescein (DCFH), which was measured with an anchored cell analysis and sorting system. The cytotoxic effects of CDDP (IC50 15.0 ± 2.5 gIM) were significantly enhanced by BSO (IC50 9.3 ± 2.6 gM, P < 0.01) and DEM (IC50 10.3 ± 0.3 gM, P < 0.01). BSO and DEM produced a significant depletion in intracellular GSH levels (9.6 ± 0.4 nmol 10-6 cells, 17.9 ± 1.0 nmol 10-6 cells) compared with the controls (30.5 ± 0.6 nmol 10-6 cells). Intracellular DCF production in KU7 cells treated with CDDP (1.35 ± 0.33 g1M) was significantly enhanced by the addition of BSO (4.43 ± 0.33 gM) or DEM (3.12 ± 0.22 gM) at 150 min. These results suggest that ROS may play a substantial role in CDDPinduced cytotoxicity and that GSH depletors augment its cytotoxicity through an enhancement of ROS generation in bladder cancer cells.

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“…Furthermore, serum IL-8 levels were markedly elevated in Patient 1. Oxidative stress is important in DS pathology, and reactive oxygen species (ROS) levels are important for IL-8 expression (Busciglio and Yankner 1995;Ko et al 2014). Neutrophils are effector cells that kill bacteria or destroy affected tissues, predominantly through ROS production.…”

Section: Discussionmentioning

confidence: 99%

Plasma TGF-<i>β</i>1 Levels Are Elevated in Down Syndrome Infants with Transient Abnormal Myelopoiesis

Maeda

Imamura

et al. 2016

Tohoku J. Exp. Med.

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Infants with Down syndrome (DS) are at risk of developing a transient myeloproliferative disorder during the neonatal period, known as transient abnormal myelopoiesis (TAM). It is characterized by clonal myeloproliferation and is typically self-limiting. However, TAM can be a life-threatening disorder, when complicated by liver fibrosis. Here, we evaluated cytokine profiles in two male DS infants having TAM with or without liver dysfunction. The first patient, Patient 1, had hyperleukocytosis with cholestatic liver dysfunction, coagulopathy, and increased counts of blasts and was treated with exchange transfusion (ExT) due to the serious general condition. In Patient 1, serum interleukin (IL)-8 and plasma transforming growth factor (TGF)-β1 levels were markedly elevated before ExT (1,518.2 pg/mL and 17,635 pg/mL, respectively). After ExT, serum IL-8 and plasma TGF-β1 levels decreased to 40.7 pg/mL and 6,847 pg/mL, respectively. However, Patient 1 died on day 56 due to cholestatic liver dysfunction; namely, this patient represents fatal TAM. The second patient, Patient 2, had hyperleukocytosis with increased counts of blasts without liver dysfunction and was treated with cytarabine. In Patient 2, plasma TGF-β1 levels, but not plasma IL-8, were elevated (9,068 pg/mL and 28 pg/mL, respectively). Patient 2 was discharged on day 47. In summary, plasma TGF-β 1 levels were elevated in the two DS infants with TAM, regardless of the presence or absence of hepatic fibrosis. Importantly, fatal TAM is assoicated with the elevated serum level of IL-8. We thus propose that IL-8 may be involved in the pathogenesis of liver fibrosis.

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Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro

Cited by 698 publications

References 24 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells

Plasma TGF-<i>β</i>1 Levels Are Elevated in Down Syndrome Infants with Transient Abnormal Myelopoiesis

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