상단 PDF Role of Bcl-xL in Doxorubicin-Induced Cell Death: Apoptosis and Mitotic Cell Death

Caffeine-induced endothelial cell death and the inhibition of angiogenesis

Caffeine-induced endothelial cell death and the inhibition of angiogenesis

Hua Li 1 , Sheng-Yu Jin 2 , Hyun-Joon Son 1 , Je Hoon Seo 1 , Goo-Bo Jeong 3 1 Department of Anatomy, Chungbuk National University Medical School, Cheongju, Korea, 2 Department of Hematology, Affiliated Hospital of Yanbian University, Yanji, China, 3 Department of Anatomy and Cell Biology, Gachon University School of Medicine, Incheon, Korea Abstract: Numerous studies have shown that adenosine or adenosine agonists can stimulate angiogenesis. However, the effect of caffeine (a known adenosine receptor antagonist) on angiogenesis has not been previously studied. Accordingly, this study was undertaken to examine the effect of caffeine on angiogenesis and to clarify the mechanism involved. Chick chorioallantoic membrane assays were used to investigate the effect of caffeine on angiogenesis and proliferation assays using human umbilical vein endothelial cells (HUVECs), were used to study its effects on specific aspects of angiogenesis. The expressions of caspase-3 and Bcl-2 were examined by western blotting, immunofluorescence staining was used to identify HUVEC morphological changes, and fluorescence activated cell sorting (FACS) and DAPI staining were used to detect HUVEC apoptosis. Caffeine was found to inhibit blood vessel formation dose-dependently and to inhibit the proliferation of HUVECs time- and dose- dependently. FACS analysis and DAPI staining showed that inhibitory effect of caffeine on HUVEC proliferation was the result of apoptosis and the up-regulation of thrombospondin-1 (TSP-1). Furthermore, TSP-1 levels were down-regulated by NECA but were unaffected by CGS21680, indicating that caffeine regulated TSP-1 expression via adenosine A 2B receptor. In addition, caffeine up-regulated caspase-3 and down-regulated Bcl-2 at the protein level. These results suggest that the inhibitory effect of caffeine on angiogenesis is associated, at least in part, with its induction of endothelial cell apoptosis, probably mediated by a caspase-3 dependent mechanism.
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Role of inducible heat shock protein 70 in radiation-induced cell death

Role of inducible heat shock protein 70 in radiation-induced cell death

Cell death To study whether shortened G2/M phase arrest and al- tered response of cell cycle–related protein expressions by hsp70 could affect radiation-induced cell death, Hoechst 33258 staining was performed. As shown in Figure 6A, 4 Gy of gamma rays induced an extensive nuclear conden- sation and fragmentation in the vector control cells, whereas overexpression of Hsp70 drastically diminished this phenomenon. The function of inducible Hsp70 in ra- diation-induced mitotic arrest was further studied by us- ing nocodazole, a blocking agent in the M phase. As shown in Figure 6B, about 60% in the control vector cells and 40% in the transfected cells induced mitotic arrest by nocodazole treatment. In addition, when apoptotic cells were counted, nocodazole treatment reduced apoptosis and the reduction was greater in the control vector cells than the hsp70-transfected cell, suggesting the protection of the cells from mitotic cell death by Hsp70.
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The switching role of beta-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes

The switching role of beta-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes

However, Bcl-2 exhibited a quite distinct ‘switching response’ profile, with an initial increase at the nanomolar concentration range of ISO followed by a further decrease to below its basal level (B50%) in a micromolar concentration range (Fig. 3l). Bcl-2 is known to inhibit mitochondrial apoptosis and necrosis 26,27 , and the survival effect of Bcl-2 is largely supported by other findings such as the reduction of ATP consumption and the inhibition of autophagy 28–30 . Therefore, the increase of Bcl-2 can protect cardiomyocytes from cell death, whereas its decrease can promote cell death 31–33 . Together our simulation results show that the survival or death of cardiomyocytes might depend on the stimulation strength of b-AR, given by ISO concentration in our study, through the regulation of the expression level of Bcl-2.
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Cell death map in drug-induced ototoxicity: apoptosis, autophagy, and necroptosis

Cell death map in drug-induced ototoxicity: apoptosis, autophagy, and necroptosis

내재적 아포토시스는 미토콘드리아를 매개로 caspase-9 이 활성화됨으로써 유도되며 이 경로의 주 조절자는 BCL-2 family 단백질들이다. BCL-2 family 는 BH3-only 단백질 (Bim, Bid, Noxa 등), BCL-2 (혹은 BCL-xL, MCL1), 미토콘드리아 pore (MOMP, mitochondria outer membrane pore)를 생성하는 BAX 와 BAK 으로 나뉜다. 정상적인 상태에서는 BCL-2 가 BAX/BAK 의 pore 형성을 억제하는데, 내재적 아포토시스를 자극하는 신호에 따라 BH3-only 단백질이 증가하고 활성화되면 이들이 BCL-2 를 저해하거나 BAX/BAK 을 활성화함으로써 MOMP 가 형성된다. 사이토크롬 c 가 MOMP 를 통하여 세포질로 유출되면 Apaf-1 의 거대 복합체인 아폽토좀이 형성된다. 아폽토좀은 pro-caspase-9 을 활성화하고 caspase-9 이 다시 caspase-3 나 -7 과 같은 executor caspase 를 활성화함으로써 아포토시스가 개시된다 (Li et al., 1998; Schuler and Green, 2001;
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Cyclosporin A aggravates hydrogen peroxide–induced cell death in kidney proximal tubule epithelial cells

Cyclosporin A aggravates hydrogen peroxide–induced cell death in kidney proximal tubule epithelial cells

Daeun Moon 1 , Jinu Kim 1,2 1 Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju, 2 Department of Anatomy, Jeju National University School of Medicine, Jeju, Korea Abstract: Cyclosporin A (CsA) does not only exert a toxic effect on kidney parenchymal cells, but also protects them against necrotic cell death by inhibiting opening of mitochondrial permeability transition pore. However, whether CsA plays a role in hydrogen peroxide–induced kidney proximal tubular cell death is currently unclear. In the present study, treatment with CsA further increased apoptosis and necrosis in HK-2 human kidney proximal tubule epithelial cells during exposure to hydrogen peroxide. In addition, hydrogen peroxide–induced p53 activation and BH3 interacting-domain death agonist (BID) expression were higher in CsA-treated cells than those in non-treated cells, whereas hydrogen peroxide–induced activation of mitogen- activated protein kinases including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase and activation of protein kinase B were not significantly altered by treatment with CsA. In oxidant-antioxidant system, reactive oxygen species (ROS) production induced by hydrogen peroxide was further enhanced by treatment with CsA. However, expression levels of antioxidant enzymes including manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase were not altered by treatment with hydrogen peroxide or CsA. Treatment with CsA further enhanced mitochondrial membrane potential induced by exposure to hydrogen peroxide, although it did not alter endoplasmic reticulum stress based on expression of glucose-regulated protein 78 and 94. Taken together, these data suggest that CsA can aggravate hydrogen peroxide-induced cell death through p53 activation, BID expression, and ROS production.
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JKSSJournal of the Korean Surgical Society pISSN 2233-7903ㆍ

Outcome of triple-negative breast cancer in patients with or without markers regulating cell cycle and cell death

should inhibit apoptosis and therefore relate to a worse outcome [1]. On the contrary, the expression of bcl-2 in breast cancer has been found to be associated with favor- able prognostic factors such as small tumor size, ER pos- itivity, low nuclear grade and to predict a better outcome [7,10,17]. These unexpected results may be explained by the fact that the ability of bcl-2 to inhibit apoptosis de- pends on the intracellular balance among a number of its family members, with other pro-apoptotic members such as Bax counteracting its action [7,18]. Given its anti- apoptotic function, bcl-2 should be expected to correlate with worse prognosis. On the contrary, high levels of bcl-2 expression have been reported as associated to favorable tumor characteristics, such as low tumor size, low tumor grade, low proliferative activity and mainly with ex- pression of ER and PgR [19]. These associations account for the favorable prognostic impacts reported for bcl-2 ex- pression on DFS and OS in breast cancer, either node neg- ative and node positive, even if an independent prognostic role has been confirmed only in some series [20,21]. Our data do not support the association of bcl-2 expression with other favorable prognostic factors and mainly with ERs expression, even if the percentages of bcl-2 and ERs expression in the study population are in line with the oth- er series [22]. On the other hand, data regarding outcome in our series are consistent with other studies; that bcl-2 ex- pression doesn’t correlate with better outcome, either for DFS and OS. Reasons for this unfavorable prognostic val- ue of bcl-2 expression are not clear; possible explanations may include the pro- apoptotic activity of other members of the bcl-2 family, an inhibitory activity of bcl-2 on cell proliferation or the estrogen-inducibility of bcl-2 ex- pression [10]. In addition, data regarding outcome in our series are not consistent with other studies; that CK5/6 positivity correlates with better outcome, either for DFS and OS. Reasons for this favorable prognostic value of CK5/6 expression are not clear; possible explanations may include the small sample size, short-term follow-up peri- od and no differences in survival rate between TNBC groups according to basal type.
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Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer

Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer

IGFBP-3R Mediates IGFBP-3- induced Growth Inhibition and Apoptosis—To determine whether IGFBP-3R mediates antiprolifera- tive effect of IGFBP-3, the growth inhibitory actions of endogenous IGFBP-3 via IGFBP-3R were ini- tially tested using IGFBP-3-express- ing Hs578T and MDA231 human breast cancer cells, PC-3 prostate cancer cells, and NCI-H157 non- small cell lung carcinoma cells. Sig- nificant cell growth inhibition was observed in Ad:IGFBP-3R-infected in a m.o.i.-dependent manner but not Ad:EGFP-infected Hs578T cells (Fig. 4A). IGFBP-3R overexpression resulted in growth inhibition up to 90% in IGFBP-3-expressing cancer cells, whereas adenoviral vector itself shows no growth inhibition (Table 1). It was further tested whether IGFBP-3R-induced growth inhibition results from induction of apoptosis. Treatment with the pan-caspase inhibitor z-VAD-fmk resulted in a complete abrogation of both etoposide- and IGFBP-3R-in- duced cell growth inhibition in Hs578T cells, suggesting that the IGFBP-3R might play a role in IGFBP-3-induced apoptosis (Fig.
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A new anti-proliferative drug induces mitotic arrest and apoptosis in human pancreatic cancer cell lines

A new anti-proliferative drug induces mitotic arrest and apoptosis in human pancreatic cancer cell lines

20 2. #765 induces mitotic arrest by regulating cell cycle-related proteins in human pancreatic cancer cells To investigate whether #765-induced inhibition of cell proliferation was caused by arresting the cell cycle, the effect of #765 on cell cycle in pancreatic cancer cells was examined by flow cytometry. As shown in Figure 3A and Figure 3B, #765 significantly led to accumulation of cells at G 2 /M phase and decrease of cell population at G 1 and S phase in both Mia PaCa-2 and PANC-1 cells. Also, treatment of #765 with higher concentration caused a clear increase of cell population at subG1, indicating that #765 induced cell death. Since #765 induced G 2 /M arrest in human pancreatic cancer cells, the expression of cell cycle regulatory proteins was evaluated by western blotting. Paclitaxel was used as a positive control of causing mitotic arrest. It was reported that dephosphorylation of Cdc2 at Tyr15 is a key regulatory step in activating Cdc2/cyclinB1 complex and further promotes G 2 /M transition. 29 As shown in Figure 4A, expression of phospho-Cdc2 (Tyr15) was significantly decreased in both Mia PaCa-2 and PANC-1 cells treated with both
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Calcium overload is essential for the acceleration of staurosporine-induced cell death following neuronal differentiation in PC12 cells.

Calcium overload is essential for the acceleration of staurosporine-induced cell death following neuronal differentiation in PC12 cells.

Differentiation of neuronal cells has been shown to ac- celerate stress-induced cell death, but the underlying mechanisms are not completely understood. Here, we find that early and sustained increase in cytosolic ([Ca 2+ ] c ) and mitochondrial Ca 2+ levels ([Ca 2+ ] m ) is es- sential for the increased sensitivity to staurosporine- induced cell death following neuronal differentiation in PC12 cells. Consistently, pretreatment of differ- entiated PC12 cells with the intracellular Ca 2+ -chelator EGTA-AM diminished staurosporine-induced PARP cleavage and cell death. Furthermore, Ca 2+ overload and enhanced vulnerability to staurosporine in differ- entiated cells were prevented by Bcl-X L overexpr- ession. Our data reveal a new regulatory role for differ- entiation-dependent alteration of Ca 2+ signaling in cell death in response to staurosporine.
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Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells

Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells

Received October 30, 2014; Accepted November 29, 2014; Epub December 15, 2014; Published January 1, 2015 Abstract: STAT3 has been recognized as an efficacious drug target for prostate cancer because of its constitutive activation in this fatal disease. We recently identified the root bark of Morus alba Linn. as a potential STAT3 inhibitor among 33 phytomedicines traditionally used in Korea. Morusin, an active compound isolated from the root bark of Morus alba, has shown anti-oxidant and anti-inflammatory effects. In the present study, we examined whether morusin has a potential as an anti-cancer agent in prostate cancer. We found that morusin suppressed viability of prostate cancer cells, but little effect in normal human prostate epithelial cells. Morusin also reduced STAT3 activity by inhibiting its phosphorylation, nuclear accumulation, and DNA binding activity. In addition, morusin down-regu- lated expression of STAT3 target genes encoding Bcl-xL, Bcl-2, Survivin, c-Myc and Cyclin D1, which are involved in regulation of apoptosis and cell cycle. Furthermore, morusin induced apoptosis in human prostate cancer cells by reducing STAT3 activity. Taken together, these results suggest that morusin could be a potentially therapeutic agent for prostate cancer by reducing STAT3 activity and inducing apoptosis.
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BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin

BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin

CP cell line pairs. These data suggest that, although the BAD pathway is important in determination of cisplatin-induced apoptosis, likely via the phosphorylation status of the BAD protein, there are multiple other molecular mechanisms that underlie OVCA chemo-sensitivity and also by which changes in BAD phosphorylation can occur. This also further under- scores the previously recognized molecular heterogeneity of ovarian cancer development and response to therapy. Our findings underscore the complexity of the role of the BCL2 family of proteins in cell survival and apoptosis, as well as the pro- versus anti-apoptotic influence of the BAD serine-128 site. BAD expression levels and also post-translational events likely influence OVCA cell apoptotic signaling and subsequent sensitivity to cytotoxic challenges. Our data provide additional evidence to support an important role for the BAD apoptotic pathway not only as a potential biomarker of OVCA chemo- resistance but also as an appealing therapeutic target.
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Tannic acid-induced apoptosis in FaDu hypopharyngeal squamous cell carcinoma

Tannic acid-induced apoptosis in FaDu hypopharyngeal squamous cell carcinoma

Treating cells with 200 µM of TA for 24 hours caused 80% of cell death (Fig. 1). 2. Tannic acid induced cell cycle arrest and apoptosis Flow cytometry was used to examine the cell cycle distribu- tion under the TA treatment. The analysis on cell cycle revealed that under the low concentration of TA (25 µM) cells were sig- nificantly inhibited in cell cycle progression with 30% of cells arrested at G2/M phase. Meanwhile, cell population at sub-G1 phase was dose-dependently increased indicating that high dose of TA induced apoptosis on FaDu cells (Fig. 2). To further confirm the changes in cell division and cellular nucleus, the effect of TA on cell cycle progression was examined by immu- nofluorescence imaging. Under the treatment of 25 µM TA for 24 hours, the number of cells in division process was increased with doubled centrosomes and bipolar mitotic spindles while at higher doses cells were in apoptosis with nuclei condensed
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The role of microRNAs in cell death pathways

The role of microRNAs in cell death pathways

Conclusion In this review, we have summarized and discussed how miRNAs regulate apoptosis, ER stress, necroptosis, and autophagy by target- ing a wide range of components of these pathways and document- ed the aberrant expression of miRNAs in cancer and the oncogen- ic or tumor-suppressor roles of miRNAs. miRNAs discussed in this review could be used as promising diagnostic and prognostic Fig. 4. miRNAs involved in the autophagy pathways. Autophagy occurs under a variety of conditions, such as cell growth signaling, glucose deficiency, hypoxia, genotoxicity, and endoplasmic reticulum (ER) stress, and activates signaling pathways that initiate or inhibit the autophagy cascade. The mTOR and AMPK proteins are important regulators of the autophagy pathway. mLST8, mammalian lethal with Sec13 protein 8, also referred to as GβL; mTOR, mammalian target of rapamycin; Raptor, regulatory-associated protein of mTOR;
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Mechanism of ethanol-induced purkinje cell death in developing rat cerebellum: Its Implication in apoptosis and oxidative damage

Mechanism of ethanol-induced purkinje cell death in developing rat cerebellum: Its Implication in apoptosis and oxidative damage

The ability of oxidative stress to provoke necrotic cell death as a résu1ï of massive cellular damages associated t 。 1ipid peroxidation18) and a1teration of proteins20) and nucleic acids19) have been well docwnented for a long time. ROS has been a1so know 끼 to act as signalling molecu1es in apoptotic pathway. For example , some anti-oxidants can inhibit activation of caspase and subsequent steps leading to apoptotic cell death17l. 1n the present study , 8-0HdG imnnmoreactivity in cells of Purkinje cell layer was observed for a longer time unti1 24 h 따 'ter ethanol administration , at which time point the active caspase-3 and -9 immunoreactivities were gone by. This longer duration of 8 OHdG immunoreactivity may reflect the persistent production of ROS leve1s in response to ethanol exposure , since it has been demonstrated 낭 lat ROS levels in the extract of whole cerebellum remains elevated by 24 h after ethano1 administration24l. Therefore , it is plausible that the 1ater increase of ROS levels may convert the apoptotic pathway of p1 미 r 매매 e cell death into necrotic pathway ,which may also reflect the absence of DNA fragmentation in TUNEL staining
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A pattern of cell death induced by 40 kHz ultrasound in yeast cell model

A pattern of cell death induced by 40 kHz ultrasound in yeast cell model

Keywords: Cell death, 40 kHz ultrasound, yeast, Reactive oxygen species PACS numbers: 43.35.Wa., 43.80.Gx 초 록: 초음파는 세포사멸을 포함하여 의학 및 생물학분야에 널리 응용되고 있으나 그 정확한 기작에 대해선 논쟁의 여지가 있다. 본 연구에서는 40 kH 초음파 조사시스템을 단세포 효모에 적합하게 개발하고 세포사멸 유도시 40 kH 초음 파의 생물학적 현상을 살펴보았다. 아이오딘화 칼륨 선량 측정법을 이용하여 1.5 ml 실험튜브에 40 kH 초음파 조사 시스 템의 최적 조건을 맞추어 세포사멸을 시간 의존적 방식으로 연구하였고 초음파 조사과정동안 온열효과와는 별개로 세포 사멸이 관찰되었다. 40 kH 초음파와 과산화수소의 동시 처리는 세포사멸에 상조적인 효과가 관찰되어 활성산소가 40 kH 초음파사멸에 관련이 있었다. 그러나 활성산소 저해제, NAC(N-acetyl-Lcysteine)는 초음파에 의한 세포사멸에 약 한 영향만을 미쳤고 다른 세포사멸, 괴사억제제[글리실리진(glycyrrhizin) 또는 zVAD-fmk] 역시도 세포사멸을 완전히 억제하진 못하였다. 본 연구를 통하여 40 kH 초음파에 의한 세포사멸에는 온열효과나 활성산소만으로 사멸이 유도되지 는 않는 것으로 보인다.
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Protection effect of EC on radiation-induced cell death of auditory cell in vitro and in vivo

Protection effect of EC on radiation-induced cell death of auditory cell in vitro and in vivo

청 청각 각 각세 세 세포 포 포사 사 사멸 멸 멸에 에 에 대 대 대한 한 한 녹 녹 녹차 차 차추 추 추출 출 출 E E Ep p pi i ic c ca a at t te e ec c ch h hi i in n n의 의 의 보 보 보호 호 호효 효 효과 과 과 방사선은 현재 암 치료용으로 널리 사용되고 있으며 특히 두경부암의 경 우 생명을 유지시키는데 중요한 장기와 구조물이 복잡하게 위치하고 있어 종양 발생으로 인한 중대한 기능 손실과 외모의 변형이 문제시 되고 있다.그러나 방 사선치료는 인해 정상 조직이나 기관의 모양과 기능은 정상 상태로 유지시키면 서 악성 종양조직은 선택적으로 파괴시켜 널리 사용되고 있다.그러나 불행히도 두경부암에서 방사선을 조사하면 청력이 손실된다고 보고되어 있다.따라서 본 실험에서는 방사선에 의해 유도되는 청력손실에 따른 녹차추출 Epi catechi n(EC) 의 효과에 대해 확인하고자 하였다.
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CIIA is a novel regulator of detachment-induced cell death.

CIIA is a novel regulator of detachment-induced cell death.

Detachment-induced cell death, or anoikis, is a type of apoptosis that occurs when epithelial cells lose their attachment to the extracellular matrix. Anoikis serves as a physiologic barrier to metastasis. Deviation from the tightly regulated mechanism of detachment-induced cell death might result in progression to metastatic cancer. Here, we investigated the function of CIIA in the regulation of anoikis. CIIA protein was upregulated in colon cancer tissue samples. Knockdown of CIIA in metastatic colorectal carcinoma SW620 and KM12SM cells promoted detachment-induced cell death through the regulation of caspase activation. Knockdown of CIIA also inhibited anchorage-independent growth in soft agar and colony formation after suspension stress. These observations suggest that CIIA is a novel negative regulator of anoikis. Cancer Res; 70(15); 6352–8. ©2010 AACR.
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The Role of PKC-δ in Hypoxia-induced Cerebrovascular Endothelial cell death.

The Role of PKC-δ in Hypoxia-induced Cerebrovascular Endothelial cell death.

3 뇌혈관 세포주를 저산소에 노출시킨 지 1 시간째 PKC-δ의 활성 가장 증가하였고 4시간까지 지속되었다.저산소에 의한 뇌혈관 내피세포 사멸과 정에서 PKC-δ의 역할을 알아보기 위해 PKC-δ 저해제인 rottl eri n을 처리한 결 과,저해제의 농도가 증가함에 따라 세포 사멸이 현저히 증가하였으며 저산소 자 극 후 PKC-δ[r]

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Gangliosides induce autophagic cell death in astrocytes

Gangliosides induce autophagic cell death in astrocytes

Gisslen et al., 1997). Under pathological states, the composi- tion and volume of the extracellular space change, thereby slowing down the movement of various molecules and increasing their local concentrations at injured sites (Sykova, 2005). Thus, the concentration of gangliosides in the extra- cellular space at injured sites can be greatly increased, up to mg·mL -1 (Jou et al., 2006). Abnormally released gangliosides under pathological conditions may influence cell survival or death of neurons and astrocytes. Our results have important implications in the role of gangliosides in brain pathologies and may provide a link between astrocyte autophagy and the pathological role of gangliosides in brain. Astrocytes play a key role in the maintenance of normal brain physiology and, in many neuropathologies, and their dysfunction leads to disruption of neuronal function (Barres and Barde, 2000;
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Role of RIP3 in DNA damaging agent-induced breast cancer cell death

Role of RIP3 in DNA damaging agent-induced breast cancer cell death

Our dat a i ndi c at e t hatRI P3 e xpr e ss i on i s l i ke l y se l ec t e d agai ns tdur i ng c ance rgr owt h orpr ogr es s i on,wi t h me t hyl at i on oft he ge nomi c r e gi on ne ar t heRI PK3t r ans c r i pt i on st ar ts i t el e adi ng t oRI P3s i l enci ng.Si nceRI P3pl ays a gr e at e r r ol e i n r e s ponse t o c he mot he r ape ut i c s t han has bee n pr e vi ousl y appr e c i at ed.The r e spons e ofc e l l s t o 5-AD s ugge s t st he e xc i t i ng pos si bi l i t y t hat RI P3 e xpr e s si on may be mani pul at ed i n c anc e r c e l l s t o make t he m s ensi t i ve t o r e gul at e d ne cr os i s ,we pr opos e t hathypomet hyl at i on age nt s ,i n c ombi nat i on wi t h s t andar d c he mot he r apy,may be use f uli n t r e at i ng c anc e r s t hat l ac k RI P3 e xpr e s si on. RI P3 de f i c i e nc y i s l i ke l y t o have i mpor t ant bi ol ogi c al and t he r ape ut i c c ons e que nc es ,i nc l udi ng pos si bl e e f f ec t s on t he r e s pons es oft umorc e l l s t o c he mot he r apy.How RI P3 i s act i vat e d by f r om dr ugs wi t h s uc h mec hani st i c di f f e r ence s i s an i mpor t antmat t e r f or f ut ur e i nve st i gat i on and wewi l li nve s t i gat ehow t het umorsuppr e s sorr ol ei n RI P3 haveanymec hani sm.
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