Involvement of Caspase 3 Mediated Apoptosis in Hematopoietic Cytotoxicity of Metabolites of Ethylene Glycol Monomethyl Ether.

Takagi, Akira; Yamada, Takayuki; Hayashi, Koji; Nakade, Yuusuke; Kojima, Tetsuhito; Takamatsu, Junki; Shibata, Eiji; Ichihara, Gaku; Takeuchi, Yasuhiro; Murate, Takashi

doi:10.2486/indhealth.40.371

Cited by 8 publications

(4 citation statements)

References 5 publications

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“…A significant downregulation of caspase‐3 (Figure a–e) in T11TS treated glioma associated BMHSCs compared to glioma control BMHSCs clearly indicates its defensive anti‐apoptotic role against ENU mediated glioma orchestrated apoptosis of bone marrow HSCs in both the mature and immature compartments. This is in agreement with previous reports showing strong activation of caspase‐3, the main downstream caspase in methoxy acetaldehyde (MALD) induced apoptosis of human bone marrow cells and repression of apoptosis following treatments with cell permeable caspase‐3 inhibitors (Takagi et al, ).…”

Section: Discussionsupporting

confidence: 93%

T11TS repress gliomagenic apoptosis of bone marrow hematopoietic stem cells

Mondal¹,

Hazra²,

Datta³

et al. 2017

Journal Cellular Physiology

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Combating gliomagenic global immunosuppression is one of the emerging key for improving prognosis in malignant glioma. Apoptosis plays a pivotal role within the adult hematopoietic system particularly in regulating the cells of immune system. Gliomagenic regulation of apoptotic mediators within bone marrow milieu has not been elucidated. We previously demonstrated that administration of membrane glycopeptides T11 target structure (T11TS) not only rejuvenate bone marrow hematopoietic stem cells (BMHSCs) from glioma mediated hibernation by inhibiting gliomagenic overexpression of Ang-1/Tie-2 but also stimulate glioma mediated diminution of expression CD34, c-kit, and Sca-1 markers. In the present study, we investigated the impact of glioma on apoptotic signaling cascades of BMHSCs and consequences following T11TS therapy. Bone marrow smear and Annexin V staining confirm gliomagenic acceleration of apoptotic fate of BMHSCs whereas T11TS treatment in gliomabearing rats disrupted apoptosis of BMHSCs. Flowcytometry, immunoblotting, and immunofluorescence imagining results revealed multi potent T11TS not only significantly downregulates gliomagenic overexpression of Fas, Fas L, Bid, and caspase-8, the pro-apoptotic extrinsic mediators but also strongly inhibits cytosolic release of cytochrome-c, Apf-1, and Bax to deactivate gliomagenic caspase-9, 3 the key intrinsic apoptotic mediators followed by up modulation of anti-apoptotic Bcl-2 in glioma associated HSCs. T11TS is also able to diminish the perforin-granzyme B mediated apoptotic verdict of BMHSCs during gliomagenesis. The antiapoptotic action of T11TS on glioma associated BMHSCs provide a crucial insight into how T11TS exerts its immunomodulatory action against glioma mediated immune devastation. K E Y W O R D Sapoptosis, glioma, HSCs, immunotherapy, T11TS

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Section: Discussionsupporting

confidence: 93%

T11TS repress gliomagenic apoptosis of bone marrow hematopoietic stem cells

Mondal¹,

Hazra²,

Datta³

et al. 2017

Journal Cellular Physiology

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show abstract

“…These findings showed organ-specific effects on developing germ cells. At the concentrations tested, all four compounds have been shown to be non-cytolethal in other cell lines [64][65][66][67][68][69][70]. Similarly, none of the compounds were cytolethal to somatic cells, and we did not observe overt cytolethality other than a 30% loss of viability with BPA.…”

Section: The Durand Model Can Be Used To Provide Mechanistic Insight ...mentioning

confidence: 48%

Use of a rat ex-vivo testis culture method to assess toxicity of select known male reproductive toxicants

Goldstein

Seyler

Durand

et al. 2016

Reproductive Toxicology

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“…Alenzi et al (2002) reported that Fas and caspase activation may play an important role in regulating myeloid progenitor cell kinetics. Caspase-3 was also reported to play an important role in inducing hematopoietic toxicity by ethylene glycol monomethyl ether and its metabolites (Takagi et al, 2002). Furthermore, Page et al (2003) reported that 7,12-Dimethylbenz(a)anthracene caused pre-B cell apoptosis and immunotoxicity via activation of caspase-8 and -9.…”

Section: Discussionmentioning

confidence: 98%

Flow Cytometric Analyses on Lineage-Specific Cell Surface Antigens of Rat Bone Marrow to Seek Potential Myelotoxic Biomarkers: Status After Repeated Dose of 5-Fluorouracil

et al. 2004

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Flow cytometry (FCM) analysis of CD45, CD45R, CD71 and CD90 expression on Crj:CD(SD)IGS rat bone marrow cells was done after 5-fluorouracil (5-FU) administration to examine whether these lineage-specific cell surface antigens could be myelotoxic biomarkers. The expression of CD45 (CD45Low and CD45High: differing in expression intensity), CD45R, CD71 and CD90 on bone marrow cells coincided with previous reports. After repeated administration of 5-FU at 50 mg/kg/day for 1-5 days, a time-dependent decrease in cells expressing CD45Low, CD71 and CD90 was observed, whereas a decrease in the CD45High expressing cells was not observed. Furthermore, the decrease was dose-dependent in CD45Low, CD71 and CD90 expressing cells after administration of 5-FU between 2 and 50 mg/kg/day for 4 days. After 4-day repeated dose of 5-FU at 50 mg/kg/day followed by a recovery period, the change in number of CD45Low, CD45R, CD71 and CD90 cells to the bottom and in recovery showed different kinetics. In contrast, the change in number of CD45High cells was minimal, and relatively stable after 5-FU administration. The results suggest that CD45, CD45R and CD90 could each be potential myelotoxic biomarkers for a total proportion of common leukocytes including T- and B-lymphocytes, for a total proportion of B-lymphocytes, and for a total proportion of T-lymphocytes plus immature B-lymphocytes and common progenitor cells, respectively. CD71 could be a single myelotoxic biomarker for erythroid cells. Further study is required for isolation of each of the myelo-lymphocytic lineages. However, the present study showed that FCM analysis could be available to assess the lineage or differentiation stage-specific response, such as the different extent and time-course or the kinetics (the time to reach the bottom and to recover to the normal level) of myelotoxic effect in rat bone marrow.

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Involvement of Caspase 3 Mediated Apoptosis in Hematopoietic Cytotoxicity of Metabolites of Ethylene Glycol Monomethyl Ether.

Cited by 8 publications

References 5 publications

T11TS repress gliomagenic apoptosis of bone marrow hematopoietic stem cells

T11TS repress gliomagenic apoptosis of bone marrow hematopoietic stem cells

Use of a rat ex-vivo testis culture method to assess toxicity of select known male reproductive toxicants

Flow Cytometric Analyses on Lineage-Specific Cell Surface Antigens of Rat Bone Marrow to Seek Potential Myelotoxic Biomarkers: Status After Repeated Dose of 5-Fluorouracil

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