Neuronal and Glial Alterations Due to Focal Cortical Hypoxia Induced by Direct Cobalt Chloride (CoCl2) Brain Injection

Caltana, Laura; Merelli, Amalia; Lazarowski, Alberto; Brusco, Alicia

doi:10.1007/s12640-009-9038-9

Cited by 57 publications

(48 citation statements)

References 23 publications

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“…Therefore, we investigated the influence of LXA 4 on HIF-1α protein content in H22 cells. Like in some other tumor cells (38,39), it was also found that HIF-1α was undetectable in control H22 cells but strongly enhanced in cytoplasm and accumulated in nuclei under CoCl 2 -mimiced hypoxic condition. Unlike other antiangiogenic agents that only blockaded VEGF but not HIF-1α (40), we found that CoCl 2 stabilization of HIF-1α was markedly countered by LXA 4 .…”

Section: Discussionsupporting

confidence: 61%

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Chen

Hao

et al. 2010

Molecular Cancer Therapeutics

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Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A 4 (LXA 4 ) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA 4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA 4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA 4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164-74. ©2010 AACR.

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Section: Discussionsupporting

confidence: 61%

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Chen

Hao

et al. 2010

Molecular Cancer Therapeutics

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“…The severity of this damage was related to the CoCl 2 doses administered, where a fast HIF-1a up-regulation (occurring as soon as 1 h after cobalt injection) was documented (Caltana et al 2009). In several experimental models of cerebral hypoxia, a maximal expression of HIF-1a is observed 5 h after the hypoxic stress, which declines to basal levels at 12 h (Jones and Bergeron 2001;Pascual et al 2001;Stroka et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…All other chemical substances were of analytical grade. CoCl 2 was purchased from (Sigma) and 50 mM solution was freshly prepared as previously described (Lazarowski et al 2007a;Caltana et al 2009). …”

Section: Chemicals and Antibodiesmentioning

confidence: 99%

“…Because cobalt chloride (CoCl 2 ) stabilizes or induces the accumulation of HIF-1a, CoCl 2 exposure has been widely used as a hypoxia-mimicking agent in both in vivo (Badr et al 1999) and in vitro experiments (Caltana et al 2009). Many reports have shown that cobalt up-regulates a similar group of genes than those observed during hypoxia (Lee et al 2001;Vengellu et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Merelli

Caltana

Girimonti³

et al. 2010

Neurotox Res

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Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia, hypoxia-inducible factor-1α (HIF-1α) activates several genes as erythropoietin receptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene (MDR-1) related with drug-refractory phenotype. Brain cortical injection of CoCl(2) produces focal hypoxia-like lesion with neuronal and glial alterations, as well as HIF-1α stabilization and MDR-1 overexpression. Intranasal (IN) drug delivery can by-pass blood-brain barrier (BBB) where MDR-1 is normally expressed. We evaluated the effects of IN-rHu-Epo administration on spontaneous motor activity (SMA) and the brain pattern expression of HIF-1α, MDR-1, and Epo-R in our cobalt-induced hypoxia model. Adult male Wistar rats were injected by stereotaxic surgery in frontoparietal cortex, with CoCl(2) (2 μl-50 mM; n = 20) or saline (controls; n = 20). Ten rats of each group were treated with IN-rHu-Epo 24 U or IN-saline. In addition, erythropoietic stimulation was evaluated by reticulocytes (Ret) account during three consecutive days, after intraperitoneal (i.p.)-recombinant-human Epo (rHu-Epo) (950 U; n = 6) or IN-rHu-Epo (24 U; n = 6) administration. SMA was evaluated by open field and rotarod tests, before and after surgical procedures during five consecutive days. Histological and immunostaining studies of HIF-1α, MDR-1, and Epo-R were performed on brain slides. A significant difference in SMA was observed in the hypoxic rats of IN-rHu-Epo-administered group as compared with Co-Saline-treated subjects and controls (p < 0.001). HIF-1α, EPO-R, and MDR-1 were overexpressed in the hypoxic cortex areas, while in contralateral hemisphere or controls, they were negatives. Reticulocytes were only increased in intraperitoneal (i.p.)-rHu-Epo-administered group. In spite of MDR-1 overexpression being detected in neurons, the coexpression of Epo-R could explain the positive effects observed on SMA of IN-rHu-Epo-administered group.

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“…Low glucose, high glucose, and hypoxic media were prepared according to previous reports [18,19] LG+Hypoxia and HG+Hypoxia) [23][24][25].…”

Section: Culture Of Hrecs In Natural and Simulated Dr Environmentsmentioning

confidence: 99%

Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy

Shao

Yin

et al. 2017

Cell Physiol Biochem

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Background/Aims: Diabetic retinopathy (DR) is one of the main causes of blindness in the world. Our previous study showed that transthyretin (TTR) regulates key genes in the Tie2 pathway and inhibits the development of neovascularization in DR, but the mechanism is still unclear. Here, we investigated how TTR affects the progression of neovascularization in DR. Methods: Natural and simulated DR media (hyperglycemia and hypoxia) were used to culture human retinal microvascular endothelial cells (hRECs). Flow cytometry was employed to investigate the effect of TTR on apoptosis of hRECs. Fluorescent labeling and immunofluorescence staining were used to determine the TTR distribution in hRECs. The membrane proteins of hRECs were extracted and applied to a sepharose-TTR column, and the captured proteins were identified by Mass Spectrometric analysis. Gene knock-down and western blotting assays were used to study the key signal pathway of the most abundant identified protein. Results: TTR induced apoptosis of hRECs in an environment that simulated hypoxia. Immunofluorescent staining showed that TTR could enter the nuclei of hRECs. A total of 30 unique TTR-captured proteins were identified by Mass Spectrometry, and glucoseregulated protein 78 (GRP78) was one of the most abundant. Western blotting and gene knock-down indicated that TTR might upregulate GRP78 and facilitate apoptosis through the eIF2α/CHOP pathway. Conclusions: In the DR environment (hyperglycemia and hypoxia), TTR was shown to repress neovascularization by promoting apoptosis of hRECs through a GRP78-dependent pathway.

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Neuronal and Glial Alterations Due to Focal Cortical Hypoxia Induced by Direct Cobalt Chloride (CoCl2) Brain Injection

Cited by 57 publications

References 23 publications

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy

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