Molecular and Physiological Factors of Neuroprotection in Hypoxia-tolerant Models: Pharmacological Clues for the Treatment of Stroke

Nathaniel, Thomas I.; Soyinka, Julius O.; Adedeji, Adekunle; Imeh-Nathaniel, Adebobola

doi:10.4137/jen.s22512

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…McNab () was the first to suggest that subterranean rodents live under constant hypoxia and hypercapnia. Physiological adaptations of burrowing mammals to the subterrestrial microclimate, especially mechanisms allowing them to cope with severe hypoxia and hypercapnia, have been studied (Larson, Drew, Folkow, Milton, & Park, ; Larson & Park, ; Nathaniel, Soyinka, Adedeji, & Imeh‐Nathaniel, ; Park et al., ; Schmidt, Hangmann, Shams, Avivi, & Hankeln, ; Shams, Avivi, & Nevo, ). However, evidence accumulates that subterranean mammals, including African mole‐rats, Middle East mole‐rats and North American moles, as well as theoretical models, do not necessarily live in constant hypoxic and hypercapnic microenvironments (Roper, Bennett, Conradt, & Molteno, ; Schaefer & Sadleir, ; Shams, Nevo, & Avivi, ; Withers, ).…”

Section: Introductionmentioning

confidence: 99%

The microenvironment of naked mole‐rat burrows in East Africa

et al. 2017

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Naked mole-rats (Heterocephalus glaber) can be extremely long-lived and are resistant to cancer. Hence, they have been proposed as a model organism for delayed ageing. Adaptation to a constant hypoxic and hypercapnic environment has been suggested as reason for their apparent ability to tolerate oxidative stress. Nevertheless, little is known about the natural habitat to which the species evolved. Naked mole-rat burrow environments were assessed in Ethiopia and Kenya. Despite reported thermolability of naked mole-rats, skin temperature upon capture varied (23.7-35.4°C), mostly within the species' thermoneutral zone, demonstrating their ability to maintain homoiothermy even under wide fluctuations of burrow temperature (24.6-48.8°C) and humidity (31.2%-92.8%), which are far greater than previously reported. Burrow temperature regularly alternates during the daytime and night-time, driving convective currents that circulate air in the tunnels. Consequently, concentrations of CO 2 and O 2 in burrows only slightly deviated from surface atmosphere. This contradicts the assumption of constant hypoxia/hypercapnia in subterranean burrows. In addition to diffusion, animal movement and occasional wind-driven ventilation, our data support the temperature-driven convective model of circulation. The naked mole-rat burrow is a relatively normoxic subterranean microenvironment with considerable fluctuations in temperature and humidity. La temp erature des terriers alterne r eguli erement entre le jour et la nuit, entraînant

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Section: Introductionmentioning

confidence: 99%

The microenvironment of naked mole‐rat burrows in East Africa

et al. 2017

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“…Hypoxia, or low oxygen tension, is a unique environmental stress that not only represents the insufficient oxygen supply to cells and tissues but also occurs during a range of physiologic and pathophysiological circumstances, including development, inflammation, tissue ischemia, and tumor growth (1)(2)(3). Aerobic organisms and cells have developed complex adaptive mechanisms to maintain oxygen homeostasis and evolved physiologic and biochemical responses to survive hypoxic stress (4)(5)(6). Two well-studied O 2 -sensitive signaling pathways are implicated in promoting hypoxia tolerance: signaling through mTOR (mammalian target of rapamycin) that regulates mRNA translation initiation and signaling through activation of the unfolded protein response that alleviates endoplasmic reticulum stress (3,7).…”

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confidence: 99%

The zebrafish miR‐462/miR‐731 cluster is induced under hypoxic stress via hypoxia‐inducible factor 1α and functions in cellular adaptations

Huang

Chen

et al. 2015

FASEB j.

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Hypoxia, a unique and essential environmental stress, evokes highly coordinated cellular responses, and hypoxia-inducible factor (HIF) 1 in the hypoxia signaling pathway, an evolutionarily conserved cellular signaling pathway, acts as a master regulator of the transcriptional response to hypoxic stress. MicroRNAs (miRNAs), a major class of posttranscriptional gene expression regulators, also play pivotal roles in orchestrating hypoxia-mediated cellular adaptations. Here, global miRNA expression profiling and quantitative real-time PCR indicated that the up-regulation of the miR-462/miR-731 cluster in zebrafish larvae is induced by hypoxia. It was further validated that miR-462 and miR-731 are up-regulated in a Hif-1α-mediated manner under hypoxia and specifically target ddx5 and ppm1da, respectively. Overexpression of miR-462 and miR-731 represses cell proliferation through blocking cell cycle progress of DNA replication, and induces apoptosis. In situ detection revealed that the miR-462/miR-731 cluster is highly expressed in a consistent and ubiquitous manner throughout the early developmental stages. Additionally, the transcripts become restricted to the notochord, pharyngeal arch, liver, and gut regions from postfertilization d 3 to 5. These data highlight a previously unidentified role of the miR-462/miR-731 cluster as a crucial signaling mediator for hypoxia-mediated cellular adaptations and provide some insights into the potential function of the cluster during embryonic development.

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“…Previous studies suggested that delivering the desired genes into the cells may overcome some limitations of cells and facilitate therapeutic efficiency after cell transplantation [9,10]. Hypoxia inducible factor-1 alpha (HIF-1a) is one of the most important regulators in response to oxygen levels, and the stabilization of HIF-1a in cells may promote activation and migration [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HIF-1α in Mesenchymal Stem Cells Contributes to Repairing Hypoxic-Ischemic Brain Damage in Rats

Lin

Zhou

et al. 2016

Blood

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Introduction: Preclinical researches on the use of mesenchymal stem cells (MSCs) transplantation to treat hypoxic-ischemic (HI) brain damage have received some encouraging results. However, the insufficient migration of active cells to damaged tissues has limited their potential therapeutic effects. There is a good evidence that hypoxia inducible factor-1 alpha (HIF-1α) promotes the viability and migration of cells. This study was designed to investigate whether overexpression of HIF-1α in MSCs could be effective to enhance the therapeutic efficiency. Methods: MSCs were obtained from rat femoral and tibial bone marrow, and cells with HIF-1α overexpression were gained by recombinant lentiviral vector. The proliferation and migration of MSCs were assessed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and transwell culture system. Additionally, the therapeutic efficiency of MSCs after transplantion on HI brain damage in rats were investigated by Morris water maze test and histological examination to analyse the cognitive and pathological changes, and the recruitment in the hippocampus was also observed microscopically. Results: (1) As evidenced by phase contrast and fluorescence microscopy, more than 90% of the cells were GFP-positive when infected with the HIF-1α or GFP lentiviral, and the protein expression of HIF-1α in HIF-1α transduced MSCs was approximately 2-fold that in normal MSCs and GFP transduced MSCs (P<0.01). The results of MTT assay showed that overexpression of HIF-1α promoted the viability and proliferation of MSCs (P<0.01). (2) Meantime, we found MSCs were enhanced the migration both in vitro and in vivo experiments. According to transwell assay, the number of cells migrating to the lower compartment in HIF-1α overexpression group was more than other two groups (P<0.01). In vivo experiments in HI-induced rats, the number of MSCs in the hippocampus increased gradually in a time-dependent manner from day 7 to day 21 after transplantation. And a remarkably increased in the recruitment of HIF-1α transduced MSCs was observed in the hippocampus at every time point compared with GFP transduced MSCs (P<0.01). (3) HIF-1α overexpression also elevated the therapeutic efficiency of MSCs on behavioral and histological aspect in HI-induced brain damaged rats. Morris water maze test suggested that the rats suffered from cognitive dysfunction due to HI treatment. There were a significantly increased of time in the target quadrant in both MSCs transplanted groups compared with HI-vehicle group, but a more increase in the amount of time have been found in HIF-1α overexpressed MSCs group (P<0.01). In contrast with sham group, the pathological changes of the hippocampus in the HI-vehicle group revealed serious injury, and the cells were disordered and cavitation was visible by hematoxylin and eosin staining, but the damages were partly mitigated in HIF-1α overexpressed MSCs transplanted group as compared to other groups. Conclusion: Taken together, these data indicated that overexpression of HIF-1α could improve the therapeutic efficiency of MSCs, and transplantation of MSCs with HIF-1α overexpression may represent an attractive therapeutic option to treat HI brain damage in the future. Footnotes: This work was financially supported by National Natural Science Foundation of China (Gant No. 81270566, Gant No. 81500114). Disclosures No relevant conflicts of interest to declare.

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Molecular and Physiological Factors of Neuroprotection in Hypoxia-tolerant Models: Pharmacological Clues for the Treatment of Stroke

Cited by 4 publications

References 25 publications

The microenvironment of naked mole‐rat burrows in East Africa

The microenvironment of naked mole‐rat burrows in East Africa

The zebrafish miR‐462/miR‐731 cluster is induced under hypoxic stress via hypoxia‐inducible factor 1α and functions in cellular adaptations

Overexpression of HIF-1α in Mesenchymal Stem Cells Contributes to Repairing Hypoxic-Ischemic Brain Damage in Rats

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