Einfluss von Ischämie/Hypoxie auf die HIF-1-Aktivität und Expression von hypoxieabhängigen Genen in der Kochlea der neugeborenen Ratte

Mazurek, Birgit; Rheinländer, Cornelia; Fuchs, Frank-Uwe; Amarjargal, Nyamaa; Kuban, Ralf‐Jürgen; Ungethüm, Ute; Haupt, H.; Kietzmann, Thomas; Gross, Johann

doi:10.1007/s00106-005-1371-6

Cited by 9 publications

(2 citation statements)

References 28 publications

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“…Although oxygen-responsive changes include upregulation of all of these factors (Damert et al 1997; Gerber et al 1997; Hu et al 1998; Caniggia et al 2000; Kietzmann et al 2003; Whitlock et al 2005; Mazurek et al 2006; Stockmann and Fandrey 2006; Peyssonnaux et al 2008), it is clear that HIF-1α is also activated by nonhypoxic conditions (Yee Koh et al 2008), and it seems likely that the regulation of individual target genes may vary based upon the stress leading to elevation of HIF-1. Thus, in glaucoma, HIF-1 activation may not necessarily be a specific indicator of hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma

Ergorul

Huang

et al. 2010

J Mol Neurosci

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Low levels of hypoxia have been suggested to be a mechanism of retinal damage in glaucoma. To test the hypothesis that the activation of the hypoxia-responsive transcription factor hypoxia inducible factor-1α (HIF-1α) is involved in the pathophysiology of glaucoma, we used a rat model of glaucoma to study (1) HIF-1α retinal protein levels by immunoblot analysis, (2) cellular localization of HIF-1α in the retina by immunohistochemistry, and (3) expression of retinal HIF-1 gene targets by quantitative real-time polymerase chain reaction. Glaucoma was unilaterally induced in rats by injecting hypertonic saline in episcleral veins. We find that HIF-1α protein was increased in the retina following elevation of intraocular pressure, specifically in Müller glia and astrocytes but not in activated microglia. Eight established HIF-1 target genes were measured in experimental glaucoma. Retinal Epo, Flt-1, Hsp-27, Pai-1, and Vegfa mRNA levels were increased and Et-1, Igf2, and Tgfβ3 levels were decreased in the glaucomatous retinas. Thus, the increase in HIF-1α levels in Müller glia and astrocytes is accompanied by a marked up regulation of some, but not all, HIF-1 transcriptional targets. These data support the hypothesis that HIF-1α becomes transcriptionally active in astrocytes and Müller cells but not microglia or neurons in glaucoma, arguing against a global hypoxia stimulus to the retina.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma

Ergorul

Huang

et al. 2010

J Mol Neurosci

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“…Hypoxia and ischemia play an important role in the pathogenesis of tinnitus and hearing loss. [ 43 ] B. Mazurek investigated the possible cellular and molecular biological causes of peripheral hearing loss and tinnitus, discussed the role of hypoxia and ischemia in the cochlea and in the etiology of the neurosensory types of tinnitus, and found that HIF-1 may act as a key transcription factor play important roles in cellular adaptation to hypoxia. TNF plays a regulatory role in reducing, maintaining and improving inflammatory responses, and Riva C et al also explored auditory function in cd/1 mice at 4, 12, and 24 weeks of age and correlated it with the presence of oxidative damage in the cochlea and the regulation of cochlear HIF-1 responsive target genes, associated with multiple inflammatory pathways such as TNF-α, or cell death with p53 protein, Bax protein and surviving factors with insulin-like growth factor-1.…”

Section: Discussionmentioning

confidence: 99%

Prediction of network pharmacology and molecular docking-based strategy to determine potential pharmacological mechanism of Liuwei Dihuang pill against tinnitus

Wu¹,

Zhu²,

Cao³

et al. 2022

Medicine

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Background: Liuwei Dihuang Pill is widely used to treat tinnitus in China. However, the underlying mechanism of Liuwei Dihuang Pill in treating tinnitus still remains unclear.Objective: To explore the potential pharmacological mechanism of Liuwei Dihuang Pill in the treatment of tinnitus based on network pharmacology and molecular docking. Methods:The active components of the Liuwei Dihuang Pill were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database. Cytoscape software was used to draw the active componenttarget network diagram of Liuwei Dihuang Pill, and obtain the core components. Then the corresponding targets were also obtained from the TCMSP database. Targets related to tinnitus were obtained from the GeneCards, DisGeNET, TTD and DrugBank databases. The String database was used to construct protein-protein interaction (PPI) network of common targets of drugs and diseases, then the core targets were screened out. The Annotation, Visualization and Integrated Discovery (DAVID) database was used for gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis of common targets. Finally, the molecular docking between the core component and the core target was carried out by AutoDock.Results: The core components of Liuwei Dihuang Pill in the treatment of tinnitus including quercetin, stigmasterol, kaempferol, β-sitosterol, tetrahydroalstonine, which may act on core targets such as STAT3, transcription factor AP-1 (JUN), tumor necrosis factor (TNF), interleukin-6 and MAPK3. HIF-1 signaling pathway, Influenza A, P53 signaling pathway, and Toll-like receptor signaling pathway play a role in anti-inflammatory, improving microcirculation in the blood-labyrinth barrier, increasing cochlear blood flow, and preventing hair cell damage. The molecular docking results showed that the affinity between core components and core targets was good. Conclusion:The potential mechanism of Liuwei Dihuang Pill in the treatment of tinnitus was preliminarily discussed in this study, which may provide a theoretical basis and evidence for further experimental research.Abbreviations: AKT1 = serine/threonine kinase 1, BP = biological processes, CC = closeness centrality, DAVID = the Annotation, Visualization and Integrated Discovery, DL = drug-likeness, GO = gene ontology, HIF = hypoxia-inducible factor, JUN = transcription factor AP-1, KEGG = Kyoto encyclopedia of genes and genomes, MAPK = mitogen-activated protein kinase, OB = oral bioavailability, PPI = protein-protein interaction, STAT = signal transducer and activator of transcription, TCM = traditional Chinese medicines, TCMSP = traditional Chinese medicine systems pharmacology database and analysis platform, Th = helper T cell, TNF = tumor necrosis factor, TP53 = tumor protein P53.

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Pathogenesis and treatment of presbyacusis

Mazurek

Stöver²,

Haupt³

et al. 2008

HNO

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Factors responsible for presbyacusis include physiological ageing processes as well as endogenous or exogenous causes. In the industrial countries, two main exogenous causes are exposure to loud noise and obesity. Pathomechanisms contributing to presbyacusis are hypoxia/ischemia, reactive species formation and oxidative stress, apoptotic and necrotic death of hair cells and spiral ganglion cells as well as inherited and acquired mutations in the mitochondrial DNA. Important for the successful treatment of presbyacusis is a timely fitting of hearing aids on both ears to improve communication and provide the auditory system with acoustic information. Using the hearing aids will also elevate the detection threshold of an existing tinnitus signal. At present, several therapeutic strategies based on pharmacological intervention are under discussion. The application of antioxidants or caloric restriction are considered to prevent or reduce oxidative stress-induced damage. Animal experiments evidenced that superoxide dismutase 2 (SOD2) strongly decreases in age; thus, a further approach may be the overexpression or modulation of the SOD2 within the cochlea. Adenoviral-mediated gene transfer technology would be a tempting approach to address this type of therapy. Finally, hair cell regeneration could be a possible treatment of presbyacusis in the future.

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Einfluss von Ischämie/Hypoxie auf die HIF-1-Aktivität und Expression von hypoxieabhängigen Genen in der Kochlea der neugeborenen Ratte

Abstract: The present data underline the contribution of radical forming processes to the pathogenesis of inner ear diseases. For experimental research, it is important to note that organotypic culture may be coupled with hypoxia.

Cited by 9 publications

References 28 publications

Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma

Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma

Prediction of network pharmacology and molecular docking-based strategy to determine potential pharmacological mechanism of Liuwei Dihuang pill against tinnitus

Pathogenesis and treatment of presbyacusis

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