Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway

Huang, Yi; Kuo, Cheng-Hsiang; Peng, I‐Chen; Chang, Yu-Chieh; Tseng, Sung-Huei; Conway, Edward M.; Wu, Hua‐Lin

doi:10.1007/s00018-021-03950-3

Cited by 14 publications

(8 citation statements)

References 63 publications

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“…Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that regulates the body’s response under hypoxia, and its transcription activity is determined by the HIF-1α (Ikeda et al 2021 ). Under hypoxia, HIF-1α is stably expressed to activate the expression of target genes (Huang et al 2021 ). Studies have confirmed that HIF-1α activated mitophagy by up-regulating its target gene Bcl-2 and adenovirus E1B 19 kDa interacting protein 3 (BNIP3) (Fu et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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Background Hypoxia is one of the important characteristics of synovial microenvironment in rheumatoid arthritis (RA), and plays an important role in synovial hyperplasia. In terms of cell survival, fibroblast-like synovial cells (FLSs) are relatively affected by hypoxia. In contrast, fibroblast-like synovial cells from patients with RA (RA-FLSs) are particularly resistant to hypoxia-induced cell death. The purpose of this study was to evaluate whether fibroblast-like synovial cells in patients with osteoarthritis (OA-FLSs) and RA-FLSs have the same adaptation to hypoxia. Methods CCK-8, flow cytometry and BrdU were used to detect the proliferation of OA-FLSs and RA-FLSs under different oxygen concentrations. Apoptosis was detected by AV/PI, TUNEL and Western blot, mitophagy was observed by electron microscope, laser confocal microscope and Western blot, the state of mitochondria was detected by ROS and mitochondrial membrane potential by flow cytometry, BNIP3 and HIF-1α were detected by Western blot and RT-qPCR. The silencing of BNIP3 was achieved by stealth RNA system technology. Results After hypoxia, the survival rate of OA-FLSs decreased, while the proliferation activity of RA-FLSs further increased. Hypoxia induced an increase in apoptosis and inhibition of mitophagy in OA-FLSs, but not in RA-FLSs. Hypoxia led to a more lasting adaptive response. RA-FLSs displayed a more significant increase in the expression of genes transcriptionally regulated by HIF-1α. Interestingly, they showed higher BNIP3 expression than OA-FLSs, and showed stronger mitophagy and proliferation activities. BNIP3 siRNA experiment confirmed the potential role of BNIP3 in the survival of RA-FLSs. Inhibition of BNIP3 resulted in the decrease of cell proliferation, mitophagy and the increase of apoptosis. Conclusion In summary, RA-FLSs maintained intracellular redox balance through mitophagy to promote cell survival under hypoxia. The mitophagy of OA-FLSs was too little to maintain the redox balance of mitochondria, resulting in apoptosis. The difference of mitophagy between OA-FLSs and RA-FLSs under hypoxia is mediated by the level of BNIP3 expression.

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Section: Introductionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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“… 16 This can be achieved by interfering with the hypoxia sensing mechanisms in retinal cells in an OIR model. Several compounds that can antagonize HIF-1α have also been shown to reduce neovascularization after intraocular injection in an OIR model, 17 – 20 associated with Müller cell-specific HIF-1α deletion. 21 Deletion of HIF-2α, rather than HIF-1α deletion, in retinal astrocytes also reduces neovascularization.…”

mentioning

confidence: 99%

Comparative Analysis Reveals Novel Changes in Plasma Metabolites and Metabolomic Networks of Infants With Retinopathy of Prematurity

Yang

Luo

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Advances in mass spectrometry have provided new insights into the role of metabolomics in the etiology of several diseases. Studies on retinopathy of prematurity (ROP), for example, overlooked the role of metabolic alterations in disease development. We employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways, which were significantly affected in early stages of pathogenesis toward ROP. Methods This was a multicenter, retrospective, matched-pair, case-control study. We collected plasma from 57 ROP cases and 57 strictly matched non-ROP controls. Non-targeted ultra-high-performance liquid chromatography–tandem mass spectroscopy (UPLC-MS/MS) was used to detect the metabolites. Machine learning was employed to reveal the most affected metabolites and pathways in ROP development. Results Compared with non-ROP controls, we found a significant metabolic perturbation in the plasma of ROP cases, which featured an increase in the levels of lipids, nucleotides, and carbohydrate metabolites and lower levels of peptides. Machine leaning enabled us to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism, and arginine pathway) were strongly correlated with the development of ROP. Moreover, the severity of ROP was associated with the levels of creatinine and ribitol; also, overactivity of aerobic glycolysis and lipid metabolism was noted in the metabolic profile of ROP. Conclusions The results suggest a strong correlation between metabolic profiling and retinal neovascularization in ROP pathogenesis. These findings provide an insight into the identification of novel metabolic biomarkers for the diagnosis and prevention of ROP, but the clinical significance requires further validation.

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“…Hypoxia regulates on the basis of hypoxia-inducing factors (HIFs) and their interactions with stemness pathways, transcriptions factors, and other cancerous agents [152,155,156]. Pillar interactions include HIF-1α with TGF-β1 via a SMAD-dependent pathway [157][158][159][160][161] or with Notch-1 [162,163] for hypoxic initiation of EMT, with VEGF [164][165][166] for angiogenic regulation, and with GLUT-1/3 [167,168] and hexokinase (HK)-1/2 [169][170][171][172] for a shift towards glycolytic metabolism [169]. Other common associated markers include LOX [173][174][175], MMP [173][174][175], Twist [176,177], STAT3/IL-6 [178][179][180][181][182][183], MAPK/ERK [184][185][186], Sox-2 [187][188][189][190], Oct-4 [191][192][193], and c-Myc [194]…”

Section: Stem Cell Involvement In Tumor Microenvironment Regulationmentioning

confidence: 99%

Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems

Nayak

Warrier

Kumar

2022

Stem Cell Rev and Rep

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The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates—nanocarriers (NCs) especially—have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Graphical abstract Central role of CSCs in regulation of cellular components within the TME

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Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway

Cited by 14 publications

References 63 publications

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Comparative Analysis Reveals Novel Changes in Plasma Metabolites and Metabolomic Networks of Infants With Retinopathy of Prematurity

Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems

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