Hypoxia, acidification and oxidative stress in cells cultured at large distances from an oxygen source

D’Aiuto, Natali; Hochmann, Jimena; Millán, Magdalena; Paolo, Andrés Di; Bologna‐Molina, Ronell; Silveira, José Sotelo; Arocena, Miguel

doi:10.1038/s41598-022-26205-y

Cited by 17 publications

(9 citation statements)

References 29 publications

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“…Hypoxic conditions are also associated with higher intracellular levels of oxidative stress, particularly in the form of increased reactive oxygen species (ROS), produced mainly at the mitochondrial level [ 25 , 26 ]. In addition, SIRT3 holds a pivotal role in the regulation of mitochondrial ROS production by regulating the activity of antioxidant enzymes [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury

Pezzotta,

Perico,

Corna

et al. 2023

PLoS ONE

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Sirtuin 3 (SIRT3), the main deacetylase of mitochondria, modulates the acetylation levels of substrates governing metabolism and oxidative stress. In the kidney, we showed that SIRT3 affects the proper functioning of high energy-demanding cells, such as tubular cells and podocytes. Less is known about the role of SIRT3 in regulating endothelial cell function and its impact on the progression of kidney disease. Here, we found that whole body Sirt3-deficient mice exhibited reduced renal capillary density, reflecting endothelial dysfunction, and VEGFA expression compared to wild-type mice. This was paralleled by activation of hypoxia signaling, upregulation of HIF-1α and Angiopietin-2, and oxidative stress increase. These alterations did not result in kidney disease. However, when Sirt3-deficient mice were exposed to the nephrotoxic stimulus Adriamycin (ADR) they developed aggravated endothelial rarefaction, altered VEGFA signaling, and higher oxidative stress compared to wild-type mice receiving ADR. As a result, ADR-treated Sirt3-deficient mice experienced a more severe injury with exacerbated albuminuria, podocyte loss and fibrotic lesions. These data suggest that SIRT3 is a crucial regulator of renal vascular homeostasis and its dysregulation is a predisposing factor for kidney disease. By extension, our findings indicate SIRT3 as a pharmacologic target in progressive renal disease whose treatments are still imperfect.

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Section: Resultsmentioning

confidence: 99%

Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury

Pezzotta,

Perico,

Corna

et al. 2023

PLoS ONE

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“…The tumor area is the most common hypoxic environment because it possesses the following properties: uncontrollable cell proliferation, altered metabolism, abnormal tumor blood vessels, and overexpression of some reductases (such as nitro‐reductase and azo reductase), resulting in a decrease in the oxygen delivery to the tumor area. In addition, hypoxia can result in acidification and increased oxidative stress, with profound consequences for cell physiology and tumorigenesis, [ 147 ] and hypoxia could also increase ROS production, thus leading to cell death. [ 148 , 149 ] The differences in oxygen levels between normal human organs and abnormal tissues like tumors allow site‐specific NPs to deliver RNAs to these abnormal areas.…”

Section: Internal Stimuli‐responsive Systems For Rna Deliverymentioning

confidence: 99%

Stimuli‐Responsive Nanotechnology for RNA Delivery

Zhou,

Chen,

et al. 2023

Advanced Science

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Ribonucleic acid (RNA) drugs have shown promising therapeutic effects for various diseases in clinical and preclinical studies, owing to their capability to regulate the expression of genes of interest or control protein synthesis. Different strategies, such as chemical modification, ligand conjugation, and nanotechnology, have contributed to the successful clinical translation of RNA medicine, including small interfering RNA (siRNA) for gene silencing and messenger RNA (mRNA) for vaccine development. Among these, nanotechnology can protect RNAs from enzymatic degradation, increase cellular uptake and cytosolic transportation, prolong systemic circulation, and improve tissue/cell targeting. Here, a focused overview of stimuli‐responsive nanotechnologies for RNA delivery, which have shown unique benefits in promoting RNA bioactivity and cell/organ selectivity, is provided. Many tissue/cell‐specific microenvironmental features, such as pH, enzyme, hypoxia, and redox, are utilized in designing internal stimuli‐responsive RNA nanoparticles (NPs). In addition, external stimuli, such as light, magnetic field, and ultrasound, have also been used for controlling RNA release and transportation. This review summarizes a wide range of stimuli‐responsive NP systems for RNA delivery, which may facilitate the development of next‐generation RNA medicines.

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“…In this work, we studied the relationship between hypoxia, oxidative stress, and DNA damage in HaCaT E5/E6/E7 HPV-18 cells, which are human immortalized keratinocytes transduced with the three viral oncogenes (E5, E6 and E7) of Human Papilloma Virus type 18 (HPV-18), previously developed by our group and which constitute a cellular model of an intermediate stage in viral oncogenesis 22 . When cultured in an in vitro model of the hypoxic, tumoral microenvironment, which we have previously characterized 23 , 24 , HaCaT E5/E6/E7-18 cells markedly increase ROS and RNS production, and they simultaneously display increased DNA damage and altered nuclear architecture. Our results show that both hypoxia and oncogenic transformation contribute to increase oxidative stress and DNA damage, cooperating therefore in the path towards malignant transformation in HPV-induced carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Contributions of viral oncogenes of HPV-18 and hypoxia to oxidative stress and genetic damage in human keratinocytes

Hochmann,

Millán,

Hernández

et al. 2023

Sci Rep

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Infection with high-risk human papillomaviruses like HPV-16 and HPV-18 is highly associated with the development of cervical and other cancers. Malignant transformation requires viral oncoproteins E5, E6 and E7, which promote cell proliferation and increase DNA damage. Oxidative stress and hypoxia are also key factors in cervical malignant transformation. Increased levels of reactive species of oxygen (ROS) and nitrogen (RNS) are found in the hypoxic tumor microenvironment, promoting genetic instability and invasiveness. In this work, we studied the combined effect of E5, E6 and E7 and hypoxia in increasing oxidative stress and promoting DNA damage and nuclear architecture alterations. HaCaT cells containing HPV-18 viral oncogenes (HaCaT E5/E6/E7-18) showed higher ROS levels in normoxia and higher levels of RNS in hypoxia compared to HaCaT parental cells, as well as higher genetic damage in hypoxia as measured by γH2AX and comet assays. In hypoxia, HaCaT E5/E6/E7-18 increased its nuclear dry mass and both cell types displayed marked heterogeneity in nuclear dry mass distribution and increased nuclear foci. Our results show contributions of both viral oncogenes and hypoxia to oxidative stress, DNA damage and altered nuclear architecture, exemplifying how an altered microenvironment combines with oncogenic transformation to promote tumor progression.

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Hypoxia, acidification and oxidative stress in cells cultured at large distances from an oxygen source

Cited by 17 publications

References 29 publications

Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury

Sirt3 deficiency promotes endothelial dysfunction and aggravates renal injury

Stimuli‐Responsive Nanotechnology for RNA Delivery

Contributions of viral oncogenes of HPV-18 and hypoxia to oxidative stress and genetic damage in human keratinocytes

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