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    Effect of Hypoxia on the Pathogenesis of Acinetobacter baumannii and Pseudomonas aeruginosa In Vitro and in Murine Experimental Models of Infection. Gil-Marqués María Luisa,Pachón-Ibáñez María Eugenía,Pachón Jerónimo,Smani Younes Infection and immunity Hypoxia modulates bacterial virulence and the inflammation response through hypoxia-inducible factor 1α (HIF-1α). Here we study the influence of hypoxia on and infections. , hypoxia increases the bactericidal activities of epithelial cells against and , reducing extracellular bacterial concentrations to 50.5% ± 7.5% and 90.8% ± 13.9%, respectively, at 2 h postinfection. The same phenomenon occurs in macrophages (67.6% ± 18.2% for at 2 h and 50.3% ± 10.9% for at 24 h). Hypoxia decreases the adherence of to epithelial cells (42.87% ± 8.16% at 2 h) and macrophages (52.0% ± 18.7% at 24 h), as well as that of (24.9% ± 4.5% in epithelial cells and 65.7% ± 5.5% in macrophages at 2 h). Moreover, hypoxia decreases the invasion of epithelial cells (48.6% ± 3.8%) and macrophages (8.7% ± 6.9%) by at 24 h postinfection and by at 2 h postinfection (75.0% ± 16.3% and 63.4% ± 5.4%, respectively). , hypoxia diminishes bacterial loads in fluids and tissues in animal models of infection by both pathogens. In contrast, mouse survival time was shorter under hypoxia (23.92 versus 36.42 h) with infection. No differences in the production of cytokines or HIF-1α were found between hypoxia and normoxia or We conclude that hypoxia increases the bactericidal activities of host cells against both pathogens and reduces the interaction of pathogens with host cells. Moreover, hypoxia accelerates the rate at which animals die despite the lower bacterial concentrations . 10.1128/IAI.00543-18
    Methods to study the tumor microenvironment under controlled oxygen conditions. Byrne Matthew B,Leslie Matthew T,Gaskins H Rex,Kenis Paul J A Trends in biotechnology The tumor microenvironment (TME) is a complex heterogeneous assembly composed of a variety of cell types and physical features. One such feature, hypoxia, is associated with metabolic reprogramming, the epithelial-mesenchymal transition, and therapeutic resistance. Many questions remain regarding the effects of hypoxia on these outcomes; however, only a few experimental methods enable both precise control over oxygen concentration and real-time imaging of cell behavior. Recent efforts with microfluidic platforms offer a promising solution to these limitations. In this review, we discuss conventional methods and tools used to control oxygen concentration for cell studies, and then highlight recent advances in microfluidic-based approaches for controlling oxygen in engineered platforms. 10.1016/j.tibtech.2014.09.006
    Role of mechanical cues and hypoxia on the growth of tumor cells in strong and weak confinement: A dual in vitro-in silico approach. Le Maout V,Alessandri K,Gurchenkov B,Bertin H,Nassoy P,Sciumè G Science advances Characterization of tumor growth dynamics is of major importance for cancer understanding. By contrast with phenomenological approaches, mechanistic modeling can facilitate disclosing underlying tumor mechanisms and lead to identification of physical factors affecting proliferation and invasive behavior. Current mathematical models are often formulated at the tissue or organ scale with the scope of a direct clinical usefulness. Consequently, these approaches remain empirical and do not allow gaining insight into the tumor properties at the scale of small cell aggregates. Here, experimental and numerical studies of the dynamics of tumor aggregates are performed to propose a physics-based mathematical model as a general framework to investigate tumor microenvironment. The quantitative data extracted from the cellular capsule technology microfluidic experiments allow a thorough quantitative comparison with in silico experiments. This dual approach demonstrates the relative impact of oxygen and external mechanical forces during the time course of tumor model progression. 10.1126/sciadv.aaz7130
    Hypoxia-inducible factors and innate immunity in liver cancer. Yuen Vincent Wai-Hin,Wong Carmen Chak-Lui The Journal of clinical investigation The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer. 10.1172/JCI137553
    Quantitative Mapping of Liver Hypoxia in Living Mice Using Time-Resolved Wide-Field Phosphorescence Lifetime Imaging. Liu Yawei,Gu Yuyang,Yuan Wei,Zhou Xiaobo,Qiu Xiaochen,Kong Mengya,Wang Qingbing,Feng Wei,Li Fuyou Advanced science (Weinheim, Baden-Wurttemberg, Germany) Hypoxia has been identified to contribute the pathogenesis of a wide range of liver diseases, and therefore, quantitative mapping of liver hypoxia is important for providing critical information in the diagnosis and treatment of hepatic diseases. However, the existing imaging methods are unsuitable to quantitatively assess liver hypoxia due to the need of liver-specific contrast agents and be easily affected by other imaging factors. Here, a time-resolved lifetime-based imaging method is established for quantitative mapping of the distribution of hypoxia in the livers of mice by combining a wide-field luminescence lifetime imaging system with an oxygen-sensitive nanoprobe. It is shown that the method is suitable for real-time quantification of the change of oxygen pressure in the process of hepatic ischemia-reperfusion of the mouse. Moreover, the developed lifetime imaging methodology is used to quantitatively map liver hypoxia regions in the mouse model of orthotopic liver tumor, where the average oxygen pressure in tumorous liver is far below the normal liver. 10.1002/advs.201902929
    A bioreducible N-oxide-based probe for photoacoustic imaging of hypoxia. Knox Hailey J,Hedhli Jamila,Kim Tae Wook,Khalili Kian,Dobrucki Lawrence W,Chan Jefferson Nature communications Hypoxia occurs when limited oxygen supply impairs physiological functions and is a pathological hallmark of many diseases including cancer and ischemia. Thus, detection of hypoxia can guide treatment planning and serve as a predictor of patient prognosis. Unfortunately, current methods suffer from invasiveness, poor resolution and low specificity. To address these limitations, we present Hypoxia Probe 1 (HyP-1), a hypoxia-responsive agent for photoacoustic imaging. This emerging modality converts safe, non-ionizing light to ultrasound waves, enabling acquisition of high-resolution 3D images in deep tissue. HyP-1 features an N-oxide trigger that is reduced in the absence of oxygen by heme proteins such as CYP450 enzymes. Reduction of HyP-1 produces a spectrally distinct product, facilitating identification via photoacoustic imaging. HyP-1 exhibits selectivity for hypoxic activation in vitro, in living cells, and in multiple disease models in vivo. HyP-1 is also compatible with NIR fluorescence imaging, establishing its versatility as a multimodal imaging agent. 10.1038/s41467-017-01951-0
    Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Scharping Nicole E,Rivadeneira Dayana B,Menk Ashley V,Vignali Paolo D A,Ford B Rhodes,Rittenhouse Natalie L,Peralta Ronal,Wang Yiyang,Wang Yupeng,DePeaux Kristin,Poholek Amanda C,Delgoffe Greg M Nature immunology Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8 T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. 10.1038/s41590-020-00834-9
    Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. Nath Bharath,Szabo Gyongyi Hepatology (Baltimore, Md.) Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models. 10.1002/hep.25497
    Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Wu Hui-Mei,Jiang Zi-Feng,Ding Pei-Shan,Shao Li-Jie,Liu Rong-Yu Scientific reports Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α-dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. 10.1038/srep12291
    The hypoxic tumor microenvironment: driving the tumorigenesis of non-small-cell lung cancer. Foster John G,Wong Sybil C K,Sharp Tyson V Future oncology (London, England) Since the application of molecular biology in cancer biology, lung cancer research has classically focused on molecular drivers of disease. One such pathway, the hypoxic response pathway, is activated by reduced local oxygen concentrations at the tumor site. Hypoxia-driven gene and protein changes enhance epithelial-to-mesenchymal transition, remodel the extracellular matrix, drive drug resistance, support cancer stem cells and aid evasion from immune cells. However, it is not the tumor cells alone which drive this response to hypoxia, but rather their interaction with a complex milieu of supporting cells. This review will focus on recent advances in our understanding of how these cells contribute to the tumor response to hypoxia in non-small-cell lung cancer. 10.2217/fon.14.201
    Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy of cancer. Xavierselvan Marvin,Cook Jason,Duong Jeanne,Diaz Nashielli,Homan Kimberly,Mallidi Srivalleesha Photoacoustics Photodynamic therapy (PDT) is a well-known cancer therapy that utilizes light to excite a photosensitizer and generate cytotoxic reactive oxygen species (ROS). The efficacy of PDT primarily depends on the photosensitizer and oxygen concentration in the tumor. Hypoxia in solid tumors promotes treatment resistance, resulting in poor PDT outcomes. Hence, there is a need to combat hypoxia while delivering sufficient photosensitizer to the tumor for ROS generation. Here we showcase our unique theranostic perfluorocarbon nanodroplets as a triple agent carrier for oxygen, photosensitizer, and indocyanine green that enables light triggered spatiotemporal delivery of oxygen to the tumors. We evaluated the characteristics of the nanodroplets and validated their ability to deliver oxygen via photoacoustic monitoring of blood oxygen saturation and subsequent PDT efficacy in a murine subcutaneous tumor model. The imaging results were validated with an oxygen sensing probe, which showed a 9.1 fold increase in oxygen content inside the tumor, following systemic administration of the nanodroplets. These results were also confirmed with immunofluorescence. studies showed that nanodroplets held higher rates of treatment efficacy than a clinically available benzoporphyrin derivative formulation. Histological analysis showed higher necrotic area within the tumor with perfluoropentane nanodroplets. Overall, the photoacoustic nanodroplets can significantly enhance image-guided PDT and has demonstrated substantial potential as a valid theranostic option for patient-specific photodynamic therapy-based treatments. 10.1016/j.pacs.2021.100306
    Photoluminescent oxygen-release microspheres to image the oxygen release process in vivo. Guan Ya,Niu Hong,Dang Yu,Gao Ning,Guan Jianjun Acta biomaterialia Cell therapy is a promising strategy to treat ischemic diseases, but the efficacy is limited due to high rate of cell death under low oxygen environment of the ischemic tissues. Sustained release of oxygen to continuously oxygenate the transplanted cells may augment cell survival and improve therapeutic efficacy. We have shown previously that oxygen released from oxygen-release microspheres stimulated cell survival in ischemic tissue [1]. To understand how oxygen is released in vivo and duration of release, it is attractive to image the process of oxygen release. Herein, we have developed photoluminenscent oxygen-release microspheres where the in vivo oxygen release can be non-invasively and real-time monitored by an In Vivo Imaging System (IVIS). In the oxygen-release microspheres, a complex of polyvinylpyrrolidone, HO and a fluorescent drug hypericin (HYP) was used as core, and poly(N-isopropylacrylamide-co-acrylate-oligolactide-co-hydroxyethyl methacrylate-co-N-acryloxysuccinimide) conjugated with catalase was used as shell. To distinguish fluorescent signal change for different oxygen release kinetics, the microspheres with various release profiles were developed by using the shell with different degradation rates. In vitro, the fluorescent intensity gradually decreased during the 21-day oxygen release period, consistent with oxygen release kinetics. The released oxygen significantly augmented mesenchymal stem cell (MSC) survival under hypoxic condition. In vivo, the oxygen release rate was faster. The fluorescent signal can be detected for 17 days for the microspheres with the slowest oxygen release kinetics. The implanted microspheres did not induce substantial inflammation. The above results demonstrate that the developed microspheres have potential to monitor the in vivo oxygen release. 10.1016/j.actbio.2020.08.031
    Oxygen-release microspheres capable of releasing oxygen in response to environmental oxygen level to improve stem cell survival and tissue regeneration in ischemic hindlimbs. Guan Ya,Gao Ning,Niu Hong,Dang Yu,Guan Jianjun Journal of controlled release : official journal of the Controlled Release Society Stem cell transplantation has been extensively explored to promote ischemic limb vascularization and skeletal muscle regeneration. Yet the therapeutic efficacy is low due to limited cell survival under low oxygen environment of the ischemic limbs. Therefore, continuously oxygenating the transplanted cells has potential to increase their survival. During tissue regeneration, the number of blood vessels are gradually increased, leading to the elevation of tissue oxygen content. Accordingly, less exogenous oxygen is needed for the transplanted cells. Excessive oxygen may induce reactive oxygen species (ROS) formation, causing cell apoptosis. Thus, it is attractive to develop oxygen-release biomaterials that are responsive to the environmental oxygen level. Herein, we developed oxygen-release microspheres whose oxygen release was controlled by oxygen-responsive shell. The shell hydrophilicity and degradation rate decreased as the environmental oxygen level increased, leading to slower oxygen release. The microspheres were capable of directly releasing molecular oxygen, which are safer than those oxygen-release biomaterials that release hydrogen peroxide and rely on its decomposition to form oxygen. The released oxygen significantly enhanced mesenchymal stem cell (MSC) survival without inducing ROS production under hypoxic condition. Co-delivery of MSCs and microspheres to the mouse ischemic limbs ameliorated MSC survival, proliferation and paracrine effects under ischemic conditions. It also significantly accelerated angiogenesis, blood flow restoration, and skeletal muscle regeneration without provoking tissue inflammation. The above results demonstrate that the developed microspheres have potential to augment cell survival in ischemic tissues, and promote ischemic tissue regeneration in a safer and more efficient manner. 10.1016/j.jconrel.2021.01.034
    Targeting Reactive Oxygen Species in Atherosclerosis via Chinese Herbal Medicines. Zhang Leyi,Huang Jiaqin,Zhang Danli,Lei Xiaojing,Ma Yan,Cao Yun,Chang Jingling Oxidative medicine and cellular longevity Cardio-cerebrovascular disease (CCVD) has become the leading cause of human mortality with the coming acceleration of global population aging. Atherosclerosis is among the most common pathological changes in CCVDs. It is also a multifactorial disorder; oxidative stress caused by excessive production of reactive oxygen species (ROS) has become an important mechanism of atherosclerosis. Chinese herbal medicine (CHM) is a major type of natural medicine that has made great contributions to human health. CHMs are increasingly used in the auxiliary clinical treatment of atherosclerosis. Although their mechanism of action is unclear, CHMs can exert a variety of antiatherosclerosis effects by regulating intracellular ROS. In this review, we discussed the mechanism of ROS regulation in atherosclerosis and analyzed the role of CHMs in the treatment of atherosclerosis via ROS. 10.1155/2022/1852330
    Targeting Reactive Oxygen Species in Cancer via Chinese Herbal Medicine. Qian Qiaohong,Chen Wanqing,Cao Yajuan,Cao Qi,Cui Yajing,Li Yan,Wu Jianchun Oxidative medicine and cellular longevity Recently, reactive oxygen species (ROS), a class of highly bioactive molecules, have been extensively studied in cancers. Cancer cells typically exhibit higher levels of basal ROS than normal cells, primarily due to their increased metabolism, oncogene activation, and mitochondrial dysfunction. This moderate increase in ROS levels facilitates cancer initiation, development, and progression; however, excessive ROS concentrations can lead to various types of cell death. Therefore, therapeutic strategies that either increase intracellular ROS to toxic levels or, conversely, decrease the levels of ROS may be effective in treating cancers via ROS regulation. Chinese herbal medicine (CHM) is a major type of natural medicine and has greatly contributed to human health. CHMs have been increasingly used for adjuvant clinical treatment of tumors. Although their mechanism of action is unclear, CHMs can execute a variety of anticancer effects by regulating intracellular ROS. In this review, we summarize the dual roles of ROS in cancers, present a comprehensive analysis of and update the role of CHM-especially its active compounds and ingredients-in the prevention and treatment of cancers via ROS regulation and emphasize precautions and strategies for the use of CHM in future research and clinical trials. 10.1155/2019/9240426
    Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Wang Hai,Gao Zan,Liu Xuanyou,Agarwal Pranay,Zhao Shuting,Conroy Daniel W,Ji Guang,Yu Jianhua,Jaroniec Christopher P,Liu Zhenguo,Lu Xiongbin,Li Xiaodong,He Xiaoming Nature communications Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps. Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy. Our in vivo data show that the drug-laden LSC nanoparticles in combination with NIR laser treatment can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity. 10.1038/s41467-018-02915-8