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    Surface tethering of stem cells with HO-responsive anti-oxidizing colloidal particles for protection against oxidation-induced death. Teo Jye Yng,Seo Yongbeom,Ko Eunkyung,Leong Jiayu,Hong Yu-Tong,Yang Yi Yan,Kong Hyunjoon Biomaterials Mesenchymal stem cells are the new generation of medicine for treating numerous vascular diseases and tissue defects because of their ability to secrete therapeutic factors. Poor cellular survival in an oxidative diseased tissue, however, hinders the therapeutic efficacy. To this end, we hypothesized that tethering the surface of stem cells with colloidal particles capable of discharging antioxidant cargos in response to elevated levels of hydrogen peroxide (HO) would maintain survival and therapeutic activity of the stem cells. We examined this hypothesis by encapsulating epigallocatechin gallate (EGCG) and manganese oxide (MnO) nanocatalysts into particles comprising poly(d,l-lactide-co-glycolide)-block-hyaluronic acid. The MnO nanocatalysts catalyzed the decomposition of HO into oxygen gas, which increased the internal pressure of particles and accelerated the release of EGCG by 1.5-fold. Consequently, stem cells exhibited 1.2-fold higher metabolic activity and 2.8-fold higher secretion level of pro-angiogenic factor in sub-lethal HO concentrations. These stem cells, in turn, performed a greater angiogenic potential with doubled number of newly formed mature blood vessels. We envisage that the results of this study will contribute to improving the therapeutic efficacy of a wide array of stem cells. 10.1016/j.biomaterials.2019.01.039
    Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Sands Scott A,Edwards Bradley A,Terrill Philip I,Butler James P,Owens Robert L,Taranto-Montemurro Luigi,Azarbarzin Ali,Marques Melania,Hess Lauren B,Smales Erik T,de Melo Camila M,White David P,Malhotra Atul,Wellman Andrew The European respiratory journal A possible precision-medicine approach to treating obstructive sleep apnoea (OSA) involves targeting ventilatory instability (elevated loop gain) using supplemental inspired oxygen in selected patients. Here we test whether elevated loop gain and three key endophenotypic traits (collapsibility, compensation and arousability), quantified using clinical polysomnography, can predict the effect of supplemental oxygen on OSA severity.36 patients (apnoea-hypopnoea index (AHI) >20 events·h) completed two overnight polysomnographic studies (single-blinded randomised-controlled crossover) on supplemental oxygen (40% inspired) sham (air). OSA traits were quantified from the air-night polysomnography. Responders were defined by a ≥50% reduction in AHI (supine non-rapid eye movement). Secondary outcomes included blood pressure and self-reported sleep quality.Nine of 36 patients (25%) responded to supplemental oxygen (ΔAHI=72±5%). Elevated loop gain was not a significant univariate predictor of responder/non-responder status (primary analysis). In analysis, a logistic regression model based on elevated loop gain and other traits (better collapsibility and compensation; cross-validated) had 83% accuracy (89% before cross-validation); predicted responders exhibited an improvement in OSA severity (ΔAHI 59±6% 12±7% in predicted non-responders, p=0.0001) plus lowered morning blood pressure and "better" self-reported sleep.Patients whose OSA responds to supplemental oxygen can be identified by measuring their endophenotypic traits using diagnostic polysomnography. 10.1183/13993003.00674-2018
    Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Sies Helmut,Jones Dean P Nature reviews. Molecular cell biology 'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (HO) and the superoxide anion radical (O), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, HO is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation). 10.1038/s41580-020-0230-3
    CNS function and dysfunction during exposure to hyperbaric oxygen in operational and clinical settings. Ciarlone Geoffrey E,Hinojo Christopher M,Stavitzski Nicole M,Dean Jay B Redox biology Hyperbaric oxygen (HBO) is breathed during hyperbaric oxygen therapy and during certain undersea pursuits in diving and submarine operations. What limits exposure to HBO in these situations is the acute onset of central nervous system oxygen toxicity (CNS-OT) following a latent period of safe oxygen breathing. CNS-OT presents as various non-convulsive signs and symptoms, many of which appear to be of brainstem origin involving cranial nerve nuclei and autonomic and cardiorespiratory centers, which ultimately spread to higher cortical centers and terminate as generalized tonic-clonic seizures. The initial safe latent period makes the use of HBO practical in hyperbaric and undersea medicine; however, the latent period is highly variable between individuals and within the same individual on different days, making it difficult to predict onset of toxic indications. Consequently, currently accepted guidelines for safe HBO exposure are highly conservative. This review examines the disorder of CNS-OT and summarizes current ideas on its underlying pathophysiology, including specific areas of the CNS and fundamental neural and redox signaling mechanisms that are thought to be involved in seizure genesis and propagation. In addition, conditions that accelerate the onset of seizures are discussed, as are current mitigation strategies under investigation for neuroprotection against redox stress while breathing HBO that extend the latent period, thus enabling safer and longer exposures for diving and medical therapies. 10.1016/j.redox.2019.101159
    The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline. Rochwerg Bram,Einav Sharon,Chaudhuri Dipayan,Mancebo Jordi,Mauri Tommaso,Helviz Yigal,Goligher Ewan C,Jaber Samir,Ricard Jean-Damien,Rittayamai Nuttapol,Roca Oriol,Antonelli Massimo,Maggiore Salvatore Maurizio,Demoule Alexandre,Hodgson Carol L,Mercat Alain,Wilcox M Elizabeth,Granton David,Wang Dominic,Azoulay Elie,Ouanes-Besbes Lamia,Cinnella Gilda,Rauseo Michela,Carvalho Carlos,Dessap-Mekontso Armand,Fraser John,Frat Jean-Pierre,Gomersall Charles,Grasselli Giacomo,Hernandez Gonzalo,Jog Sameer,Pesenti Antonio,Riviello Elisabeth D,Slutsky Arthur S,Stapleton Renee D,Talmor Daniel,Thille Arnaud W,Brochard Laurent,Burns Karen E A Intensive care medicine PURPOSE:High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings. METHODS:We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions. RESULTS:The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty). CONCLUSIONS:This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians. 10.1007/s00134-020-06312-y
    High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension. Di Caprio Giuseppe,Schonbrun Ethan,Gonçalves Bronner P,Valdez Jose M,Wood David K,Higgins John M Proceedings of the National Academy of Sciences of the United States of America Sickle cell disease (SCD) is caused by a variant hemoglobin molecule that polymerizes inside red blood cells (RBCs) in reduced oxygen tension. Treatment development has been slow for this typically severe disease, but there is current optimism for curative gene transfer strategies to induce expression of fetal hemoglobin or other nonsickling hemoglobin isoforms. All SCD morbidity and mortality arise directly or indirectly from polymer formation in individual RBCs. Identifying patients at highest risk of complications and treatment candidates with the greatest curative potential therefore requires determining the amount of polymer in individual RBCs under controlled oxygen. Here, we report a semiquantitative measurement of hemoglobin polymer in single RBCs as a function of oxygen. The method takes advantage of the reduced oxygen affinity of hemoglobin polymer to infer polymer content for thousands of RBCs from their overall oxygen saturation. The method enables approaches for SCD treatment development and precision medicine. 10.1073/pnas.1914056116
    Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling. DeFrates Kelsey G,Franco Daniela,Heber-Katz Ellen,Messersmith Phillip B Biomaterials Historically, the field of regenerative medicine has aimed to heal damaged tissue through the use of biomaterials scaffolds or delivery of foreign progenitor cells. Despite 30 years of research, however, translation and commercialization of these techniques has been limited. To enable mammalian regeneration, a more practical approach may instead be to develop therapies that evoke endogenous processes reminiscent of those seen in innate regenerators. Recently, investigations into tadpole tail regrowth, zebrafish limb restoration, and the super-healing Murphy Roths Large (MRL) mouse strain, have identified ancient oxygen-sensing pathways as a possible target to achieve this goal. Specifically, upregulation of the transcription factor, hypoxia-inducible factor one alpha (HIF-1α) has been shown to modulate cell metabolism and plasticity, as well as inflammation and tissue remodeling, possibly priming injuries for regeneration. Since HIF-1α signaling is conserved across species, environmental or pharmacological manipulation of oxygen-dependent pathways may elicit a regenerative response in non-healing mammals. In this review, we will explore the emerging role of HIF-1α in mammalian healing and regeneration, as well as attempts to modulate protein stability through hyperbaric oxygen treatment, intermittent hypoxia therapy, and pharmacological targeting. We believe that these therapies could breathe new life into the field of regenerative medicine. 10.1016/j.biomaterials.2020.120646
    Oxygen Toxicity in Critically Ill Adults. American journal of respiratory and critical care medicine Oxygen supplementation is one of the most common interventions in critically ill patients. Despite over a century of data suggesting both beneficial and detrimental effects of supplemental oxygen, optimal arterial oxygenation targets in adult patients remain unclear. Laboratory animal studies have consistently showed that exposure to a high Fi causes respiratory failure and early death. Human autopsy studies from the 1960s purported to provide histologic evidence of pulmonary oxygen toxicity in the form of diffuse alveolar damage. However, concomitant ventilator-induced lung injury and/or other causes of acute lung injury may explain these findings. Although some observational studies in general populations of critically adults showed higher mortality in association with higher oxygen exposures, this finding has not been consistent. For some specific populations, such as those with cardiac arrest, studies have suggested harm from targeting supraphysiologic Pa levels. More recently, randomized clinical trials of arterial oxygenation targets in narrower physiologic ranges were conducted in critically ill adult patients. Although two smaller trials came to opposite conclusions, the two largest of these trials showed no differences in clinical outcomes in study groups that received conservative versus liberal oxygen targets, suggesting that either strategy is reasonable. It is possible that some strategies are of benefit in some subpopulations, and this remains an important ongoing area of research. Because of the ubiquity of oxygen supplementation in critically ill adults, even small treatment effects could have a large impact on a global scale. 10.1164/rccm.202102-0417CI
    A Metal-Phenolic Nanosensitizer Performs Hydrogen Sulfide-Reprogrammed Oxygen Metabolism for Cancer Radiotherapy Intensification and Immunogenicity. Angewandte Chemie (International ed. in English) Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics. 10.1002/anie.202200830
    Tumor cell-activated "Sustainable ROS Generator" with homogeneous intratumoral distribution property for improved anti-tumor therapy. Liu Junjie,Zhao Xiu,Nie Weimin,Yang Yue,Wu Chengcheng,Liu Wei,Zhang Kaixiang,Zhang Zhenzhong,Shi Jinjin Theranostics Photodynamic therapy (PDT) holds a number of advantages for tumor therapy. However, its therapeutic efficiency is limited by non-sustainable reactive oxygen species (ROS) generation and heterogeneous distribution of photosensitizer (PS) in tumor. Herein, a "ustainable OS enerator" (SRG) is developed for efficient antitumor therapy. SRG was prepared by encapsulating small-sized MnO-Ce6 nanoparticles (MC) into dendritic mesoporous silica nanoparticles (DMSNs) and then enveloped with hyaluronic acid (HA). Due to the high concentration of HAase in tumor tissue, the small-sized MC could be released from DMSNs and homogeneously distributed in whole tumor. Then, the released MC would be uptaken by tumor cells and degraded by high levels of intracellular glutathione (GSH), disrupting intracellular redox homeostasis. More importantly, the released Ce6 could efficiently generate singlet oxygen (O) under laser irradiation until the tissue oxygen was exhausted, and the manganese ion (Mn) generated by degraded MC would then convert the low toxic by-product (HO) of PDT to the most harmful ROS (·OH) for sustainable and recyclable ROS generation. MC could be homogeneously distributed in whole tumor and significantly reduced the level of intracellular GSH. At 2 h after PDT, obvious intracellular ROS production was still observed. Moreover, during oxygen recovery in tumor tissue, ·OH could be continuously produced, and the nanosystem could induce 82% of cell death comparing with 30% of cell death induced by free Ce6. For PDT, SRG achieved a complete inhibition on tumor growth. Based on these findings, we conclude that the designed SRG could induce sustainable ROS generation, homogeneous intratumoral distribution and intracellular redox homeostasis disruption, presenting an efficient strategy for enhanced ROS-mediated anti-tumor therapy. 10.7150/thno.50028
    Tumor reoxygenation for enhanced combination of radiation therapy and microwave thermal therapy using oxygen generation in situ by CuO nanosuperparticles under microwave irradiation. Chen Zengzhen,Guo Wenna,Wu Qiong,Tan Longfei,Ma Tengchuang,Fu Changhui,Yu Jie,Ren Xiangling,Wang Jianming,Liang Ping,Meng Xianwei Theranostics As known, radiation therapy (RT) can exacerbate the degree of hypoxia of tumor cells, which induces serious resistance to RT and in turn, is the greatest obstacle to RT. Reoxygenation can restore the hypoxic state of tumor cells, which plays an important role in reshaping tumor microenviroment for achieving optimal therapeutic efficacy. Herein, we report for the first time that microwave (MW)-triggered IL-Quercetin-CuO-SiO@ZrO-PEG nanosuperparticles (IQuCS@Zr-PEG NSPs) have been used to achieve an optimal RT therapeutic outcomes by the strategy of upregulating tumor reoxygenation, hypoxic cells acquire oxygen and return to normal state. : We prepared a promising multifunctional nanosuperparticle to upregulate tumor reoxygenation by utilizing CuO nanoparticle to generate oxygen under MW irradiation in the tumor microenvironment. The IQuCS@Zr-PEG NSPs were obtained by introducing CuO nanoparticles, MW sensitizer of 1-butyl-3-methylimidazolium hexafluorophosphate (IL), radiosensitizer of Quercetin (Qu) and surface modifier of monomethoxy polyethylene glycol sulfhyl (mPEG-SH, 5k Da) into mesoporous sandwich SiO@ZrO nanosuperparticles (SiO@ZrO NSPs). The release oxygen by IQuCS@Zr-PEG NSPs under MW irradiation was investigated by a microcomputer dissolved oxygen-biochemical oxygen demand detector (DO-BOD) test. Finally, we used the Tc-HL91 labeled reoxygenation imaging, Cellular immunofluorescence, immunohistochemistry, and TUNEL experiments to verify that this unique MW-responsive reoxygenation enhancer can be used to stimulate reshaping of the tumor microenvironment. : Through experiments we found that the IQuCS@Zr-PEG NSPs can persistently release oxygen under the MW irradiation, which upregulates tumor reoxygenation and improve the combined tumor treatment effect of RT and microwave thermal therapy (MWTT). Cellular immunofluorescence and immunohistochemistry experiments demonstrated that the IQuCS@Zr-PEG NSPs can downregulate the expression of hypoxia-inducible factor 1α (HIF-1α) under MW irradiation. The Tc-HL91 labeled reoxygenation imaging experiment also showed that the oxygen generated by IQuCS@Zr-PEG NSPs under MW irradiation can significantly increase the reoxygenation capacity of tumor cells, thus reshaping the tumor microenvironment. The high inhibition rate of 98.62% was achieved in the antitumor experiments . In addition, the IQuCS@Zr-PEG NSPs also had good computed tomography (CT) imaging effects, which can be used to monitor the treatment of tumors in real-time. : The proof-of-concept strategy of upregulating tumor reoxygenation is achieved by MW triggered IQuCS@Zr-PEG NSPs, which has exhibited optimal therapeutic outcomes of combination of RT and MWTT tumor. Such unique MW-responsive reoxygenation enhancer may stimulate the research of reshaping tumor microenvironment for enhancing versatile tumor treatment. 10.7150/thno.42818
    Enhanced Ferroptosis by Oxygen-Boosted Phototherapy Based on a 2-in-1 Nanoplatform of Ferrous Hemoglobin for Tumor Synergistic Therapy. Xu Tian,Ma Yuying,Yuan Qinling,Hu Huixin,Hu Xinkai,Qian Zhiyu,Rolle Janiqua Kyiesha,Gu Yueqing,Li Siwen ACS nano Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 and was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform. 10.1021/acsnano.9b09426
    Simultaneous spatiotemporal tracking and oxygen sensing of transient implants in vivo using hot-spot MRI and machine learning. Spanoudaki Virginia,Doloff Joshua C,Huang Wei,Norcross Samuel R,Farah Shady,Langer Robert,Anderson Daniel G Proceedings of the National Academy of Sciences of the United States of America A varying oxygen environment is known to affect cellular function in disease as well as activity of various therapeutics. For transient structures, whether they are unconstrained therapeutic transplants, migrating cells during tumor metastasis, or cell populations induced by an immunological response, the role of oxygen in their fate and function is known to be pivotal albeit not well understood in vivo. To address such a challenge in the case of generation of a bioartificial pancreas, we have combined fluorine magnetic resonance imaging and unsupervised machine learning to monitor over time the spatial arrangement and the oxygen content of implants encapsulating pancreatic islets that are unconstrained in the intraperitoneal (IP) space of healthy and diabetic mice. Statistically significant trends in the postimplantation temporal dependence of oxygen content between aggregates of 0.5-mm or 1.5-mm alginate microcapsules were identified in vivo by looking at their dispersity as well as arrangement in clusters of different size and estimating oxygen content on a pixel-by-pixel basis from thousands of 2D images. Ultimately, we found that this dependence is stronger for decreased implant capsule size consistent with their tendency to also induce a larger immunological response. Beyond the bioartificial pancreas, this work provides a framework for the simultaneous spatiotemporal tracking and oxygen sensing of other cell populations and biomaterials that change over time to better understand and improve therapeutic design across diverse applications such as cellular transplant therapy, treatments preventing metastatic formation, and modulators for improving immunologic response, for all of which oxygen is a major mechanistic component. 10.1073/pnas.1815909116
    Mn-rich oxide/persistent luminescence nanoparticles achieve light-free generation of singlet oxygen and hydroxyl radicals for responsive imaging and tumor treatment. Ding Dandan,Feng Yushuo,Qin Ruixue,Li Shi,Chen Lei,Jing Jinpeng,Zhang Chutong,Sun Wenjing,Li Yimin,Chen Xiaoyuan,Chen Hongmin Theranostics X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Herein, we report Mn-rich manganese oxide (MnO)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnO shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes . Furthermore, the biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. In the tumor region, the MnO shell is quickly decomposed to produce Mn and oxygen (O) to directly generate singlet oxygen (O). The resulting Mn transforms endogenous HO into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn ions and ZGGOs also exhibit excellent T-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Both the responsive dual-mode imaging and simultaneous self-supplied O for the production of O and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy. 10.7150/thno.62437
    MTH1 inhibitor amplifies the lethality of reactive oxygen species to tumor in photodynamic therapy. Zhao Lingzhi,Li Junyao,Su Yaoquan,Yang Liqiang,Chen Liu,Qiang Lei,Wang Yajing,Xiang Huijing,Tham Huijun Phoebe,Peng Juanjuan,Zhao Yanli Science advances Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS. 10.1126/sciadv.aaz0575
    Reactive oxygen species produced by altered tumor metabolism impacts cancer stem cell maintenance. Tuy Kaysaw,Rickenbacker Lucas,Hjelmeland Anita B Redox biology Controlling reactive oxygen species (ROS) at sustainable levels can drive multiple facets of tumor biology, including within the cancer stem cell (CSC) population. Tight regulation of ROS is one key component in CSCs that drives disease recurrence, cell signaling, and therapeutic resistance. While ROS are well-appreciated to need oxygen and are a product of oxidative phosphorylation, there are also important roles for ROS under hypoxia. As hypoxia promotes and sustains major stemness pathways, further consideration of ROS impacts on CSCs in the tumor microenvironment is important. Furthermore, glycolytic shifts that occur in cancer and may be promoted by hypoxia are associated with multiple mechanisms to mitigate oxidative stress. This altered metabolism provides survival advantages that sustain malignant features, such as proliferation and self-renewal, while producing the necessary antioxidants that reduce damage from oxidative stress. Finally, disease recurrence is believed to be attributed to therapy resistant CSCs which can be quiescent and have changes in redox status. Effective DNA damage response pathways and/or a slow-cycling state can protect CSCs from the genomic catastrophe induced by irradiation and genotoxic agents. This review will explore the delicate, yet complex, relationship between ROS and its pleiotropic role in modulating the CSC. 10.1016/j.redox.2021.101953
    A White-Box Machine Learning Approach for Revealing Antibiotic Mechanisms of Action. Yang Jason H,Wright Sarah N,Hamblin Meagan,McCloskey Douglas,Alcantar Miguel A,Schrübbers Lars,Lopatkin Allison J,Satish Sangeeta,Nili Amir,Palsson Bernhard O,Walker Graham C,Collins James J Cell Current machine learning techniques enable robust association of biological signals with measured phenotypes, but these approaches are incapable of identifying causal relationships. Here, we develop an integrated "white-box" biochemical screening, network modeling, and machine learning approach for revealing causal mechanisms and apply this approach to understanding antibiotic efficacy. We counter-screen diverse metabolites against bactericidal antibiotics in Escherichia coli and simulate their corresponding metabolic states using a genome-scale metabolic network model. Regression of the measured screening data on model simulations reveals that purine biosynthesis participates in antibiotic lethality, which we validate experimentally. We show that antibiotic-induced adenine limitation increases ATP demand, which elevates central carbon metabolism activity and oxygen consumption, enhancing the killing effects of antibiotics. This work demonstrates how prospective network modeling can couple with machine learning to identify complex causal mechanisms underlying drug efficacy. 10.1016/j.cell.2019.04.016
    Commensal Enterobacteriaceae Protect against Salmonella Colonization through Oxygen Competition. Litvak Yael,Mon Khin K Z,Nguyen Henry,Chanthavixay Ganrea,Liou Megan,Velazquez Eric M,Kutter Laura,Alcantara Monique A,Byndloss Mariana X,Tiffany Connor R,Walker Gregory T,Faber Franziska,Zhu Yuhua,Bronner Denise N,Byndloss Austin J,Tsolis Renée M,Zhou Huaijun,Bäumler Andreas J Cell host & microbe Neonates are highly susceptible to infection with enteric pathogens, but the underlying mechanisms are not resolved. We show that neonatal chick colonization with Salmonella enterica serovar Enteritidis requires a virulence-factor-dependent increase in epithelial oxygenation, which drives pathogen expansion by aerobic respiration. Co-infection experiments with an Escherichia coli strain carrying an oxygen-sensitive reporter suggest that S. Enteritidis competes with commensal Enterobacteriaceae for oxygen. A combination of Enterobacteriaceae and spore-forming bacteria, but not colonization with either community alone, confers colonization resistance against S. Enteritidis in neonatal chicks, phenocopying germ-free mice associated with adult chicken microbiota. Combining spore-forming bacteria with a probiotic E. coli isolate protects germ-free mice from pathogen colonization, but the protection is lost when the ability to respire oxygen under micro-aerophilic conditions is genetically ablated in E. coli. These results suggest that commensal Enterobacteriaceae contribute to colonization resistance by competing with S. Enteritidis for oxygen, a resource critical for pathogen expansion. 10.1016/j.chom.2018.12.003
    Microbiome: The microbiota maintains oxygen balance in the gut. Vacca Irene Nature reviews. Microbiology 10.1038/nrmicro.2017.112
    Radical-mediated C-S bond cleavage in C2 sulfonate degradation by anaerobic bacteria. Xing Meining,Wei Yifeng,Zhou Yan,Zhang Jun,Lin Lianyun,Hu Yiling,Hua Gaoqun,N Nanjaraj Urs Ankanahalli,Liu Dazhi,Wang Feifei,Guo Cuixia,Tong Yang,Li Mengya,Liu Yanhong,Ang Ee Lui,Zhao Huimin,Yuchi Zhiguang,Zhang Yan Nature communications Bacterial degradation of organosulfonates plays an important role in sulfur recycling, and has been extensively studied. However, this process in anaerobic bacteria especially gut bacteria is little known despite of its potential significant impact on human health with the production of toxic HS. Here, we describe the structural and biochemical characterization of an oxygen-sensitive enzyme that catalyzes the radical-mediated C-S bond cleavage of isethionate to form sulfite and acetaldehyde. We demonstrate its involvement in pathways that enables C2 sulfonates to be used as terminal electron acceptors for anaerobic respiration in sulfate- and sulfite-reducing bacteria. Furthermore, it plays a key role in converting bile salt-derived taurine into HS in the disease-associated gut bacterium Bilophila wadsworthia. The enzymes and transporters in these anaerobic pathways expand our understanding of microbial sulfur metabolism, and help deciphering the complex web of microbial pathways involved in the transformation of sulfur compounds in the gut. 10.1038/s41467-019-09618-8
    Even Cancer Cells Watch Their Cholesterol! Riscal Romain,Skuli Nicolas,Simon M Celeste Molecular cell Deregulated cell proliferation is an established feature of cancer, and altered tumor metabolism has witnessed renewed interest over the past decade, including the study of how cancer cells rewire metabolic pathways to renew energy sources and "building blocks" that sustain cell division. Microenvironmental oxygen, glucose, and glutamine are regarded as principal nutrients fueling tumor growth. However, hostile tumor microenvironments render O/nutrient supplies chronically insufficient for increased proliferation rates, forcing cancer cells to develop strategies for opportunistic modes of nutrient acquisition. Recent work shows that cancer cells overcome this nutrient scarcity by scavenging other substrates, such as proteins and lipids, or utilizing adaptive metabolic pathways. As such, reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid-mediated signaling during cancer progression. In this review, we highlight more recently appreciated roles for lipids, particularly cholesterol and its derivatives, in cancer cell metabolism within intrinsically harsh tumor microenvironments. 10.1016/j.molcel.2019.09.008
    Colonocyte metabolism shapes the gut microbiota. Litvak Yael,Byndloss Mariana X,Bäumler Andreas J Science (New York, N.Y.) An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases. 10.1126/science.aat9076
    Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. Rivera-Chávez Fabian,Zhang Lillian F,Faber Franziska,Lopez Christopher A,Byndloss Mariana X,Olsan Erin E,Xu Gege,Velazquez Eric M,Lebrilla Carlito B,Winter Sebastian E,Bäumler Andreas J Cell host & microbe The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment. Clostridia depletion and aerobic Salmonella expansion were also observed in the absence of streptomycin treatment in genetically resistant mice but proceeded with slower kinetics and required the presence of functional Salmonella type III secretion systems. The Salmonella cytochrome bd-II oxidase synergized with nitrate reductases to drive luminal expansion, and both were required for fecal-oral transmission. We conclude that Salmonella virulence factors and antibiotic treatment promote pathogen expansion through the same mechanism: depletion of butyrate-producing Clostridia to elevate epithelial oxygenation, allowing aerobic Salmonella growth. 10.1016/j.chom.2016.03.004
    Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Moreno-Indias Isabel,Torres Marta,Montserrat Josep M,Sanchez-Alcoholado Lidia,Cardona Fernando,Tinahones Francisco J,Gozal David,Poroyko Valeryi A,Navajas Daniel,Queipo-Ortuño Maria I,Farré Ramon The European respiratory journal We assessed whether intermittent hypoxia, which emulates one of the hallmarks of obstructive sleep apnoea (OSA), leads to altered faecal microbiome in a murine model. In vivo partial pressure of oxygen was measured in colonic faeces during intermittent hypoxia in four anesthetised mice. 10 mice were subjected to a pattern of chronic intermittent hypoxia (20 s at 5% O2 and 40 s at room air for 6 h·day(-1)) for 6 weeks and 10 mice served as normoxic controls. Faecal samples were obtained and microbiome composition was determined by 16S rRNA pyrosequencing and bioinformatic analysis by Quantitative Insights into Microbial Ecology. Intermittent hypoxia exposures translated into hypoxia/re-oxygenation patterns in the faeces proximal to the bowel epithelium (<200 μm). A significant effect of intermittent hypoxia on global microbial community structure was found. Intermittent hypoxia increased the α-diversity (Shannon index, p<0.05) and induced a change in the gut microbiota (ANOSIM analysis of β-diversity, p<0.05). Specifically, intermittent hypoxia-exposed mice showed a higher abundance of Firmicutes and a smaller abundance of Bacteroidetes and Proteobacteria phyla than controls. Faecal microbiota composition and diversity are altered as a result of intermittent hypoxia realistically mimicking OSA, suggesting the possibility that physiological interplays between host and gut microbiota could be deregulated in OSA. 10.1183/09031936.00184314
    A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Jalili-Firoozinezhad Sasan,Gazzaniga Francesca S,Calamari Elizabeth L,Camacho Diogo M,Fadel Cicely W,Bein Amir,Swenor Ben,Nestor Bret,Cronce Michael J,Tovaglieri Alessio,Levy Oren,Gregory Katherine E,Breault David T,Cabral Joaquim M S,Kasper Dennis L,Novak Richard,Ingber Donald E Nature biomedical engineering The diverse bacterial populations that comprise the commensal microbiome of the human intestine play a central role in health and disease. A method that sustains complex microbial communities in direct contact with living human intestinal cells and their overlying mucus layer in vitro would thus enable the investigation of host-microbiome interactions. Here, we show the extended coculture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota, using a microfluidic intestine-on-a-chip that permits the control and real-time assessment of physiologically relevant oxygen gradients. When compared to aerobic coculture conditions, the establishment of a transluminal hypoxia gradient in the chip increased intestinal barrier function and sustained a physiologically relevant level of microbial diversity, consisting of over 200 unique operational taxonomic units from 11 different genera and an abundance of obligate anaerobic bacteria, with ratios of Firmicutes and Bacteroidetes similar to those observed in human faeces. The intestine-on-a-chip may serve as a discovery tool for the development of microbiome-related therapeutics, probiotics and nutraceuticals. 10.1038/s41551-019-0397-0
    Natural variation in a neural globin tunes oxygen sensing in wild Caenorhabditis elegans. Persson Annelie,Gross Einav,Laurent Patrick,Busch Karl Emanuel,Bretes Hugo,de Bono Mario Nature Behaviours evolve by iterations of natural selection, but we have few insights into the molecular and neural mechanisms involved. Here we show that some Caenorhabditis elegans wild strains switch between two foraging behaviours in response to subtle changes in ambient oxygen. This finely tuned switch is conferred by a naturally variable hexacoordinated globin, GLB-5. GLB-5 acts with the atypical soluble guanylate cyclases, which are a different type of oxygen binding protein, to tune the dynamic range of oxygen-sensing neurons close to atmospheric (21%) concentrations. Calcium imaging indicates that one group of these neurons is activated when oxygen rises towards 21%, and is inhibited as oxygen drops below 21%. The soluble guanylate cyclase GCY-35 is required for high oxygen to activate the neurons; GLB-5 provides inhibitory input when oxygen decreases below 21%. Together, these oxygen binding proteins tune neuronal and behavioural responses to a narrow oxygen concentration range close to atmospheric levels. The effect of the glb-5 gene on oxygen sensing and foraging is modified by the naturally variable neuropeptide receptor npr-1 (refs 4, 5), providing insights into how polygenic variation reshapes neural circuit function. 10.1038/nature07820
    Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Quaegebeur Annelies,Segura Inmaculada,Schmieder Roberta,Verdegem Dries,Decimo Ilaria,Bifari Francesco,Dresselaers Tom,Eelen Guy,Ghosh Debapriva,Davidson Shawn M,Schoors Sandra,Broekaert Dorien,Cruys Bert,Govaerts Kristof,De Legher Carla,Bouché Ann,Schoonjans Luc,Ramer Matt S,Hung Gene,Bossaert Goele,Cleveland Don W,Himmelreich Uwe,Voets Thomas,Lemmens Robin,Bennett C Frank,Robberecht Wim,De Bock Katrien,Dewerchin Mieke,Ghesquière Bart,Fendt Sarah-Maria,Carmeliet Peter Cell metabolism The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1(-/-) neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1(-/-) neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1(-/-) neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke. 10.1016/j.cmet.2015.12.007
    Biomimetic Nanoemulsions for Oxygen Delivery In Vivo. Zhuang Jia,Ying Man,Spiekermann Kevin,Holay Maya,Zhang Yue,Chen Fang,Gong Hua,Lee Joo Hee,Gao Weiwei,Fang Ronnie H,Zhang Liangfang Advanced materials (Deerfield Beach, Fla.) Blood transfusion is oftentimes required for patients suffering from acute trauma or undergoing surgical procedures in order to help maintain the body's oxygen levels. The continued demand worldwide for blood products is expected to put significant strain on available resources and infrastructure. Unfortunately, efforts to develop viable alternatives to human red blood cells for transfusion are generally unsuccessful. Here, a hybrid natural-synthetic nanodelivery platform that combines the biocompatibility of the natural RBC membrane with the oxygen-carrying ability of perfluorocarbons is reported. The resulting formulation can be stored long-term and exhibits a high capacity for oxygen delivery, helping to mitigate the effects of hypoxia in vitro. In an animal model of hemorrhagic shock, mice are resuscitated at an efficacy comparable to whole blood infusion. By leveraging the advantageous properties of its constituent parts, this biomimetic oxygen delivery system may have the potential to address a critical need in the clinic. 10.1002/adma.201804693
    Oxygen-Generating Biomaterials: A New, Viable Paradigm for Tissue Engineering? Gholipourmalekabadi Mazaher,Zhao Susan,Harrison Benjamin S,Mozafari Masoud,Seifalian Alexander M Trends in biotechnology There have been many attempts to provide sufficient nutrients, especially oxygen, to engineered large tissues to overcome the effects of hypoxia or poor vascularization. Delivering sufficient oxygen to the transplanted cells is one of the most critical issues that affects cell survival and correct maturation of engineered tissues. An emerging approach is using 3D scaffolds made from oxygen-generating biomaterials to tackle transport limitations deep within the engineered tissues. This class of biomaterials has opened a new window for overcoming the challenges associated with ischemia occurring within large tissue constructs. This review critically assesses oxygen-generating reagents, the main approaches for developing oxygen-generating biomaterials, and their potential as 3D scaffolds for regenerative medicine in a clinical setting. 10.1016/j.tibtech.2016.05.012
    Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1α. Adamovich Yaarit,Ladeuix Benjamin,Golik Marina,Koeners Maarten P,Asher Gad Cell metabolism The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag. 10.1016/j.cmet.2016.09.014