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Nature Reviews. Drug Discovery Mar 2024Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF... (Review)
Review
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Hypoxia; Transcription Factors; Neoplasms; Oxygen
PubMed: 38123660
DOI: 10.1038/s41573-023-00848-6 -
Signal Transduction and Targeted Therapy Nov 2023Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in... (Review)
Review
Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.
Topics: Humans; Cardiovascular Diseases; Cardiovascular System; Hypoxia; Oxygen; Epigenesis, Genetic
PubMed: 37981648
DOI: 10.1038/s41392-023-01652-9 -
Oncogene Dec 2023Tumor hypoxia resulting from abnormal and dysfunctional tumor vascular network poses a substantial obstacle to immunotherapy. In fact, hypoxia creates an... (Review)
Review
Tumor hypoxia resulting from abnormal and dysfunctional tumor vascular network poses a substantial obstacle to immunotherapy. In fact, hypoxia creates an immunosuppressive tumor microenvironment (TME) through promoting angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition (EMT), p53 inactivation, and immune evasion. Vascular normalization, a strategy aimed at restoring the structure and function of tumor blood vessels, has been shown to improve oxygen delivery and reverse hypoxia-induced signaling pathways, thus alleviates hypoxia and potentiates cancer immunotherapy. In this review, we discuss the mechanisms of tumor tissue hypoxia and its impacts on immune cells and cancer immunotherapy, as well as the approaches to induce tumor vascular normalization. We also summarize the evidence supporting the use of vascular normalization in combination with cancer immunotherapy, and highlight the challenges and future directions of this overlooked important field. By targeting the fundamental problem of tumor hypoxia, vascular normalization proposes a promising strategy to enhance the efficacy of cancer immunotherapy and improve clinical outcomes for cancer patients.
Topics: Humans; Angiogenesis Inhibitors; Neoplasms; Hypoxia; Immunotherapy; Tumor Microenvironment
PubMed: 37884747
DOI: 10.1038/s41388-023-02869-2 -
Ugeskrift For Laeger Dec 2023Home oxygen therapy is an acknowledged treatment for patients suffering from chronic hypoxaemia, due to pulmonary or cardiac disease, and may have positive effects on... (Review)
Review
Home oxygen therapy is an acknowledged treatment for patients suffering from chronic hypoxaemia, due to pulmonary or cardiac disease, and may have positive effects on survival and quality of life. The risks and side effects of the treatment are usually mild, and the equipment has developed to become relatively affordable, accessible and easy to transport. Adjustments in the oxygen settings can be necessary when travelling by airplane or during physical effort or sleep. Prescription and follow-ups are usually best maintained by hospital departments with expertise in pulmonary medicine, as argued in this review.
Topics: Humans; Quality of Life; Oxygen Inhalation Therapy; Lung; Oxygen; Denmark; Hypoxia
PubMed: 38078470
DOI: No ID Found -
Reproductive Sciences (Thousand Oaks,... Jul 2023Ferroptosis is a recently identified form of programmed cell death which is different from apoptosis, pyroptosis, necrosis, and autophagy. It is uniquely defined by... (Review)
Review
Ferroptosis is a recently identified form of programmed cell death which is different from apoptosis, pyroptosis, necrosis, and autophagy. It is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. Ferroptosis has recently been implicated in multiple human diseases, such as tumors, ischemia-reperfusion injury, acute kidney injury, neurological diseases, and asthma among others. Intriguingly, ferroptosis is associated with placental physiology and trophoblast injury. Circumstances such as accumulation of lipid reactive oxygen species (ROS) due to hypoxia-reperfusion and anoxia-reoxygenation of trophoblast during placental development, the abundance of trophoblastic iron and PUFA, physiological uterine contractions, or pathological placental bed perfusion, cause placental trophoblasts' susceptibility to ferroptosis. Ferroptosis of trophoblast can cause placental dysfunction, which may be involved in the occurrence and development of placenta-related diseases such as gestational diabetes mellitus, preeclampsia, fetal growth restriction, preterm birth, and abortion. The regulatory mechanisms of trophoblastic ferroptosis still need to be explored further. Here, we summarize the latest progress in trophoblastic ferroptosis research on placental-related diseases, provide references for further understanding of its pathogenesis, and propose new strategies for the prevention and treatment of placental-related diseases.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Placenta; Ferroptosis; Premature Birth; Apoptosis; Lipid Peroxidation; Iron; Placenta Diseases; Hypoxia
PubMed: 36930425
DOI: 10.1007/s43032-023-01193-0 -
Nature Reviews. Disease Primers Jun 2024Millions of people visit high-altitude regions annually and more than 80 million live permanently above 2,500 m. Acute high-altitude exposure can trigger high-altitude... (Review)
Review
Millions of people visit high-altitude regions annually and more than 80 million live permanently above 2,500 m. Acute high-altitude exposure can trigger high-altitude illnesses (HAIs), including acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE). Chronic mountain sickness (CMS) can affect high-altitude resident populations worldwide. The prevalence of acute HAIs varies according to acclimatization status, rate of ascent and individual susceptibility. AMS, characterized by headache, nausea, dizziness and fatigue, is usually benign and self-limiting, and has been linked to hypoxia-induced cerebral blood volume increases, inflammation and related trigeminovascular system activation. Disruption of the blood-brain barrier leads to HACE, characterized by altered mental status and ataxia, and increased pulmonary capillary pressure, and related stress failure induces HAPE, characterized by dyspnoea, cough and exercise intolerance. Both conditions are progressive and life-threatening, requiring immediate medical intervention. Treatment includes supplemental oxygen and descent with appropriate pharmacological therapy. Preventive measures include slow ascent, pre-acclimatization and, in some instances, medications. CMS is characterized by excessive erythrocytosis and related clinical symptoms. In severe CMS, temporary or permanent relocation to low altitude is recommended. Future research should focus on more objective diagnostic tools to enable prompt treatment, improved identification of individual susceptibilities and effective acclimatization and prevention options.
Topics: Humans; Altitude Sickness; Altitude; Acclimatization; Brain Edema; Pulmonary Edema; Hypertension, Pulmonary; Hypoxia
PubMed: 38902312
DOI: 10.1038/s41572-024-00526-w -
Cancer Research Jan 2024Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors...
UNLABELLED
Expanding the utility of chimeric antigen receptor (CAR)-T cells in solid tumors requires improving their efficacy and safety. Hypoxia is a feature of most solid tumors that could be used to help CAR-T cells discriminate tumors from normal tissues. In this study, we developed hypoxia-responsive CAR-T cells by engineering the CAR to be under regulation of hypoxia-responsive elements and selected the optimal structure (5H1P-CEA CAR), which can be activated in the tumor hypoxic microenvironment to induce CAR-T cells with high polyfunctionality. Hypoxia-responsive CAR T cells were in a "resting" state with low CAR expression under normoxic conditions. Compared with conventional CAR-T cells, hypoxia-responsive CAR-T cells maintained lower differentiation and displayed enhanced oxidative metabolism and proliferation during cultivation, and they sowed a capacity to alleviate the negative effects of hypoxia on T-cell proliferation and metabolism. Furthermore, 5H1P-CEA CAR-T cells exhibited decreased T-cell exhaustion and improved T-cell phenotype in vivo. In patient-derived xenograft models, hypoxia-responsive CAR-T cells induced more durable antitumor activity than their conventional counterparts. Overall, this study provides an approach to limit CAR expression to the hypoxic tumor microenvironment that could help to enhance CAR T-cell efficacy and safety in solid tumors.
SIGNIFICANCE
Engineering CAR-T cells to upregulate CAR expression under hypoxic conditions induces metabolic reprogramming, reduces differentiation, and increases proliferation to enhance their antitumor activity, providing a strategy to improve efficacy and safety.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Hypoxia; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 37874330
DOI: 10.1158/0008-5472.CAN-23-1038 -
Journal of Cardiothoracic and Vascular... Oct 2023
Topics: Humans; Prostheses and Implants; Respiration Disorders; Hypoxia; Bronchoscopy
PubMed: 37188585
DOI: 10.1053/j.jvca.2023.04.022 -
JAMA Apr 2024Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.
IMPORTANCE
Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.
OBJECTIVE
To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU).
DESIGN, SETTING, AND PARTICIPANTS
Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023.
INTERVENTIONS
Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU.
MAIN OUTCOMES AND MEASURES
The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days.
RESULTS
Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital.
CONCLUSION AND RELEVANCE
In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04425031.
Topics: Adult; Humans; Male; Aged; Female; COVID-19; Oxygen; Respiration, Artificial; Oxygen Inhalation Therapy; Hypoxia
PubMed: 38501214
DOI: 10.1001/jama.2024.2934 -
Clinics in Perinatology Mar 2024Neonates with a perinatal hypoxic insult and subsequent neonatal encephalopathy are at risk of acute pulmonary hypertension (aPH) in the transitional period. The... (Review)
Review
Neonates with a perinatal hypoxic insult and subsequent neonatal encephalopathy are at risk of acute pulmonary hypertension (aPH) in the transitional period. The phenotypic contributors to aPH following perinatal asphyxia include a combination of hypoxic vasoconstriction of the pulmonary vascular bed, right heart dysfunction, and left heart dysfunction. Therapeutic hypothermia is the standard of care for neonates with moderate-to-severe hypoxic ischemic encephalopathy. This review summarizes the underlying risk factors, causes of aPH in neonates with perinatal asphyxia, discusses the unique phenotypical contributors to disease, and explores the impact of the initial insult and subsequent therapeutic hypothermia on aPH.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Asphyxia; Hypertension, Pulmonary; Asphyxia Neonatorum; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Hypoxia
PubMed: 38325938
DOI: 10.1016/j.clp.2023.11.007