Carbon Chemist

Tag: Medicinal Chemistry

  • Insilico Medicine’s AI-driven approach yields promising PTPN2/N1 inhibitor for cancer immunotherapy

    Insilico Medicine’s AI-driven approach yields promising PTPN2/N1 inhibitor for cancer immunotherapy

    [ad_1]

    In recent years, cancer immunotherapy, exemplified by PD-1 and its ligand PD-L1 blockade, has made remarkable advances. But while immunotherapy drugs offer new treatment possibilities, only about 20% to 40% of patients respond to these treatments. The majority either don’t respond or develop drug resistance. Researchers are now looking for ways to enhance the scope of tumor immunotherapy in order to benefit a wider range of patients. 

    One such avenue is through the protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its close superfamily member, PTPN1, identified in previous research as crucial modulators involved in the regulation of immune cells signaling pathways that promote tumorigenesis by attenuating tumor-directed immunity. While promising, the development of PTPN2/PTPN1 inhibitors has faced challenges as a result of unfavorable pharmacokinetics due to the highly cationic active site and the relatively shallow nature of the protein surface.

    In a significant milestone, researchers at Abbvie discovered the dual PTPN2/N1 inhibitor ABBV-CLS-484 through structure-based drug design and optimization of drug-like properties. Now, clinical stage artificial intelligence (AI)-driven drug discovery company Insilico Medicine (“Insilico”) has initiated a program with a fast-follow strategy to design a novel PTPN2/N1 inhibitor with drug-likeness properties and in vivo oral absorption, supported by the Company’s generative AI drug design engine Chemistry42. The research was published in the European Journal of Medicinal Chemistry on April 5.

    Scientists inputted the structure of the known PTPN2/N1 inhibitor as a reference compound to Chemistry42 as a starting point and generated a series of novel PTPN2/N1 inhibitors based on ligand-based drug design strategy. They further optimized and synthesized the most promising molecules and obtained candidates with desirable ADME properties. Insilico’s compound demonstrated enhanced oral absorption, systemic exposure, and equivalent biological activities compared to the reference compound in in vitro studies. Furthermore, Insilico’s compound demonstrated the same efficacious dose as the reference compound in murine model. 

    One of the most significant advances in the research was validating the fast follow ability of Chemistry42, the molecular generation and design engine of Pharma.AI, which allows users to rapidly improve existing molecules with more desirable properties. In this paper, we reported a novel PTPN2/PTPN1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy. Further investigation is currently ongoing.”


    Xiao Ding, PhD, vice president and head of medicinal chemistry of Insilico Medicine

    Insilico Medicine is a pioneer in using generative AI for drug discovery and development. The Company first described the concept of using generative AI for the design of novel molecules in a peer-reviewed journal in 2016. Then, Insilico developed and validated multiple approaches and features for its generative adversarial network (GAN)-based AI platform and integrated those algorithms into the commercially available Pharma.AI platform, which includes generative biology, chemistry, and medicine and has been used to produce a robust pipeline of promising therapeutic assets in multiple disease areas, including fibrosis, cancer, immunology and aging-related disease, a number of which have been licensed. Since 2021, Insilico has nominated 18 preclinical candidates in its comprehensive portfolio of over 30 assets and has advanced six pipelines to the clinical stage. In March 2024, the Company published a paper in Nature Biotechnology that discloses the raw experimental data and the preclinical and clinical evaluation of its lead drug – a potentially first-in-class TNIK inhibitor for the treatment of idiopathic pulmonary fibrosis discovered and designed using generative AI currently in Phase II trials with patients. 

    Source:

    Journal reference:

    Zheng, J., et al. (2024) Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors. European Journal of Medicinal Chemistry. doi.org/10.1016/j.ejmech.2024.116390.

    [ad_2]

    Source link

  • Researchers develop precise drugs to target HIV’s Nef protein

    Researchers develop precise drugs to target HIV’s Nef protein

    [ad_1]

    A team of University of Michigan researchers has successfully modified a naturally occurring chemical compound in the lab, resulting in advanced lead compounds with anti-HIV activity.

    Their results, published March 7 in the Journal of Medicinal Chemistry, offer a new path forward in the development of drugs that could potentially help cure-;rather than treat-;HIV.

    Although effective treatments are available to manage HIV, a cure has remained elusive due to the virus’s ability to hide from the immune system, lying dormant in reservoirs of infected cells.

    With most viruses, when people get infected, they get sick for a while and then the immune system kicks in and the virus is cleared. But with HIV, once a patient is infected, that virus will persist for their entire life-;meaning they must remain on treatments indefinitely.”


    Kathleen Collins, Professor, Microbiology and Immunology, University of Michigan

    One key to HIV’s ability to remain hidden in patients’ cells is a protein that the virus makes, called Nef. This protein shuts down a system that the cell would normally use to alert the immune system to an infection, thus preventing the immune cells from recognizing and clearing the virus.

    Collins and her lab have studied this protein for more than 15 years, investigating how it works and how it can be disabled. She and David Sherman, professor at the U-M Life Sciences Institute, previously discovered that a chemical found in nature can inhibit HIV Nef, allowing the immune system to find and eliminate virally infected cells: a compound called concanamycin A (CMA), which is produced by a soil-derived microorganism.

    In its natural form, however, CMA presents several challenges as a potential therapeutic. The first challenge the team had to overcome was supply. While CMA is a naturally occurring compound, the original bacteria that produces it does so in quantities far too small to be useful for testing and modification in the lab.

    Another major challenge with developing CMA as an anti-HIV drug is that Nef is not CMA’s primary target.

    “CMA’s main job in human cells is to inhibit an enzyme called V-ATPase, which we absolutely do not want to block in this case,” said Sherman, who is also a professor at the U-M College of Pharmacy, Medical School, and College of Literature, Science, and the Arts. “So, we needed to find a way to modify CMA’s activity, widening the effective dosage gap between when it starts to inhibit the target we’re aiming for-;HIV Nef -; without affecting V-ATPase, its typical cellular target.”

    With this latest research, the team has overcome both of these challenges. Using bioengineering, Sherman’s team was able to develop a bacterial strain that increased CMA production 2,000-fold. Synthetic chemists in the lab then created more than 70 new variations of the compound, swapping out different chemical groups, to test for their potency against HIV Nef.

    Collins’ lab team ran the new compounds through a battery of tests to measure their toxicity to cells, as well as how they affected the activities of both HIV Nef and V-ATPase.

    “Even though we know that CMA is extremely active against the HIV Nef protein, all drugs have side effects,” said Collins, also a professor of internal medicine at the Medical School. “And so we wanted to ensure we’ve done everything we can to minimize the side effect profile of the drug before we consider putting it into an animal or human.”

    The team now has several CMA analogs that show high potency in blocking HIV Nef at very low dosage levels, without interrupting off-target effects or causing toxicity in human cells. They caution, however, that several important steps remain before the compounds would be ready for further testing in a clinical setting.

    “We are really encouraged, though, because our groups have solved some very important problems,” Sherman said. “We have engineered microorganisms to produce sustainable supplies of the natural product molecules and have really good chemical methods to make new analogs. And we have the methodologies in place to continue tracking the critical toxicity and potency parameters to further reduce off-target effects.”

    Source:

    Journal reference:

    McCauley, M., et al. (2024). Structure–Activity Relationships of Natural and Semisynthetic Plecomacrolides Suggest Distinct Pathways for HIV-1 Immune Evasion and Vacuolar ATPase-Dependent Lysosomal Acidification. Journal of Medicinal Chemistry. doi.org/10.1021/acs.jmedchem.3c01574.

    [ad_2]

    Source link

  • Rare gene mutations in hereditary Alzheimer’s disease disrupt amyloid production, study shows

    Rare gene mutations in hereditary Alzheimer’s disease disrupt amyloid production, study shows

    [ad_1]

    A University of Kansas study of rare gene mutations that cause hereditary Alzheimer’s disease shows these mutations disrupt production of a small sticky protein called amyloid.

    Plaques composed of amyloid are notoriously found in the brain in Alzheimer’s disease and have long been considered responsible for the inexorable loss of neurons and cognitive decline. Using a model species of worm called C. elegans that’s often used in labs to study diseases at the molecular level, the research team came to the surprising conclusion that the stalled process of amyloid production -; not the amyloid itself -; can trigger loss of critical connections between nerve cells.

    The research, appearing in the journal Cell Reports, was headed by Michael Wolfe, Mathias P. Mertes Professor of Medicinal Chemistry at KU. 

    The research team focused on the rare inherited mutations because these mutations are found in genes that encode proteins that produce amyloid. 

    If we can understand what’s happening in this inherited form of the disease where a single mutation can trigger it. that might be a clue to what’s going on in all the other cases.” 


    Michael Wolfe, Mathias P. Mertes Professor of Medicinal Chemistry at KU

    The rare mutations are particularly devastating, as they fate the mutation carrier to Alzheimer’s disease in middle age, and children of a mutation carrier have a 50% chance of inheriting the disease-causing mutation.

    Wolfe said hereditary Alzheimer’s disease shows the same pathology, the same presentation clinically and the same progression of symptoms as the “common, garden-variety” of Alzheimer’s related to old age.

    “You see the same amyloid plaques in the hereditary disease,” he said. “We think that these inherited mutations, though rare, are key to what’s going on with all Alzheimer’s disease.”

    Wolfe, who earned his doctorate at KU and returned to the university seven years ago for collaborative research opportunities, joined forces with Brian Ackley, associate professor of molecular biology at KU, whose lab specializes in research with the C. elegans model worm. The research team also included other KU collaborators as well as investigators in Beijing, China, and at Harvard Medical School.

    Co-authors with KU’s Department of Medicinal Chemistry were Sujan Devkota, Vaishnavi Nagarajan, Arshad Noorani and Sanjay Bhattarai; co-authors at KU’s Department of Molecular Biosciences were Ackley and Yinglong Miao; and co-authors from KU’s Center for Computational Biology were Hung Do and Anita Saraf. Other KU co-authors were Caitlin Overmeyer of the Graduate Program in Neurosciences and Justin Douglas of KU’s Nuclear Magnetic Resonance Core Lab. The KU personnel collaborated with Rui Zhou of Tsinghua University in Beijing and Masato Maesako of Harvard Medical School.

    Wolfe said the discovery could point the way toward new approaches to Alzheimer’s therapies, and he hoped fellow researchers and developers of drug therapies would pay close attention to his team’s results. 

    “Our findings suggest what’s needed is a stimulator of the amyloid-producing enzyme, to restart stalled processes and address both problems: eliminating stalled protein complexes that lead to degeneration of nerve cell connections and producing more soluble forms of amyloid. This approach could address both contributing factors simultaneously.”

    Source:

    Journal reference:

    Devkota, S., et al (2024). Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Reports. doi.org/10.1016/j.celrep.2024.113761.

    [ad_2]

    Source link

  • Targeting hypoxia-inducible factors: therapeutic opportunities and challenges

    [ad_1]

  • Taylor, C. T. & McElwain, J. C. Ancient atmospheres and the evolution of oxygen sensing via the hypoxia-inducible factor in metazoans. Physiology 25, 272–279 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Mills, D. B. et al. The last common ancestor of animals lacked the HIF pathway and respired in low-oxygen environments. eLife 7, e31176 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Liu, Y., Cox, S. R., Morita, T. & Kourembanas, S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ. Res. 77, 638–643 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Poth, J. M., Brodsky, K., Ehrentraut, H., Grenz, A. & Eltzschig, H. K. Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J. Mol. Med. 91, 183–193 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Eltzschig, H. K., Sitkovsky, M. V. & Robson, S. C. Purinergic signaling during inflammation. N. Engl. J. Med. 367, 2322–2333 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Prabhakar, N. R. & Semenza, G. L. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol. Rev. 92, 967–1003 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Semenza, G. L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537–547 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Eckle, T. et al. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat. Med. 18, 774–782 (2012). This study reports that adenosine-dependent Per2 stabilization facilitates HIF-elicited cardiac metabolic adaptation and ischaemia tolerance.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion — from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Smith, T. G., Robbins, P. A. & Ratcliffe, P. J. The human side of hypoxia-inducible factor. Br. J. Haematol. 141, 325–334 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Manalo, D. J. et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659–669 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Neudecker, V., Yuan, X., Bowser, J. L. & Eltzschig, H. K. MicroRNAs in mucosal inflammation. J. Mol. Med. 95, 935–949 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Neudecker, V., Brodsky, K. S., Kreth, S., Ginde, A. A. & Eltzschig, H. K. Emerging roles for microRNAs in perioperative medicine. Anesthesiology 124, 489–506 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ju, C. et al. Hypoxia-inducible factor-1alpha-dependent induction of miR122 enhances hepatic ischemia tolerance. J. Clin. Invest. 131, e140300 (2021). This paper demonstrates that miRNAs can function in feed-forward loops by repressing PHDs, thereby enhancing their transcriptional induction through HIFs and providing tissue protection during liver ischemia–reperfusion injury.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wang, G. L. & Semenza, G. L. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J. Biol. Chem. 268, 21513–21518 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Semenza, G. L., Nejfelt, M. K., Chi, S. M. & Antonarakis, S. E. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc. Natl Acad. Sci. USA 88, 5680–5684 (1991). This study is among the first reports from the Nobel laureate Gregg Semenza to describe a novel protein as a HIF that functions as a transcriptional enhancer of EPO.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Semenza, G. L., Koury, S. T., Nejfelt, M. K., Gearhart, J. D. & Antonarakis, S. E. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc. Natl Acad. Sci. USA 88, 8725–8729 (1991).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Fandrey, J., Schodel, J., Eckardt, K. U., Katschinski, D. M. & Wenger, R. H. Now a nobel gas: oxygen. Pflug. Arch. 471, 1343–1358 (2019).

    Article 
    CAS 

    Google Scholar     

  • Ivan, M. et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001). This study reports the identification of VHL tumour suppressor protein as a key molecule in the oxygen-dependent degradation of HIFα.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Jaakkola, P. et al. Targeting of HIF-alpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001). This study describes EGL9 as a key dioxygenase for oxygen-dependent HIF prolyl hydroxylation in C. elegans and defined isoforms of conserved HIF-PHDs in mammalian cells.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Eltzschig, H. K. et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J. Exp. Med. 202, 1493–1505 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K. et al. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104, 3986–3992 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Thompson, L. F. et al. Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200, 1395–1405 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wicks, E. E. & Semenza, G. L. Hypoxia-inducible factors: cancer progression and clinical translation. J. Clin. Invest. 132, e159839 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K. & Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 364, 656–665 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bowser, J. L., Lee, J. W., Yuan, X. & Eltzschig, H. K. The hypoxia–adenosine link during inflammation. J. Appl. Physiol. 123, 1303–1320 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eckle, T. et al. HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. PLoS Biol. 11, e1001665 (2013). This study demonstrates that HIF1α is stabilized in the lungs during ARDS, and functions in endogenous lung protection by optimizing glucose metabolism in alveolar epithelial cells.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bartels, K., Grenz, A. & Eltzschig, H. K. Hypoxia and inflammation are two sides of the same coin. Proc. Natl Acad. Sci. USA 110, 18351–18352 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Karhausen, J. et al. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 114, 1098–1106 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Clambey, E. T. et al. Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc. Natl Acad. Sci. USA 109, E2784–E2793 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Campbell, E. L. et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014). This study shows that infiltrating neutrophils deplete local oxygen to stabilize HIF and promote intestinal inflammation resolution in murine colitis models.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K., Bratton, D. L. & Colgan, S. P. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat. Rev. Drug. Discov. 13, 852–869 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 7, 277ra230 (2015).

    Article 

    Google Scholar     

  • Lee, J. W., Ko, J., Ju, C. & Eltzschig, H. K. Hypoxia signaling in human diseases and therapeutic targets. Exp. Mol. Med. 51, 1–13 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ong, S. G. et al. HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore. Cardiovasc. Res. 104, 24–36 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Guo, Y. et al. Systematic review with meta-analysis: HIF-1alpha attenuates liver ischemia-reperfusion injury. Transpl. Rev. 29, 127–134 (2015).

    Article 

    Google Scholar     

  • Gao, R. Y. et al. Hypoxia-inducible factor-2alpha reprograms liver macrophages to protect against acute liver injury through the production of interleukin-6. Hepatology 71, 2105–2117 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Kapitsinou, P. P. et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J. Clin. Invest. 124, 2396–2409 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hill, P. et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 19, 39–46 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Woods, P. S. et al. HIF-1alpha induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury. eLife 11, e77457 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kim, Y. I. et al. Local stabilization of hypoxia-inducible factor-1alpha controls intestinal inflammation via enhanced gut barrier function and immune regulation. Front. Immunol. 11, 609689 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Dowdell, A. S. et al. The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis. Mol. Biol. Cell 31, 2249–2258 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Lin, A. E. et al. Role of hypoxia inducible factor-1alpha (HIF-1alpha) in innate defense against uropathogenic escherichia coli infection. PLoS Pathog. 11, e1004818 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bhandari, T. & Nizet, V. Hypoxia-inducible factor (HIF) as a pharmacological target for prevention and treatment of infectious diseases. Infect. Dis. Ther. 3, 159–174 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Suhara, T. et al. Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle. Proc. Natl Acad. Sci. USA 112, 11642–11647 (2015). This study shows that PHD2 is a novel therapeutic target for lactic acidosis and indicates that pharmacological enhancement of PHD2 might benefit infectious and ischaemic diseases.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Sanghani, N. S. & Haase, V. H. Hypoxia-inducible factor activators in renal anemia: current clinical experience. Adv. Chronic Kidney Dis. 26, 253–266 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eckardt, K. U. et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N. Engl. J. Med. 384, 1601–1612 (2021). This study reports two randomized, phase III clinical trials that showed that HIF-PHDi vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and efficacy in correcting anaemia in patients with CKD undergoing dialysis.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Chertow, G. M. et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N. Engl. J. Med. 384, 1589–1600 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Chen, N. et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N. Engl. J. Med. 381, 1001–1010 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Chen, N. et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N. Engl. J. Med. 381, 1011–1022 (2019). This study reports the results from a randomized and multicentre phase III clinical trial that showed that HIF-PHDi roxadustat was noninferior to parenteral epoetin alfa in correcting anaemia in Chinese patients undergoing dialysis.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhou, J. & Gong, K. Belzutifan: a novel therapy for von Hippel-Lindau disease. Nat. Rev. Nephrol. 18, 205–206 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Jonasch, E. et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N. Engl. J. Med. 385, 2036–2046 (2021). This study reports the results from a randomized and multicentre phase III clinical trial that showed the safety and efficacy of HIF2α inhibitor belzutifan as a treatment for RCC and non-RCC neoplasms in patients with VHL disease.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kamihara, J. et al. Belzutifan, a potent HIF2alpha inhibitor, in the pacak-zhuang syndrome. N. Engl. J. Med. 385, 2059–2065 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Choueiri, T. K. & Kaelin, W. G. Jr. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat. Med. 26, 1519–1530 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Salman, S. et al. HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy. J. Clin. Invest. 132, e156774 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Pullamsetti, S. S., Mamazhakypov, A., Weissmann, N., Seeger, W. & Savai, R. Hypoxia-inducible factor signaling in pulmonary hypertension. J. Clin. Invest. 130, 5638–5651 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhang, J. et al. HIF-1alpha and HIF-2alpha redundantly promote retinal neovascularization in patients with ischemic retinal disease. J. Clin. Invest. 131, e139202 (2021). This article provides evidence that targeting both HIF1α and HIF2α is necessary to prevent retinal neovascularization in patients with sickle cell retinopathy.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Dengler, V. L., Galbraith, M. & Espinosa, J. M. Transcriptional regulation by hypoxia inducible factors. Crit. Rev. Biochem. Mol. Biol. 49, 1–15 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Semenza, G. L. Pharmacologic targeting of hypoxia-inducible factors. Annu. Rev. Pharmacol. Toxicol. 59, 379–403 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Diao, X. et al. Identification of oleoylethanolamide as an endogenous ligand for HIF-3alpha. Nat. Commun. 13, 2529 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wu, D., Potluri, N., Lu, J., Kim, Y. & Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature 524, 303–308 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Semenza, G. L. & Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell Biol. 12, 5447–5454 (1992).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997). This study reports the identification of EPAS1/HIF2α as an important player in vascularization.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Mastrogiannaki, M., Matak, P. & Peyssonnaux, C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 122, 885–892 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Knutson, A. K., Williams, A. L., Boisvert, W. A. & Shohet, R. V. HIF in the heart: development, metabolism, ischemia, and atherosclerosis. J. Clin. Invest. 131, e137557 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol. Cell Biol. 23, 9361–9374 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Takeda, N. et al. Differential activation and antagonistic function of HIF-alpha isoforms in macrophages are essential for NO homeostasis. Genes Dev. 24, 491–501 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Branco-Price, C. et al. Endothelial cell HIF-1alpha and HIF-2alpha differentially regulate metastatic success. Cancer Cell 21, 52–65 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Makino, Y. et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550–554 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. & Poellinger, L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J. Biol. Chem. 277, 32405–32408 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Semenza, G. L. The genomics and genetics of oxygen homeostasis. Annu. Rev. Genomics Hum. Genet. 21, 183–204 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • McNeill, L. A. et al. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the beta-carbon of asparagine-803. Biochem. J. 367, 571–575 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Freedman, S. J. et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. Proc. Natl Acad. Sci. USA 99, 5367–5372 (2002). This report provides the solution structure as a mechanism of the specific recognition of CBP–p300 by HIF1α.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhang, N. et al. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab. 11, 364–378 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hirota, K. HIF-alpha prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review. Biomedicines 9, 468 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999). This study shows that VHL tumour suppressor gene product pVHL is important for oxygen-dependent degradation of HIFα.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Iwai, K. et al. Identification of the von Hippel–Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc. Natl Acad. Sci. USA 96, 12436–12441 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Schofield, C. J. & Ratcliffe, P. J. Signalling hypoxia by HIF hydroxylases. Biochem. Biophys. Res. Commun. 338, 617–626 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Kasper, L. H. et al. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J. 24, 3846–3858 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wenger, R. H., Stiehl, D. P. & Camenisch, G. Integration of oxygen signaling at the consensus HRE. Sci. STKE 2005, re12 (2005).

    Article 
    PubMed 

    Google Scholar     

  • Hartmann, H. et al. Hypoxia-independent activation of HIF-1 by Enterobacteriaceae and their siderophores. Gastroenterology 134, 756–767 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Appelhoff, R. J. et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J. Biol. Chem. 279, 38458–38465 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Yeh, T. L. et al. Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials. Chem. Sci. 8, 7651–7668 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Markolovic, S., Wilkins, S. E. & Schofield, C. J. Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases. J. Biol. Chem. 290, 20712–20722 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hodges, V. M., Rainey, S., Lappin, T. R. & Maxwell, A. P. Pathophysiology of anemia and erythrocytosis. Crit. Rev. Oncol. Hematol. 64, 139–158 (2007).

    Article 
    PubMed 

    Google Scholar     

  • Dame, C. et al. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 92, 3218–3225 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhang, Y. et al. Erythropoietin action in stress response, tissue maintenance and metabolism. Int. J. Mol. Sci. 15, 10296–10333 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Obara, N. et al. Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood 111, 5223–5232 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Souma, T., Suzuki, N. & Yamamoto, M. Renal erythropoietin-producing cells in health and disease. Front. Physiol. 6, 167 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Haase, V. H. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int. Suppl. 11, 8–25 (2021).

    Article 

    Google Scholar     

  • Macdougall, I. C. et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int. 81, 727–732 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Warnecke, C. et al. Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J. 18, 1462–1464 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Flamme, I. et al. Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects. PLoS ONE 9, e111838 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kapitsinou, P. P. et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116, 3039–3048 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Minamishima, Y. A. & Kaelin, W. G. Jr. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science 329, 407 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Peyssonnaux, C. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117, 1926–1932 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Qian, Z. M. et al. Divalent metal transporter 1 is a hypoxia-inducible gene. J. Cell Physiol. 226, 1596–1603 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Taylor, M. et al. Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044–2055 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Singh, A. K. et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N. Engl. J. Med. 385, 2313–2324 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Singh, A. K. et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N. Engl. J. Med. 385, 2325–2335 (2021). This study reports the results from a randomized phase III clinical trial that demonstrated that HIF-PHDi daprodustat was noninferior to ESAs in cardiovascular safety and efficacy in correcting anaemia in patients with CKD undergoing dialysis.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Koeppen, M. et al. Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury. Nat. Commun. 9, 816 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K., Bonney, S. K. & Eckle, T. Attenuating myocardial ischemia by targeting A2B adenosine receptors. Trends Mol. Med. 19, 345–354 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bowser, J. L., Phan, L. H. & Eltzschig, H. K. The hypoxia-adenosine link during Intestinal Inflammation. J. Immunol. 200, 897–907 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Vohwinkel, C. U., Hoegl, S. & Eltzschig, H. K. Hypoxia signaling during acute lung injury. J. Appl. Physiol. 119, 1157–1163 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eckle, T. et al. Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J. Immunol. 192, 1249–1256 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Vohwinkel, C. U. et al. HIF1A-dependent induction of alveolar epithelial PFKFB3 dampens acute lung injury. JCI Insight 7, e157855 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhao, C. et al. Deficiency of HIF-1alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells. Emerg. Microbes Infect. 9, 691–706 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • McClendon, J. et al. Hypoxia-inducible factor 1alpha signaling promotes repair of the alveolar epithelium after acute lung injury. Am. J. Pathol. 187, 1772–1786 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Gong, H. et al. HIF2alpha signaling inhibits adherens junctional disruption in acute lung injury. J. Clin. Invest. 125, 652–664 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Jiang, X. et al. Endothelial hypoxia-inducible factor-2alpha is required for the maintenance of airway microvasculature. Circulation 139, 502–517 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Colgan, S. P., Furuta, G. T. & Taylor, C. T. Hypoxia and innate immunity: keeping up with the HIFsters. Annu. Rev. Immunol. 38, 341–363 (2020). This is an authoritative review on the importance of HIF in the regulation of innate immunity.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Palazon, A., Goldrath, A. W., Nizet, V. & Johnson, R. S. HIF transcription factors, inflammation, and immunity. Immunity 41, 518–528 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Taylor, C. T. & Scholz, C. C. The effect of HIF on metabolism and immunity. Nat. Rev. Nephrol. 18, 573–587 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • McGettrick, A. F. & O’Neill, L. A. J. The role of HIF in immunity and inflammation. Cell Metab. 32, 524–536 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Berg, N. K. et al. Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury. FASEB J. 35, e21334 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Wu, G. et al. Hypoxia exacerbates inflammatory acute lung injury via the Toll-like receptor 4 signaling pathway. Front. Immunol. 9, 1667 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wing, P. A. C. et al. Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells. Cell Rep. 35, 109020 (2021). This is the first study to show the potential benefit of HIF-PHDi during SARS-CoV-2 infection.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wing, P. A. C. et al. Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model. PLoS Pathog. 18, e1010807 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Nakamura, M., Imamura, T., Sobajima, M. & Kinugawa, K. Initial experience of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with heart failure and renal anemia. Heart Vessels 38, 284–290 (2023).

    Article 
    PubMed 

    Google Scholar     

  • Wen, T., Zhang, X., Wang, Z. & Zhou, R. Hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with renal anemia: a meta-analysis of randomized trials. Nephron 144, 572–582 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Bartels, K., Karhausen, J., Clambey, E. T., Grenz, A. & Eltzschig, H. K. Perioperative organ injury. Anesthesiology 119, 1474–1489 (2013).

    Article 
    PubMed 

    Google Scholar     

  • Williams, G. W., Berg, N. K., Reskallah, A., Yuan, X. & Eltzschig, H. K. Acute respiratory distress syndrome: contemporary management and novel approaches during COVID-19. Anesthesiology 134, 270–282 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Gumbert, S. D. et al. Perioperative acute kidney injury. Anesthesiology 132, 180–204 (2020).

    Article 
    PubMed 

    Google Scholar     

  • Macdougall, I. C. New anemia therapies: translating novel strategies from bench to bedside. Am. J. Kidney Dis. 59, 444–451 (2012).

    Article 
    PubMed 

    Google Scholar     

  • Agrawal, D. et al. Desidustat in anemia due to non-dialysis-dependent chronic kidney disease: a phase 3 study (DREAM-ND). Am. J. Nephrol. 53, 352–360 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Maxwell, P. H. & Eckardt, K. U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat. Rev. Nephrol. 12, 157–168 (2016). This is an authoritative review that discusses the advantages and challenges of using HIF-PHDis as treatment for renal anaemia.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Percy, M. J. et al. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood 111, 5400–5402 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Percy, M. J. et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N. Engl. J. Med. 358, 162–168 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Percy, M. J. et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc. Natl Acad. Sci. USA 103, 654–659 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Beck, J., Henschel, C., Chou, J., Lin, A. & Del Balzo, U. Evaluation of the carcinogenic potential of roxadustat (FG-4592), a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase in CD-1 mice and Sprague Dawley rats. Int. J. Toxicol. 36, 427–439 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Provenzano, R. et al. Efficacy and cardiovascular safety of roxadustat for treatment of anemia in patients with non-dialysis-dependent CKD: pooled results of three randomized clinical trials. Clin. J. Am. Soc. Nephrol. 16, 1190–1200 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kiriakidis, S. et al. Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor. Kidney Int. 92, 900–908 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Schejbel, L. et al. Molecular basis of hereditary C1q deficiency–revisited: identification of several novel disease-causing mutations. Genes Immun. 12, 626–634 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Fallah, J. & Rini, B. I. HIF inhibitors: status of current clinical development. Curr. Oncol. Rep. 21, 6 (2019).

    Article 
    PubMed 

    Google Scholar     

  • Aquino-Galvez, A. et al. Effects of 2-methoxyestradiol on apoptosis and HIF-1alpha and HIF-2alpha expression in lung cancer cells under normoxia and hypoxia. Oncol. Rep. 35, 577–583 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Gheorghiade, M., van Veldhuisen, D. J. & Colucci, W. S. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation 113, 2556–2564 (2006).

    Article 
    PubMed 

    Google Scholar     

  • Zhang, H. et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc. Natl Acad. Sci. USA 105, 19579–19586 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Currie, G. M., Wheat, J. M. & Kiat, H. Pharmacokinetic considerations for digoxin in older people. Open Cardiovasc. Med. J. 5, 130–135 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ren, X., Diao, X., Zhuang, J. & Wu, D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol. Pharmacol. 102, 240–247 (2022).

    Article 
    CAS 

    Google Scholar     

  • Rapisarda, A. et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 62, 4316–4324 (2002).

    CAS 
    PubMed 

    Google Scholar     

  • Rapisarda, A. et al. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res. 64, 1475–1482 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G. & Powis, G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol. Cancer Ther. 3, 233–244 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Jacoby, J. J. et al. Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J. Thorac. Oncol. 5, 940–949 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Koh, M. Y. et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol. Cancer Ther. 7, 90–100 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Miranda, E. et al. A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. J. Am. Chem. Soc. 135, 10418–10425 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Burslem, G. M., Kyle, H. F., Nelson, A., Edwards, T. A. & Wilson, A. J. Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions. Chem. Sci. 8, 4188–4202 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Greenberger, L. M. et al. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol. Cancer Ther. 7, 3598–3608 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhang, D. L., Ghosh, M. C. & Rouault, T. A. The physiological functions of iron regulatory proteins in iron homeostasis – an update. Front. Pharmacol. 5, 124 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Dai, Z. et al. Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2alpha inhibitor. Am. J. Respir. Crit. Care Med. 198, 1423–1434 (2018). This study reports the beneficial therapeutic effect of pharmacological HIF2α inhibitor C76 in rodent models of pulmonary hypertension.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Scheuermann, T. H. et al. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc. Natl Acad. Sci. USA 106, 450–455 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wehn, P. M. et al. Design and activity of specific hypoxia-inducible factor-2alpha (HIF-2alpha) inhibitors for the treatment of clear cell renal cell carcinoma: discovery of clinical candidate (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385). J. Med. Chem. 61, 9691–9721 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Courtney, K. D. et al. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin. Cancer Res. 26, 793–803 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Courtney, K. D. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. 36, 867–874 (2018). This study reports the results from a first-in-human phase I clinical trial indicating a favourable safety profile and activity of HIF2α inhibitor PT2385 in patients with heavily pretreated ccRCC.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Xu, R. et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J. Med. Chem. 62, 6876–6893 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Choueiri, T. K. et al. Inhibition of hypoxia-inducible factor-2alpha in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat. Med. 27, 802–805 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • No authors listed. FDA OK’s HIF2α inhibitor belzutifan. Cancer Discov. 11, 2360–2361 (2021).

    Article 

    Google Scholar     

  • Wong, S. C. et al. HIF2alpha-targeted RNAi therapeutic inhibits clear cell renal cell carcinoma. Mol. Cancer Ther. 17, 140–149 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ma, Y. et al. HIF2 inactivation and tumor suppression with a tumor-directed RNA-silencing drug in mice and humans. Clin. Cancer Res. 28, 5405–5418 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Muz, B., de la Puente, P., Azab, F. & Azab, A. K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 3, 83–92 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Semenza, G. L. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33, 207–214 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Rapisarda, A. et al. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 64, 6845–6848 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ardizzoni, A. et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J. Clin. Oncol. 15, 2090–2096 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Tibes, R. et al. Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α. J. Clin. Oncol. 28, 3076–3076 (2010).

    Article 

    Google Scholar     

  • Jeong, W. et al. Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1alpha), in patients with refractory solid tumors. Cancer Chemother. Pharmacol. 73, 343–348 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Wu, J. et al. Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1alpha in advanced hepatocellular carcinoma. World J. Clin. Oncol. 10, 149–160 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

    Article 

    Google Scholar     

  • Kasherman, L., Siu, D. H. W., Woodford, R. & Harris, C. A. Angiogenesis inhibitors and immunomodulation in renal cell cancers: the past, present, and future. Cancers 14, 1406 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Pandey, A. K. et al. Mechanisms of VEGF (vascular endothelial growth factor) inhibitor-associated hypertension and vascular disease. Hypertension 71, e1–e8 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Kamba, T. & McDonald, D. M. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br. J. Cancer 96, 1788–1795 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ganner, A. et al. VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma. Sci. Rep. 11, 14827 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Battelli, C. & Cho, D. C. mTOR inhibitors in renal cell carcinoma. Therapy 8, 359–367 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Toschi, A., Lee, E., Gadir, N., Ohh, M. & Foster, D. A. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495–34499 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Motzer, R. J. et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 126, 4156–4167 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell Biol. 25, 5675–5686 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Pelosci, A. LITESPARK-005 trial reveals PFS benefit of belzutifan in advanced RCC. Cancer Network, Home of the Journal ONCOLOGY (23 August 2023).

  • Stransky, L. A. et al. Sensitivity of VHL mutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway. Proc. Natl Acad. Sci. USA 119, e2120403119 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Davis, L. et al. Targeting HIF-2alpha in the tumor microenvironment: redefining the role of HIF-2alpha for solid cancer therapy. Cancers 14, 1259 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Feldman, D. R. et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 1432–1439 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Redlich, A. et al. Pseudohypoxic pheochromocytomas and paragangliomas dominate in children. Pediatr. Blood Cancer 68, e28981 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Yang, C. et al. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J. Mol. Med. 93, 93–104 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Pacak, K. et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J. Clin. Oncol. 31, 1690–1698 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yang, C. et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood 121, 2563–2566 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wang, H. et al. A transgenic mouse model of Pacak–Zhuang syndrome with an EPAS1 gain-of-function mutation. Cancers 11, 667 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Maron, B. A. Revised definition of pulmonary hypertension and approach to management: a clinical primer. J. Am. Heart Assoc. 12, e029024 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • He, M. et al. Hypoxia induces the dysfunction of human endothelial colony-forming cells via HIF-1alpha signaling. Respir. Physiol. Neurobiol. 247, 87–95 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Shan, F., Li, J. & Huang, Q. Y. HIF-1 alpha-induced up-regulation of miR-9 contributes to phenotypic modulation in pulmonary artery smooth muscle cells during hypoxia. J. Cell Physiol. 229, 1511–1520 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zeng, Y. et al. Hypoxia inducible factor-1 mediates expression of miR-322: potential role in proliferation and migration of pulmonary arterial smooth muscle cells. Sci. Rep. 5, 12098 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Luo, Y. et al. CD146-HIF-1alpha hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nat. Commun. 10, 3551 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Tang, H. et al. Endothelial HIF-2alpha contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Am. J. Physiol. Lung Cell Mol. Physiol. 314, L256–L275 (2018).

    PubMed 

    Google Scholar     

  • Hu, C. J. et al. Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension. Eur. Respir. J. 54, 1900378 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kim, Y. M. et al. Hypoxia-inducible factor-1alpha in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circ. Res. 112, 1230–1233 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kojima, H. et al. Hypoxia-inducible factor-1 alpha deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension. Physiol. Rep. 7, e14025 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yu, Y. A. et al. Nonclassical monocytes sense hypoxia, regulate pulmonary vascular remodeling, and promote pulmonary hypertension. J. Immunol. 204, 1474–1485 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Cowburn, A. S. et al. HIF2alpha–arginase axis is essential for the development of pulmonary hypertension. Proc. Natl Acad. Sci. USA 113, 8801–8806 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Labrousse-Arias, D. et al. HIF-2alpha-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. Cardiovasc. Res. 109, 115–130 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Wang, S. et al. EPAS1 (endothelial PAS domain protein 1) orchestrates transactivation of endothelial ICAM1 (intercellular adhesion molecule 1) by small nucleolar RNA host gene 5 (SNHG5) to promote hypoxic pulmonary hypertension. Hypertension 78, 1080–1091 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Tan, Q. et al. Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation. J. Biol. Chem. 288, 17134–17144 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Jiang, Y. et al. Topotecan prevents hypoxia-induced pulmonary arterial hypertension and inhibits hypoxia-inducible factor-1alpha and TRPC channels. Int. J. Biochem. Cell Biol. 104, 161–170 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ghosh, M. C. et al. Therapeutic inhibition of HIF-2alpha reverses polycythemia and pulmonary hypertension in murine models of human diseases. Blood 137, 2509–2519 (2021). This study shows the beneficial therapeutic effect of pharmacological HIF2α inhibitor belzutifan in a murine model of polycythaemia, pulmonary hypertension, pulmonary fibrosis and complications due to gain-of-function mutation of HIF2A.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Campochiaro, P. A. Ocular neovascularization. J. Mol. Med. 91, 311–321 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ozaki, H. et al. Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 40, 182–189 (1999).

    CAS 
    PubMed 

    Google Scholar     

  • Kelly, B. D. et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ. Res. 93, 1074–1081 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Barben, M., Schori, C., Samardzija, M. & Grimm, C. Targeting Hif1a rescues cone degeneration and prevents subretinal neovascularization in a model of chronic hypoxia. Mol. Neurodegener. 13, 12 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Dioum, E. M., Clarke, S. L., Ding, K., Repa, J. J. & Garcia, J. A. HIF-2alpha-haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery. Invest. Ophthalmol. Vis. Sci. 49, 2714–2720 (2008).

    Article 
    PubMed 

    Google Scholar     

  • Qin, Y. et al. PAI-1 is a vascular cell-specific HIF-2-dependent angiogenic factor that promotes retinal neovascularization in diabetic patients. Sci. Adv. 8, eabm1896 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zeng, M. et al. The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. J. Mol. Med. 95, 417–429 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Usui-Ouchi, A. et al. An allosteric peptide inhibitor of HIF-1alpha regulates hypoxia-induced retinal neovascularization. Proc. Natl Acad. Sci. USA 117, 28297–28306 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Miwa, Y. et al. Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine oxygen-induced retinopathy model. Neurochem. Int. 128, 21–31 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Pan, X. & Lv, Y. Effects and mechanism of action of PX-478 in oxygen-induced retinopathy in mice. Ophthalmic Res. 63, 182–193 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Cheng, X. et al. Marked and rapid effects of pharmacological HIF-2alpha antagonism on hypoxic ventilatory control. J. Clin. Invest. 130, 2237–2251 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Macias, D. et al. HIF-2alpha is essential for carotid body development and function. eLife 7, e34681 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Cho, H. et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Watts, E. R. & Walmsley, S. R. Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends Mol. Med. 25, 33–46 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Lee, J. W. et al. Transcription-independent induction of ERBB1 through hypoxia-inducible factor 2A provides cardioprotection during ischemia and reperfusion. Anesthesiology 132, 763–780 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zuk, A. et al. Preclinical characterization of vadadustat (AKB-6548), an oral small molecule hypoxia-inducible factor prolyl-4-hydroxylase inhibitor, for the potential treatment of renal anemia. J. Pharmacol. Exp. Ther. 383, 11–24 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Li, J. et al. PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling. J. Exp. Med. 218, e20210008 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ruan, W. et al. The hypoxia-adenosine link during myocardial ischemia-reperfusion injury. Biomedicines 10, 1939 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Conrad, C. & Eltzschig, H. K. Disease mechanisms of perioperative organ injury. Anesth. Analg. 131, 1730–1750 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hara, K., Takahashi, N., Wakamatsu, A. & Caltabiano, S. Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects. Drug. Metab. Pharmacokinet. 30, 410–418 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Kansagra, K. A. et al. Phase I clinical study of ZYAN1, a novel prolyl-hydroxylase (PHD) inhibitor to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. Clin. Pharmacokinet. 57, 87–102 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Parmar, D. V. et al. Outcomes of desidustat treatment in people with anemia and chronic kidney disease: a phase 2 study. Am. J. Nephrol. 49, 470–478 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Bottcher, M. et al. First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia. Br. J. Clin. Pharmacol. 84, 1557–1565 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Beck, H. et al. Discovery of molidustat (BAY 85-3934): a small-molecule oral HIF-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of renal anemia. ChemMedChem 13, 988–1003 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Czock, D. & Keller, F. Clinical pharmacokinetics and pharmacodynamics of roxadustat. Clin. Pharmacokinet. 61, 347–362 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Provenzano, R. et al. Oral hypoxia–inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin. J. Am. Soc. Nephrol. 11, 982–991 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Shibata, T. et al. Evaluation of food and spherical carbon adsorbent effects on the pharmacokinetics of roxadustat in healthy nonelderly adult male japanese subjects. Clin. Pharmacol. Drug. Dev. 8, 304–313 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Dhillon, S. Roxadustat: first global approval. Drugs 79, 563–572 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Provenzano, R. et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6-to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am. J. Kidney Dis. 67, 912–924 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Chen, N., Hao, C. & Liu, B. A phase 3, randomized, open-label, active-controlled study of efficacy and safety of roxadustat for treatment of anemia in subjects with CKD on dialysis. J. Am. Soc. Nephrol. 29, B5 (2018).


    Google Scholar     

  • Besarab, A. et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J. Am. Soc. Nephrol. 27, 1225–1233 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Besarab, A. et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol. Dial. Transplant. 30, 1665–1673 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Chavan, A. et al. Effect of moderate hepatic impairment on the pharmacokinetics of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Clin. Pharmacol. Drug. Dev. 10, 950–958 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Nwogu, J. I. et al. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104, 2216–2221 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Xi, L., Taher, M., Yin, C., Salloum, F. & Kukreja, R. C. Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1α and AP-1 and iNOS signaling. Am. J. Physiol. Heart Circ. Physiol. 287, H2369–H2375 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Bao, W. et al. Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat. J. Cardiovasc. Pharmacol. 56, 147–155 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Signore, P. E. et al. A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats. PLoS ONE 16, e0255022 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Philipp, S. et al. Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats. Eur. J. Heart Fail. 8, 347–354 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Vogler, M. et al. Pre-and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult. Pflügers Arch. 467, 2141–2149 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Keränen, M. et al. Differential effects of pharmacological HIF preconditioning of donors versus recipients in rat cardiac allografts. Am. J. Transplant. 13, 600–610 (2013).

    Article 
    PubMed 

    Google Scholar     

  • Eckle, T., Köhler, D., Lehmann, R., El Kasmi, K. C. & Eltzschig, H. K. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 118, 166–175 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Natarajan, R., Salloum, F. N., Fisher, B. J., Kukreja, R. C. & Fowler, A. A. III Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ. Res. 98, 133–140 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Natarajan, R. et al. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. Am. J. Physiol. Heart Circ. Physiol. 293, H1571–H1580 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ockaili, R. et al. HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation. Am. J. Physiol. Heart Circ. Physiol. 289, H542–H548 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhao, H.-X. et al. Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1α. Basic Res. Cardiol. 105, 109–118 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Huang, M. et al. Short hairpin RNA interference therapy for ischemic heart disease. Circulation 118, S226–S233 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hyvärinen, J. et al. Hearts of hypoxia-inducible factor prolyl 4-hydroxylase-2 hypomorphic mice show protection against acute ischemia–reperfusion injury. J. Biol. Chem. 285, 13646–13657 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kerkelä, R. et al. Activation of hypoxia response in endothelial cells contributes to ischemic cardioprotection. Mol. Cell. Biol. 33, 3321–3329 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hölscher, M. et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J. Biol. Chem. 286, 11185–11194 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Adluri, R. S. et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1−/−) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice. Antioxid. Redox Signal. 15, 1789–1797 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Oriowo, B. et al. Targeted gene deletion of prolyl hydroxylase domain protein 3 triggers angiogenesis and preserves cardiac function by stabilizing hypoxia inducible factor 1 alpha following myocardial infarction. Curr. Pharm. Des. 20, 1305–1310 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Xie, L. et al. Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. J. Mol. Cell. Cardiol. 80, 156–165 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Deguchi, H. et al. Roxadustat markedly reduces myocardial ischemia reperfusion injury in mice. Circ. J. 84, 1028–1033 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhong, Z. et al. Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G823–G832 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Harnoss, J. M. et al. Prolyl hydroxylase inhibition mitigates allograft injury during liver transplant. Transplantation 106, e430–e440 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Harnoss, J. M. et al. Prolyl hydroxylase inhibition enhances liver regeneration without induction of tumor growth. Ann. Surg. 265, 782–791 (2017).

    Article 
    PubMed 

    Google Scholar     

  • Schneider, M. et al. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 138, 1143–1154 (2010). e1141–1142.

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Liu, J. et al. Double knockdown of PHD1 and Keap1 attenuated hypoxia-induced injuries in hepatocytes. Front. Physiol. 8, 291 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Mollenhauer, M. et al. Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy. Langenbecks Arch. Surg. 397, 1313–1322 (2012).

    Article 
    PubMed 

    Google Scholar     

  • Matsumoto, M. et al. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J. Am. Soc. Nephrol. 14, 1825–1832 (2003).

    Article 
    PubMed 

    Google Scholar     

  • Bernhardt, W. M. et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J. Am. Soc. Nephrol. 17, 1970–1978 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Xie, D. et al. Kidney-targeted delivery of prolyl hydroxylase domain protein 2 small interfering RNA with nanoparticles alleviated renal ischemia/reperfusion injury. J. Pharmacol. Exp. Ther. 378, 235–243 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Jamadarkhana, P. et al. Treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates ischemic acute kidney injury. Am. J. Nephrol. 36, 208–218 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Yang, Y. et al. Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury. Clin. Sci. 132, 825–838 (2018).

    Article 
    CAS 

    Google Scholar     

  • Ito, M. et al. Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage. Kidney Int. 97, 687–701 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Bernhardt, W. et al. Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc. Natl Acad. Sci. USA 106, 21276–21281 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Tambuwala, M. M. et al. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139, 2093–2101 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165.e151 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Tambuwala, M. M. et al. Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis. J. Control. Release 217, 221–227 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Manresa, M. C. et al. Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G1076–G1090 (2016).

    Article 
    PubMed 

    Google Scholar     

  • Halligan, D. N. et al. Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 317, G90–G97 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Marks, E. et al. Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis. Inflamm. Bowel Dis. 21, 267–275 (2015).

    Article 
    PubMed 

    Google Scholar     

  • Keely, S. et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol. 7, 114–123 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Van Welden, S. et al. Haematopoietic prolyl hydroxylase‐1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. J. Pathol. 241, 547–558 (2017).

    Article 
    PubMed 

    Google Scholar     

  • Okumura, C. Y. et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J. Mol. Med. 90, 1079–1089 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zinkernagel, A. S., Peyssonnaux, C., Johnson, R. S. & Nizet, V. Pharmacologic augmentation of hypoxia-inducible factor—1α with mimosine boosts the bactericidal capacity of phagocytes. J. Infect. Dis. 197, 214–217 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Hirota, S. A. et al. Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. Gastroenterology 139, 259–269.e253 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Schaible, B. et al. Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa. PLoS ONE 8, e56491 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hirai, K., Furusho, H., Hirota, K. & Sasaki, H. Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss. Int. J. Oral Sci. 10, 12 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wood, J. G. et al. Heme oxygenase‐1 upregulation following prolyl hydroxylase inhibition attenuates hypoxia‐induced microvascular inflammation. FASEB J. 23, 762.719 (2009).

    Article 

    Google Scholar     

  • Howard, J. M. et al. Upregulation of HIF-1 attenuates hemorrhagic shock/resuscitation-induced leukocyte adherence via an iNOS-dependent pathway. J. Am. Coll. Surg. 207, S39 (2008).

    Article 

    Google Scholar     

  • Figg, W. D. Jr. et al. Structural basis of prolyl hydroxylase domain inhibition by molidustat. ChemMedChem 16, 2082–2088 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wu, D. et al. Bidirectional modulation of HIF-2 activity through chemical ligands. Nat. Chem. Biol. 15, 367–376 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wallace, E. M. et al. A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 76, 5491–5500 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Haase, V. H. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial. Int. 21, S110–S124 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eckle, T. et al. Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J. 27, 3078–3089 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Aherne, C. M. et al. Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation. JCI Insight 3, e121521 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ruan, W. et al. Targeting myocardial equilibrative nucleoside transporter ENT1 provides cardioprotection by enhancing myeloid Adora2b signaling. JCI Insight 8, e166011 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wang, G. L. & Semenza, G. L. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl Acad. Sci. USA 90, 4304–4308 (1993).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Fraisl, P., Aragones, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat. Rev. Drug. Discov. 8, 139–152 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Aragones, J. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat. Genet. 40, 170–180 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ruan, W., Yuan, X. & Eltzschig, H. K. Circadian rhythm as a therapeutic target. Nat. Rev. Drug. Discov. 20, 287–307 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Semenza, G. L. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J. Bioenerg. Biomembr. 39, 231–234 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Carmeliet, P. et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Forsythe, J. A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol. 16, 4604–4613 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Eltzschig, H. K., Weissmuller, T., Mager, A. & Eckle, T. Nucleotide metabolism and cell-cell interactions. Methods Mol. Biol. 341, 73–87 (2006).

    CAS 
    PubMed 

    Google Scholar     

  • Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ahmad, A. et al. Adenosine A2A receptor is a unique angiogenic target of HIF-2alpha in pulmonary endothelial cells. Proc. Natl Acad. Sci. USA 106, 10684–10689 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Morote-Garcia, J. C., Rosenberger, P., Kuhlicke, J. & Eltzschig, H. K. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111, 5571–5580 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Yuan, X. et al. Alternative adenosine receptor activation: the netrin-Adora2b link. Front. Pharmacol. 13, 944994 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Heck-Swain, K. L. et al. Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1. Front. Cardiovasc. Med. 9, 970415 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ohta, A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol. 7, 109 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Choudhry, H. & Harris, A. L. Advances in hypoxia-inducible factor biology. Cell Metab. 27, 281–298 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

[ad_2]

Source link

  • Drug targeting in psychiatric disorders — how to overcome the loss in translation?

    [ad_1]

  • Howes, O. D. & Baxter, L. The drug treatment deadlock in psychiatry and the route forward. World Psychiatry 22, 2–3 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Marder, S. R., Laughren, T. & Romano, S. J. Why are innovative drugs failing in phase III? Am. J. Psychiatry 174, 829–831 (2017).

    Article 
    PubMed 

    Google Scholar     

  • Spark, D. L., Fornito, A., Langmead, C. J. & Stewart, G. D. Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics. Transl. Psychiatry 12, 147 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Tricklebank, M. D., Robbins, T. W., Simmons, C. & Wong, E. H. F. Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology. Psychopharmacology 238, 1417–1436 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Correll, C. U. et al. The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents. World Psychiatry 22, 48–74 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Krystal, A. D. et al. The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development. Nat. Rev. Drug. Discov. 18, 82–84 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Sarter, M. & Tricklebank, M. Revitalizing psychiatric drug discovery. Nat. Rev. Drug. Discov. 11, 423–424 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bakken, T. E. et al. Comparative cellular analysis of motor cortex in human, marmoset and mouse. Nature 598, 111–119 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yao, Z. et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184, 3222–3241.e26 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Gouwens, N. W. et al. Integrated morphoelectric and transcriptomic classification of cortical GABAergic cells. Cell 183, 935–953.e19 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Scala, F. et al. Phenotypic variation of transcriptomic cell types in mouse motor cortex. Nature 598, 144–150 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Clark, I. C. et al. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science 372, eabf1230 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Albert, P. R. & Le François, B. Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Front. Neurosci. 4, 35 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Negi, S. K. & Guda, C. Global gene expression profiling of healthy human brain and its application in studying neurological disorders. Sci. Rep. 7, 897 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Sjöstedt, E. et al. An atlas of the protein-coding genes in the human, pig, and mouse brain. Science 367, eaay5947 (2020).

    Article 
    PubMed 

    Google Scholar     

  • Siletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. Science 382, eadd7046 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Sinkeviciute, I. et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. NPJ Schizophr. 4, 22 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Schmidt, E. R. E. et al. A human-specific modifier of cortical connectivity and circuit function. Nature 599, 640–644 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Defelipe, J. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity. Front. Neuroanat. 5, 29 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Sousa, A. M. M., Meyer, K. A., Santpere, G., Gulden, F. O. & Sestan, N. Evolution of the human nervous system function, structure, and development. Cell 170, 226–247 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Franjic, D. et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110, 452–469.e14 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Jorstad, N. L. et al. Transcriptomic cytoarchitecture reveals principles of human neocortex organization. Science 382, eadf6812 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Agarwal, D. et al. A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nat. Commun. 11, 4182 (2020).

    Article 

    Google Scholar     

  • Tran, M. N. et al. Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain. Neuron 109, 3088–3103.e5 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Sorrells, S. F. et al. Immature excitatory neurons develop during adolescence in the human amygdala. Nat. Commun. 10, 2748 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Winkler, E. A. et al. A single-cell atlas of the normal and malformed human brain vasculature. Science 375, eabi7377 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Batiuk, M. Y. et al. Upper cortical layer-driven network impairment in schizophrenia. Sci. Adv. 8, eabn8367 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Haney, J. R. et al. Broad transcriptomic dysregulation across the cerebral cortex in ASD. Nature 611, 532–539 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Nagy, C. et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat. Neurosci. 23, 771–781 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Howes, O. D., Thase, M. E. & Pillinger, T. Treatment resistance in psychiatry: state of the art and new directions. Mol. Psychiatry 27, 58–72 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Planert, H. et al. Cellular and synaptic diversity of layer 2-3 pyramidal neurons in human individuals. Preprint at https://doi.org/10.1101/2021.11.08.467668 (2023).

  • Johansen, N. et al. Interindividual variation in human cortical cell type abundance and expression. Science 382, eadf2359 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Asp, M., Bergenstråhle, J. & Lundeberg, J. Spatially resolved transcriptomes—next generation tools for tissue exploration. BioEssays 42, 1900221 (2020).

    Article 

    Google Scholar     

  • Fang, R. et al. Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH. Science 377, 56–62 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Pfisterer, U. et al. Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis. Nat. Commun. 11, 5038 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Petukhov, V. et al. Case-control analysis of single-cell RNA-seq studies. Preprint at https://doi.org/10.1101/2022.03.15.484475 (2022).

  • Fischer, D. S., Schaar, A. C. & Theis, F. J. Modeling intercellular communication in tissues using spatial graphs of cells. Nat. Biotechnol. 41, 332–336 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Campagnola, L. et al. Local connectivity and synaptic dynamics in mouse and human neocortex. Science 375, eabj5861 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Berg, J. et al. Human neocortical expansion involves glutamatergic neuron diversification. Nature 598, 151–158 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kalmbach, B. E. et al. Signature morpho-electric, transcriptomic, and dendritic properties of human layer 5 neocortical pyramidal neurons. Neuron 109, 2914–2927.e5 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Lee, B. R. et al. Signature morphoelectric properties of diverse GABAergic interneurons in the human neocortex. Science 382, eadf6484 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Artigas, F. et al. Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS. Nat. Rev. Drug. Discov. 16, 1–2 (2016).

    Article 
    PubMed 

    Google Scholar     

  • Krystal, A. D. et al. A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia. Nat. Med. 26, 760–768 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Stuart, T. & Satija, R. Integrative single-cell analysis. Nat. Rev. Genet. 20, 257–272 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Perkel, J. M. Single-cell analysis enters the multiomics age. Nature 595, 614–616 (2021).

    Article 
    CAS 

    Google Scholar     

  • Kharchenko, P. V. The triumphs and limitations of computational methods for scRNA-seq. Nat. Methods 18, 723–732 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • No authors listed.Method of the Year 2019: single-cell multimodal omics. Nat. Methods 17, 1 (2020).

    Article 

    Google Scholar     

  • Yuste, R. et al. A community-based transcriptomics classification and nomenclature of neocortical cell types. Nat. Neurosci. 23, 1456–1468 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bhaduri, A. et al. An atlas of cortical arealization identifies dynamic molecular signatures. Nature 598, 200–204 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Callaway, E. M. et al. A multimodal cell census and atlas of the mammalian primary motor cortex. Nature 598, 86–102 (2021).

    Article 
    CAS 

    Google Scholar     

  • Ziffra, R. S. et al. Single-cell epigenomics reveals mechanisms of human cortical development. Nature 598, 205–213 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhong, S. et al. Decoding the development of the human hippocampus. Nature 577, 531–536 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Regev, A. et al. The human cell atlas. eLife 6, e27041 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Herring, C. A. et al. Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution. Cell 185, 4428–4447.e28 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yang, A. C. et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 595, 565–571 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ji, A. L. et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell 182, 497–514.e22 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Chen, W. T. et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 182, 976–991.e19 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Li, Y. E. et al. An atlas of gene regulatory elements in adult mouse cerebrum. Nature 598, 129–136 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kozareva, V. et al. A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types. Nature 598, 214–219 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zhang, M. et al. Spatially resolved cell atlas of the mouse primary motor cortex by MERFISH. Nature 598, 137–143 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Di Bella, D. J. et al. Molecular logic of cellular diversification in the mouse cerebral cortex. Nature 595, 554–559 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • La Manno, G. et al. Molecular architecture of the developing mouse brain. Nature 596, 92–96 (2021).

    Article 
    PubMed 

    Google Scholar     

  • Romanov, R. A. et al. Molecular design of hypothalamus development. Nature 582, 246–252 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Lui, J. H. et al. Differential encoding in prefrontal cortex projection neuron classes across cognitive tasks. Cell 184, 489–506.e26 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Malwade, S. et al. Identification of vulnerable interneuron subtypes in 15q13.3 microdeletion syndrome using single-cell transcriptomics. Biol. Psychiatry 91, 727–739 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Gouwens, N. W. et al. Classification of electrophysiological and morphological neuron types in the mouse visual cortex. Nat. Neurosci. 22, 1182–1195 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Joglekar, A. et al. A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain. Nat. Commun. 12, 463 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bandler, R. C. et al. Single-cell delineation of lineage and genetic identity in the mouse brain. Nature 601, 404–409 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Peng, H. et al. Morphological diversity of single neurons in molecularly defined cell types. Nature 598, 174–181 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Liu, H. et al. DNA methylation atlas of the mouse brain at single-cell resolution. Nature 598, 120–128 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yao, Z. et al. A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Nature 598, 103–110 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Krienen, F. M. et al. Innovations present in the primate interneuron repertoire. Nature 586, 262–269 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bakken, T. E. et al. Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans. eLife 10, e64875 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Borm, L. E. et al. Scalable in situ single-cell profiling by electrophoretic capture of mRNA using EEL FISH. Nat. Biotechnol. 41, 222–231 (2022).

    PubMed 
    PubMed Central 

    Google Scholar     

  • Yu, Y. et al. Interneuron origin and molecular diversity in the human fetal brain. Nat. Neurosci. 24, 1745–1756 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Shi, Y. et al. Mouse and human share conserved transcriptional programs for interneuron development. Science 374, eabj6641 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Eze, U. C., Bhaduri, A., Haeussler, M., Nowakowski, T. J. & Kriegstein, A. R. Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia. Nat. Neurosci. 24, 584–594 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Close, J. L. et al. Single-cell profiling of an in vitro model of human interneuron development reveals temporal dynamics of cell type production and maturation. Neuron 93, 1035–1048 e5 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • La Manno, G. et al. Molecular diversity of midbrain development in mouse, human, and stem cells. Cell 167, 566–580.e19 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Samudyata et al. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol. Psychiatry 27, 3939–3950 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Yang, S. M., Michel, K., Jokhi, V., Nedivi, E. & Arlotta, P. Neuron class-specific responses govern adaptive myelin remodeling in the neocortex. Science 370, eabd2109 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Hao, Z.-Z. et al. Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations. Nat. Neurosci. 25, 805–817 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Lei, Y. et al. Spatially resolved gene regulatory and disease-related vulnerability map of the adult macaque cortex. Nat. Commun. 13, 1–20 (2022).

    Article 

    Google Scholar     

  • Khodosevich, K. & Sellgren, C. M. Neurodevelopmental disorders—high-resolution rethinking of disease modeling. Mol. Psychiatry 28, 34–43 (2023).

    Article 
    PubMed 

    Google Scholar     

  • Liu, Y., Beyer, A. & Aebersold, R. On the dependency of cellular protein levels on mRNA abundance. Cell 165, 535–550 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Derks, J. et al. Increasing the throughput of sensitive proteomics by plexDIA. Nat. Biotechnol. 41, 50–59 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Huffman, R. G. et al. Prioritized mass spectrometry increases the depth, sensitivity and data completeness of single-cell proteomics. Nat. Methods 20, 714–722 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Specht, H. et al. Single-cell proteomic and transcriptomic analysis of macrophage heterogeneity using SCoPE2. Genome Biol. 22, 50 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Mohan, H. et al. Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex. Cereb. Cortex 25, 4839–4853 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Loomba, S. et al. Connectomic comparison of mouse and human cortex. Science 377, eabo0924 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhu, F., Nair, R. R., Fisher, E. M. C. & Cunningham, T. J. Humanising the mouse genome piece by piece. Nat. Commun. 10, 1845 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Normand, R. et al. Found in translation: a machine learning model for mouse-to-human inference. Nat. Methods 15, 1067–1073 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Drysdale, A. T. et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat. Med. 23, 28–38 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal and circuit excitability in fragile X syndrome. Neuron 87, 699–715 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Oyama, K. & Sakatani, K. Machine learning-based assessment of cognitive impairment using time-resolved near-infrared spectroscopy and basic blood test. Front. Neurol. 12, 2641 (2022).

    Article 

    Google Scholar     

  • Wu, Y. E., Pan, L., Zuo, Y., Li, X. & Hong, W. Detecting activated cell populations using single-cell RNA-seq. Neuron 96, 313–329.e6 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Lacar, B. et al. Nuclear RNA-seq of single neurons reveals molecular signatures of activation. Nat. Commun. 7, 11022 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Clancy, B., Darlington, R. B. & Finlay, B. L. Translating developmental time across mammalian species. Neuroscience 105, 7–17 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Howard, D. M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 22, 343–352 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wu, J. et al. Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors. Nat. Neurosci. 26, 1352–1364 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Piñero, J. et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 45, D833–D839 (2017).

    Article 
    PubMed 

    Google Scholar     

  • Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475–480 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhang, M. J. et al. Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data. Nat. Genet. 54, 1572–1580 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Vasistha, N. A. & Khodosevich, K. The impact of (ab)normal maternal environment on cortical development. Prog. Neurobiol. 202, 102054 (2021).

    Article 
    PubMed 

    Google Scholar     

  • Wang, Y. Y. et al. CeDR Atlas: a knowledgebase of cellular drug response. Nucleic Acids Res. 50, D1164–D1171 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Schoof, E. M. et al. Quantitative single-cell proteomics as a tool to characterize cellular hierarchies. Nat. Commun. 12, 3341 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Karlsson, M. et al. A single–cell type transcriptomics map of human tissues. Sci. Adv. 7, eabh2169 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Petukhov, V. et al. Cell segmentation in imaging-based spatial transcriptomics. Nat. Biotechnol. 40, 345–354 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Moffitt, J. R. et al. Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Ball, G. et al. Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain. PLoS Biol. 18, e3000976 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Dachet, F. et al. Selective time-dependent changes in activity and cell-specific gene expression in human postmortem brain. Sci. Rep. 11, 6078 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Kaar, S. J., Natesan, S., McCutcheon, R. & Howes, O. D. Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 172, 107704 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Lobo, M. C., Whitehurst, T. S., Kaar, S. J. & Howes, O. D. New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics. Neurosci. Biobehav. Rev. 132, 324–361 (2022).

    Article 
    PubMed 

    Google Scholar     

  • Mizuno, Y., McCutcheon, R. A., Brugger, S. P. & Howes, O. D. Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis. Neuropsychopharmacology 45, 622–631 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Lee, B. et al. Signature morphoelectric properties of diverse GABAergic interneurons in the human neocortex. Science 382, eadf6484 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Molnár, G. et al. Complex events initiated by individual spikes in the human cerebral cortex. PLOS Biol. 6, e222 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Svensson, V., Vento-Tormo, R. & Teichmann, S. A. Exponential scaling of single-cell RNA-seq in the past decade. Nat. Protoc. 13, 599–604 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Hagemann-Jensen, M. et al. Single-cell RNA counting at allele and isoform resolution using Smart-seq3. Nat. Biotechnol. 38, 708–714 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Darmanis, S. et al. A survey of human brain transcriptome diversity at the single cell level. Proc. Natl Acad. Sci. USA 112, 7285–7290 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Bakken, T. E. et al. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types. PLoS ONE 13, e0209648 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Cadwell, C. R. et al. Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat. Biotechnol. 34, 199–203 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Wang, X. et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, eaat5691 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Moses, L. & Pachter, L. Museum of spatial transcriptomics. Nat. Methods 19, 534–546 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Eng, C.-H. L. et al. Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH+. Nature 568, 235–239 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Changeux, J. P. The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily. J. Biol. Chem. 287, 40207–40215 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Broide, R. S., Winzer-Serhan, U. H., Chen, Y. & Leslie, F. M. Distribution of α7 nicotinic acetylcholine receptor subunit mRNA in the developing mouse. Front. Neuroanat. 13, 76 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Wu, J. et al. Heteromeric α7β2 nicotinic acetylcholine receptors in the brain. Trends Pharmacol. Sci. 37, 562–574 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Dineley, K. T., Pandya, A. A. & Yakel, J. L. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol. Sci. 36, 96–108 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Leonard, S. et al. Association of promoter variants in the α7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch. Gen. Psychiatry 59, 1085–1096 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Stephens, S. H. et al. Association of the 5′-upstream regulatory region of the α7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. Schizophr. Res. 109, 102–112 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Terry, A. V. & Callahan, P. M. α7 Nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: update on animal and clinical studies and strategies for the future. Neuropharmacology 170, 108053 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Tregellas, J. R. & Wylie, K. P. Alpha7 nicotinic receptors as therapeutic targets in schizophrenia. Nicotine Tob. Res. 21, 349–356 (2019).

    Article 
    PubMed 

    Google Scholar     

  • Nichols, D. E. & Nichols, C. D. Serotonin receptors. Chem. Rev. 108, 1614–1641 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Berger, M., Gray, J. A. & Roth, B. L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Meltzer, H. Y. & Massey, B. W. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr. Opin. Pharmacol. 11, 59–67 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Zhang, G. & Stackman, R. W. The role of serotonin 5-HT2A receptors in memory and cognition. Front. Pharmacol. 6, 225 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar     

  • Miyamoto, S., Miyake, N., Jarskog, L. F., Fleischhacker, W. W. & Lieberman, J. A. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatry 17, 1206–1227 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Ebdrup, B. H., Rasmussen, H., Arnt, J. & Glenthøj, B. Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin. Investig. Drugs 20, 1211–1223 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Pinard, E., Borroni, E., Koerner, A., Umbricht, D. & Alberati, D. Glycine transporter type I (GlyT1) inhibitor, bitopertin: a journey from lab to patient. Chimia 72, 477 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar     

  • Bugarski-Kirola, D. et al. Bitopertin in negative symptoms of schizophrenia—results from the phase III flashlyte and daylyte studies. Biol. Psychiatry 82, 8–16 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar     

    • [ad_2]

    Source link