bims-hypoxi Biomed News
on Hypoxia and HIF1-alpha
Issue of 2021‒06‒27
fourteen papers selected by
Ashish Kaul
University of Tsukuba
  1. How could perfluorocarbon affect cytokine storm and angiogenesis in coronavirus disease 2019 (COVID-19): role of hypoxia-inducible factor 1α.
  2. Deferoxamine enhances the migration of dental pulp cells via hypoxia-inducible factor 1α.
  3. HIF-1α aggravated traumatic brain injury by NLRP3 inflammasome-mediated pyroptosis and activation of microglia.
  4. Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor.
  5. ORAI3 contributes to hypoxia-inducible factor 1/2α-sensitive colon cell migration.
  6. Stabilization of Hypoxia-Inducible Factor Promotes Antimicrobial Activity of Human Macrophages Against Mycobacterium tuberculosis.
  7. Sohlh2 suppresses angiogenesis by downregulating HIF-1α expression in breast cancer.
  8. Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia-inducible factor-1α in colorectal cancer.
  9. HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.
  10. Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.
  11. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions.
  12. Nobiletin alleviates the hypoxia/reoxygenation-induced damage in myocardial cells by modulating the miR-433/SIRT1 axis.
  13. The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.
  14. Immunohistochemistry in postmortem diagnosis of acute cerebral hypoxia and ischemia: A systematic review.
  1. Inflamm Res. 2021 Jun 26.
    How could perfluorocarbon affect cytokine storm and angiogenesis in coronavirus disease 2019 (COVID-19): role of hypoxia-inducible factor 1α.
    Narges Moasefi, Mehdi Fouladi, Amir Hossein Norooznezhad, Reza Yarani, Adibeh Rahmani, Kamran Mansouri.
      Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), and IL-6 which are key elements of cytokine storm are by nuclear factor κβ (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches.
    Keywords:  Cytokine storm; HIF-1α; Hypoxia; Inflammation; Perfluorocarbon
    DOI:  https://doi.org/10.1007/s00011-021-01469-8
  2. Am J Transl Res. 2021 ;13(5): 4780-4787
    Deferoxamine enhances the migration of dental pulp cells via hypoxia-inducible factor 1α.
    Rong Du, Junjun Zhao, Yang Wen, Yaqin Zhu, Long Jiang.
      In previous studies, we found that deferoxamine (DFO) improved the migration of dental pulp cells (DPCs). The present study aimed to determine whether the effects of DFO on the migration of DPCs were regulated via hypoxia-inducible factor 1α (HIF-1α). Recombinant adenovirus vectors carrying short hairpin RNA (shRNA) targeting the human HIF-1α gene (pAd-GFP-shRNA-HIF-1α) and green fluorescent protein (GFP) were constructed. The expression of HIF-1α was inhibited by pAd-GFP-shRNA-HIF-1α at messenger RNA and protein levels. The secretion of stromal cell-derived factor 1α (SDF-1α) or vascular endothelial growth factor (VEGF) in DPCs treated with 10 μM DFO was higher than that in the control condition. The migration of DPCs was enhanced by 10 μM DFO. However, the effects of DFO on DPCs were partially reversed by silencing the HIF-1α gene in enzyme-linked immunosorbent assay or migration assay. Cumulatively, we conclude that DFO upregulated the secretion of SDF-1α or VEGF in DPCs and improved the migration of DPCs through HIF-1α.
    Keywords:  Deferoxamine; dental pulp cells; hypoxia-inducible factor 1α; migration
  3. J Chem Neuroanat. 2021 Jun 21. pii: S0891-0618(21)00077-6. [Epub ahead of print] 101994
    HIF-1α aggravated traumatic brain injury by NLRP3 inflammasome-mediated pyroptosis and activation of microglia.
    Dong Yuan, ShuangXian Guan, Zhen Wang, HongLiang Ni, DongLiang Ding, WenBo Xu, GuoMin Li.
      Hypoxia inducible factor 1 alpha (HIF-1α) is involved in regulating the biological functions of neuronal death after traumatic brain injury (TBI), and attaches importance in the inflammatory response, but its potential mechanism is still unknown. Our study aimed to explore the regulatory mechanism between HIF-1α and NLRP3 inflammasome after TBI. Male mice underwent controlled cortical impact (CCI) or sham-operated procedures. Brain water content and blood-brain barrier permeability were measured at the indicated time after TBI. The behavioral performance, ELISA, immunofluorescence, and western blot analysis were used to determine whether HIF-1α specifically targeted TBI-induced pyroptosis. We discovered that TBI-induced brain injury caused by external mechanical forces is characterized by edema and blood-brain barrier disorder, and the release of IL-1β, IL-18, and LDH and upregulation of HIF-1α expression, reaching the peak on the third day post-TBI. In addition, HIF-1α accumulated NLRP3 inflammasome-mediated pyroptosis and activation of microglia. The protein expressions of NLRP3, GSDMD, GSDMD-N, pro-caspase 1, and cleaved caspase 1 were markedly increased in the injured cortex, which were restored to normal levels by the interference of HIF-1α. The inactivation of HIF-1α conferred neuroprotection and alleviated brain injury after TBI. HIF-1α was implicated in TBI-induced brain injury, aggravated NLRP3 inflammasome -mediated pyroptosis, and the activation of microglia, which provided a potential target for treating TBI.
    Keywords:  HIF-1α; Microglia; NLRP3 inflammasome; Pyroptosis; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.jchemneu.2021.101994
  4. Oncogene. 2021 Jun 21.
    Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor.
    Yan Liu, Marie V Nelson, Christopher Bailey, Peng Zhang, Pan Zheng, Jeffrey S Dome, Yang Liu, Yin Wang.
      For patients with anaplastic Wilms tumor (WiT), metastasis and recurrence are common, and prognosis is generally poor. Novel therapies are needed to improve outcomes for patients with this high-risk WiT. A potential contributor to WiT development is constitutive activation of AKT by insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) signaling pathway, but the complete underlying mechanism remains unclear. Here, we demonstrate that the hypoxia-inducible factor 1α (HIF-1α)-IGF binding protein 2 (IGFBP2) axis and the tumor-specific IGF1A are key players for constitutive activation of IGF1-AKT signaling leading to the tumor malignancy. HIF-1α and IGFBP2 are highly expressed in a majority of WiT patient samples. Deficiency of either HIF-1α or IGFBP2 or IGF1 in the tumor cells significantly impairs tumor growth and nearly abrogates metastasis in xenografted mice. Pharmacologic targeting of HIF-1α by echinomycin delivered via nanoliposomes can efficiently restrain growth and metastasis of patient-derived relapsed anaplastic WiT xenografts. Liposomal echinomycin is more potent and effective in inhibiting WiT growth than vincristine in an anaplastic WiT mouse model, and eliminates metastasis by suppressing HIF-1α targets and the HIF-1α-IGFBP2 axis, which governs IGF1-AKT signaling.
    DOI:  https://doi.org/10.1038/s41388-021-01907-1
  5. Physiol Int. 2021 Jun 22.
    ORAI3 contributes to hypoxia-inducible factor 1/2α-sensitive colon cell migration.
    D Zhu, R He, W Yu, C Li, H Cheng, B Zhu, J Yan.
      Background: Hypoxia is a pivotal initiator of tumor angiogenesis and growth through the stabilization of hypoxia-inducible factors (HIFs). This study set out to examine the involvement of HIF-1α and HIF-2α in colon cancer and ascertained whether ORAI3 was involved in the pathway.Materials and methods: Patients and murine models as well as human colorectal adenocarcinoma tumor (CW2) cells were included to examine the levels of ORAI1/3 and HIF-1/2α levels. Calcium imaging was utilized to ascertain the activity of calcium channel. Scratch assay was used to assess the migration capacity of the cells.
    Results: Tumors from murine colon cancer xenograft models and patients with colon cancer displayed high ORAI1/3 and HIF-1/2α levels. Hypoxia treatment, mimicking the tumor microenvironment in vitro, increased ORAI1/3 and HIF-1/2α expression as well as store-operated Ca2+ entry (SOCE). Of note is that HIF-1/2α silencing decreased SOCE, and HIF-1/2α overexpression facilitated SOCE. Furthermore, ORAI3 rather than ORAI1 expression was inhibited by HIF-1/2α silencing while increased by ML228. Luciferase assay also confirmed that ORAI3 was elevated in the presence of ML228, indicating the linkage between HIF-1/2α and ORAI3. Additionally, colony-forming potential and cell migration capacity were decreased in siHIF-1α and siHIF-2α as well as siORAI3 cells, and the facilitating effect of ML228 on cell migration and colony-forming potential was also decreased in siORAI3 CW-2 cells, which points out the importance of ORAI3 in HIF1/2α pathway.
    Conclusion: Our findings allow to conclude that both HIF-1α and HIF-2α facilitate ORAI3 expression, hence enhancing colon cancer progression.
    Keywords:  HIF1/2α; ORAI3; colon cancer; store-operated Ca2+ entry
    DOI:  https://doi.org/10.1556/2060.2021.00137
  6. Front Immunol. 2021 ;12 678354
    Stabilization of Hypoxia-Inducible Factor Promotes Antimicrobial Activity of Human Macrophages Against Mycobacterium tuberculosis.
    Sebastian F Zenk, Sebastian Hauck, Daniel Mayer, Mark Grieshober, Steffen Stenger.
      Hypoxia-inducible factor (HIF) is a key oxygen sensor that controls gene expression patterns to adapt cellular metabolism to hypoxia. Pharmacological inhibition of prolyl-hydroxylases stabilizes HIFs and mimics hypoxia, leading to increased expression of more than 300 genes. Whether the genetic program initialized by HIFs affects immune responses against microbial pathogens, is not well studied. Recently we showed that hypoxia enhances antimicrobial activity against Mycobacterium tuberculosis (Mtb) in human macrophages. The objective of this study was to evaluate whether the oxygen sensor HIF is involved in hypoxia-mediated antimycobacterial activity. Treatment of Mtb-infected macrophages with the prolyl-hydroxylase inhibitor Molidustat reduced the release of TNFα and IL-10, two key cytokines involved in the immune response in tuberculosis. Molidustat also interferes with the p38 MAP kinase pathway. HIF-stabilization by Molidustat also induced the upregulation of the Vitamin D receptor and human β defensin 2, which define an antimicrobial effector pathway in human macrophages. Consequently, these immunological effects resulted in reduced proliferation of virulent Mtb in human macrophages. Therefore, HIFs may be attractive new candidates for host-directed therapies against infectious diseases caused by intracellular bacteria, including tuberculosis.
    Keywords:  HIF; Molidustat; human; hypoxia; macrophages; tuberculosis
    DOI:  https://doi.org/10.3389/fimmu.2021.678354
  7. Mol Cancer Res. 2021 Jun 22. pii: molcanres.0771.2020. [Epub ahead of print]
    Sohlh2 suppresses angiogenesis by downregulating HIF-1α expression in breast cancer.
    Weiwei Cui, Yunling Xiao, Ruihong Zhang, Na Zhao, Xianghong Zhang, Fuwu Wang, Yang Liu, Xiaoli Zhang, Jing Hao.
      SOHLH2 has been demonstrated the downregulation in various cancers and the involvement in tumor growth and metastasis. However, the function of SOHLH2 on tumor angiogenesis and the underlying molecular mechanisms have not been interrogated. IHC staining results revealed that SOHLH2 was negatively associated with microvessel density (MVD), tumor size, histology grade and metastasis. Overexpression of SOHLH2 inhibited the angiogenic behavior of HUVECs by a tumor cell-mediated paracrine signal, whilst knockdown of SOHLH2 promoted HUVEC angiogenic behavior. Ectopic SOHLH2 expression remarkably suppressed tumor growth and MVD in xenograft tumors, downregulated the expression of HIF-1α-mediated proangiogenic genes in vivo and in vitro, whilst knockdown of SOHLH2 had an opposite result. Furthermore, we found that upregulation of HIF-1α reversed SOHLH2-induced suppression of breast cancer angiogenesis, while KC7F2, the inhibitor of HIF-1α, could attenuate the promotion of angiogenesis by SOHLH2-silencing. Using CHIP and luciferase reporter assays, we validated that SOHLH2 could directly bind to HIF-1α promoter and repress its transcriptional activity. Collectively, SOHLH2 suppresses breast cancer angiogenesis by downregulating HIF-1α transcription and may be a potential biomarker for anti-angiogenesis therapy. Implications: SOHLH2 directly represses HIF-1α mediated angiogenesis and serves as an important inhibitor of angiogenesis in breast cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0771
  8. Mol Oncol. 2021 Jun 23.
    Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia-inducible factor-1α in colorectal cancer.
    Chao Fang, Lei Dai, Cun Wang, Chuanwen Fan, Yongyang Yu, Lie Yang, Hongxin Deng, Zongguang Zhou.
      Distant metastasis is a major cause of death in patients with colorectal cancer (CRC), but the management of advanced and metastatic CRC still remains problematic due to the distinct molecular alterations during tumor progression. Tumor angiogenesis is a key step in tumor growth, invasion, and metastasis. However, the signaling pathways involved in angiogenesis are poorly understood. The results of the present study showed that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues and higher expression of SCG2 was correlated with longer disease-free survival and overall survival of CRC patients. The results of an animal study showed that ectopic expression of SCG2 significantly inhibited CRC tumor growth by disrupting angiogenesis. Furthermore, the inhibition of expression of vascular endothelial growth factor (VEGF) by SCG2 and rescue of VEGF efficiently blocked SCG2-induced inhibition of angiogenesis. Investigations into the underlying mechanism suggested that SCG2 promoted degradation of hypoxia-inducible factor (HIF)-1α by interacting with the von Hippel-Lindau (VHL) tumor suppressor in CRC cells. Blocking of degradation of HIF-1α efficiently attenuated the SCG2-mediated decrease in expression of VEGF in CRC cells. Collectively, these results demonstrated that treatment with SCG2 efficiently inhibited CRC tumor growth by disrupting the activities of HIF-1α/VEGF, thereby clarifying the anti-tumor and anti-angiogenesis roles of SCG2 in CRC, while providing a novel therapeutic target and a potential prognostic marker of disease progression.
    Keywords:  Angiogenesis; Colorectal cancer; Hypoxia-inducible factor; Secretogranin II; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1002/1878-0261.13044
  9. Theranostics. 2021 ;11(15): 7337-7359
    HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.
    Xinyan Li, Mengshen Wang, Su Li, Yuqiong Chen, Mozhi Wang, Zhonghua Wu, Xiangyu Sun, Litong Yao, Haoran Dong, Yongxi Song, Yingying Xu.
      Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.
    Keywords:  Breast cancer; Hypoxia; Metastasis; Mitochondrial ribosome; Mitophagy
    DOI:  https://doi.org/10.7150/thno.57804
  10. Oncogene. 2021 Jun 21.
    Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.
    Audrey Lequeux, Muhammad Zaeem Noman, Malina Xiao, Kris Van Moer, Meriem Hasmim, Alice Benoit, Manon Bosseler, Elodie Viry, Tsolere Arakelian, Guy Berchem, Salem Chouaib, Bassam Janji.
      Hypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.
    DOI:  https://doi.org/10.1038/s41388-021-01846-x
  11. Trends Immunol. 2021 Jul;pii: S1471-4906(21)00099-5. [Epub ahead of print]42(7): 604-621
    Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions.
    Laís P Pral, José L Fachi, Renan O Corrêa, Marco Colonna, Marco A R Vinolo.
      Oxygen (O2) availability is a key factor regulating microbiota composition and the homeostatic function of cells in the intestinal mucosa of vertebrates. Microbiota-derived metabolites increase O2 consumption by intestinal epithelial cells (IECs), reducing its availability in the gut and leading to hypoxia. This physiological hypoxia activates cellular hypoxic sensors that adapt the metabolism and function of IECs and mucosa-resident cells, such as type-3 innate lymphoid cells (ILC3s). In this review, we discuss recent evidence suggesting that the intricate and multidirectional interactions among the microbiota, hypoxia/hypoxic sensors, and mammalian host cells (IECs and ILC3s) determine how the intestinal barrier and host-microbiota-pathogens connections are molded. Understanding these interactions might provide new treatment possibilities for dysbiosis, as well as certain inflammatory and infectious diseases.
    Keywords:  innate lymphoid cells; intestinal epithelial cells; microbiota; short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.it.2021.05.004
  12. J Food Biochem. 2021 Jun 26. e13844
    Nobiletin alleviates the hypoxia/reoxygenation-induced damage in myocardial cells by modulating the miR-433/SIRT1 axis.
    Shuxian Chen, Ting Sun, Xulin Li.
      The effect of nobiletin (NOB) on myocardial ischemia-reperfusion injury and the underlying mechanism were investigated in this study. Myocardial cells (H9c2) were cultured under hypoxia/reoxygenation (H/R) condition, followed by the treatment with NOB. Next, miR-433 overexpression or silencing was performed in H9c2 cells to further assess the efficacy of NOB. Cell viability and apoptosis were determined using MTT assays and flow cytometry, respectively. Our results demonstrated that NOB treatment led to the upregulation of SIRT1 and inhibited miR-433 expression in H9c2 cells. In addition, we found that miR-433 targeted and inhibited the expression of SIRT1. NOB treatment promoted cell viability and alleviated apoptosis in H9c2 cells. Thus, our findings indicate that NOB may relieve H/R-induced damage in H9c2 cells by modulating the miR-433/SIRT1 axis. PRACTICAL APPLICATIONS: MiR-433 targeted and inhibited the expression of SIRT1. NOB treatment promoted cell viability and alleviated apoptosis in H9c2 cells. Thus, our findings indicate that NOB could effectively relieve H/R-induced damage in H9c2 cells by modulating the miR-433/SIRT1 axis, suggesting that nobiletin may be a potential drug for the treatment of myocardial ischemia-reperfusion injury. Furthermore, this study also identified another potential therapeutic target, miR-433, for the treatment of myocardial ischemia-reperfusion injury.
    Keywords:  H9c2 cells; SIRT1; miR-433; myocardial ischemia reperfusion injury; nobiletin
    DOI:  https://doi.org/10.1111/jfbc.13844
  13. Nat Genet. 2021 Jun 21.
    The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.
    Brian M Ortmann, Natalie Burrows, Ian T Lobb, Esther Arnaiz, Niek Wit, Peter S J Bailey, Louise H Jordon, Olivia Lombardi, Ana Peñalver, James McCaffrey, Rachel Seear, David R Mole, Peter J Ratcliffe, Patrick H Maxwell, James A Nathan.
      Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.
    DOI:  https://doi.org/10.1038/s41588-021-00887-y
  14. Medicine (Baltimore). 2021 Jun 25. 100(25): e26486
    Immunohistochemistry in postmortem diagnosis of acute cerebral hypoxia and ischemia: A systematic review.
    Rosario Barranco, Alessandro Bonsignore, Francesco Ventura.
      BACKGROUND: : Discovery of evidence of acute brain ischemia or hypoxia and its differentiation from agonal hypoxia represents a task of interest but extremely difficult in forensic neuropathology. Generally, more than 50% of forensic autopsies indicate evidence of brain induced functional arrest of the organ system, which can be the result of a hypoxic/ischemic brain event. Even if the brain is the target organ of hypoxic/ischemic damage, at present, there are no specific neuropathological (macroscopic and histological) findings of hypoxic damage (such as in drowning, hanging, intoxication with carbon monoxide) or acute ischemia. In fact, the first histological signs appear after at least 4 to 6 hours. Numerous authors have pointed out how an immunohistochemical analysis could help diagnose acute cerebral hypoxia/ischemia.Data sources: This review was based on articles published in PubMed and Scopus databases in the past 25 years, with the following keywords "immunohistochemical markers," "acute cerebral ischemia," "ischemic or hypoxic brain damage," and "acute cerebral hypoxia".OBJECTIVES: : Original articles and reviews on this topic were selected. The purpose of this review is to analyze and summarize the markers studied so far and to consider the limits of immunohistochemistry that exist to date in this specific field of forensic pathology.
    RESULTS: : We identified 13 markers that had been examined (in previous studies) for this purpose. In our opinion, it is difficult to identify reliable and confirmed biomarkers from multiple studies in order to support a postmortem diagnosis of acute cerebral hypoxia/ischemia. Microtubule-associated protein 2 (MAP2) is the most researched marker in the literature and the results obtained have proven to be quite useful.
    CONCLUSION: Immunohistochemistry has provided interesting and promising results, but further studies are needed in order to confirm and apply them in standard forensic practice.
    DOI:  https://doi.org/10.1097/MD.0000000000026486
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