bims-hypoxi 2021-07-04 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021–07–04
sixteen papers selected by
Ashish Kaul, University of Tsukuba

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation.
LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium.
Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors.
Mechanical stimulation of chondrocytes regulates HIF-1α under hypoxic conditions.
Hypoxia Inducible Factor-1α Attenuates Ischemic Brain Damage by Modulating Inflammatory Response and Glial Activity.
Up-down regulation of HIF-1α in cancer progression.
Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases.
Enhanced BDNF Actions Following Acute Hypoxia Facilitate HIF-1α-Dependent Upregulation of Cav3-T-Type Ca2+ Channels in Rat Cardiomyocytes.
Hypoxia-inducible factor-1: regulatory mechanisms and drug development in stroke.
Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL.
HIF-1α and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes From Survivors and Non-Survivors Patients During Clinical Sepsis.
Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia.
STAT3/HIF-1α signaling activation mediates peritoneal fibrosis induced by high glucose.
An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor.
Study to identify predictor of hypoxia in COVID-19 infection: A single-center, retrospective study.
Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma.

Cells. 2021 Jun 08. pii: 1425. [Epub ahead of print]10(6):

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation.

Alena Shmakova, Mark Frost, Michael Batie, Niall S Kenneth, Sonia Rocha.

  PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

Keywords:  HIF-1; PBRM1; SWI/SNF; YTHDF2; hypoxia; m6A

DOI:  https://doi.org/10.3390/cells10061425
Int J Mol Sci. 2021 Jun 19. pii: 6581. [Epub ahead of print]22(12):

LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium.

Sujin Ju, Leejin Lim, Kwanhwan Wi, Changwon Park, Young-Jae Ki, Dong-Hyun Choi, Heesang Song.

  Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/β-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/β-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.

Keywords:  HIF-prolyl hydroxylases 2; hypoxia-inducible factor-1α; low-density lipoprotein receptor-related protein 5; myocardial infarction

DOI:  https://doi.org/10.3390/ijms22126581
Oncogene. 2021 Jul 02.

Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors.

Andrea L Casillas, Shailender S Chauhan, Rachel K Toth, Alva G Sainz, Amber N Clements, Corbin C Jensen, Paul R Langlais, Cindy K Miranti, Anne E Cress, Noel A Warfel.

Angiogenesis is essential for the sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Therefore, understanding the mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. In vitro and in vivo models demonstrate that expression of PIM1 is sufficient to stabilize HIF-1α and HIF-2α in normoxia and stimulate angiogenesis in a HIF-1-dependent manner. CRISPR mutants of HIF-1α (Thr455D) promoted increased tumor growth, proliferation, and angiogenesis. Moreover, HIF-1α-T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.

DOI: https://doi.org/10.1038/s41388-021-01915-1
Tissue Cell. 2021 Jun 19. pii: S0040-8166(21)00090-2. [Epub ahead of print]71 101574

Mechanical stimulation of chondrocytes regulates HIF-1α under hypoxic conditions.

Seiji Shimomura, Hiroaki Inoue, Yuji Arai, Shuji Nakagawa, Yuta Fujii, Tsunao Kishida, Masaharu Shin-Ya, Shohei Ichimaru, Shinji Tsuchida, Osam Mazda, Kenji Takahashi.

  We investigated the effects of hypoxia-inducible factor (HIF)-1α on articular cartilage under mechanical stimulation and the associated mechanisms. Chondrocytes, isolated from articular cartilage from the knee, hip, and shoulder joints of Wistar rats, were subjected to 20 % tensile stress under hypoxic (5% O2) conditions for 24 h. HIF-1α and aggrecan expression was significantly enhanced with mechanical stimulation under hypoxia but not significantly altered with mechanical stimulation under normoxia. The nuclear translocation of HIF-1α was enhanced by mechanical stress under hypoxia. Under both normoxia and hypoxia, a disintegrin and metalloproteinase with thrombospondin motifs (ADAM-TS) 5 expression was significantly reduced with mechanical stimulation compared to that in the group without mechanical stimulation. However, HIF-1α knockdown mitigated changes in aggrecan and ADAM-TS5 expression mediated by mechanical stimulation under hypoxia. The effects of treadmill running on HIF-1α production in the articular cartilage of rat knee joints were also analyzed. HIF-1α production increased in the moderate running group and decreased to the same levels as those in the control group in the excessive running group. This suggests that HIF-1α regulates aggrecan and ADAM-TS5 expression in response to mechanical stimulation under hypoxia and general mechanical stimulation in articular cartilage under hypoxia, while controlling cartilage homeostasis.

Keywords:  Arthritis; Chondrocyte; Hypoxia; Mechanical stimulation; Osteoarthritis; Treadmill

DOI:  https://doi.org/10.1016/j.tice.2021.101574
Cells. 2021 Jun 01. pii: 1359. [Epub ahead of print]10(6):

Hypoxia Inducible Factor-1α Attenuates Ischemic Brain Damage by Modulating Inflammatory Response and Glial Activity.

Nashwa Amin, Shijia Chen, Qiannan Ren, Xiaoning Tan, Benson O A Botchway, Zhiying Hu, Fengpei Chen, Shan Ye, Xiaoxue Du, Zuobing Chen, Marong Fang.

  Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.

Keywords:  acriflavine; astrocyte; dimethyloxalylglycine; endothelin-1; hypoxia-inducible factor-1; interleukin 10; proinflammatory cytokines

DOI:  https://doi.org/10.3390/cells10061359
Gene. 2021 Jun 24. pii: S0378-1119(21)00391-7. [Epub ahead of print] 145796

Up-down regulation of HIF-1α in cancer progression.

Mohsen Rashid, Leila Rostami Zadeh, Behzad Baradaran, Ommoleila Molavi, Zeinab Ghesmati, Mehdi Sabzichi, Fatemeh Ramezani.

  Hypoxia induicible factor-1 alpha (HIF-1α) is a key transcription factor in cancer progression and target therapy in cancer. HIF-1α acts differently depending on presence or absence of Oxygen. In an oxygen-immersed environment, HIF-1α completely deactivated and destroyed by the ubiquitin proteasome pathway (UPP). In contrast, in the oxygen-free environment, it escapes destruction and enters to the nucleus of cells then upregulates many genes involved in cancer progression. Overexpressed HIF-1α and downstream genes support cancer progression through various mechanisms including angiogenesis, proliferation and survival of cells, metabolism reprogramming, invasion and metastasis, cancer stem cell maintenance, induction of genetic instability, and treatment resistance. HIF-1α can be provoked by signaling pathways unrelated to hypoxia during cancer progression. Therefore, cancer development and progression can be modulated by targeting HIF-1α and its downstream signaling molecules. In this regard, HIF-1α inhibitors which are categorized into the agents that regulate HIF-1α in gene, mRNA and protein levels used as an efficient way in cancer treatment. Also, HIF-1α expression can be negatively affected by the agents suppressing the activation of mTOR, PI3k/Akt and MAPK pathways.

Keywords:  Cancer Progression; Cancer Stem Cells; Drug Resistance; HIF-1α; Invasion and Metastasis; Proliferation and apoptosis

DOI:  https://doi.org/10.1016/j.gene.2021.145796
J Alzheimers Dis. 2021 ;82(s1): S109-S126

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases.

Amalia Merelli, Marisa Repetto, Alberto Lazarowski, Jerónimo Auzmendi.

  The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.

Keywords:  ABC-transporters; Fe/Cu; HIF-1α; erythropoietin; hypoxia; inflammation; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3233/JAD-201074
Membranes (Basel). 2021 Jun 25. pii: 470. [Epub ahead of print]11(7):

Enhanced BDNF Actions Following Acute Hypoxia Facilitate HIF-1α-Dependent Upregulation of Cav3-T-Type Ca2+ Channels in Rat Cardiomyocytes.

Masaki Morishima, Takafumi Fujita, Satoshi Osagawa, Hiroshi Kubota, Katsushige Ono.

  Brain-derived neurotrophic factor (BDNF) has recently been recognized as a cardiovascular regulator particularly in the diseased condition, including coronary artery disease, heart failure, cardiomyopathy, and hypertension. Here, we investigate the role of BDNF on the T-type Ca2+ channel, Cav3.1 and Cav3.2, in rat neonatal cardiomyocytes exposed to normoxia (21% O2) and acute hypoxia (1% O2) in vitro for up to 3 h. The exposure of cardiomyocytes to hypoxia (1 h, 3 h) caused a significant upregulation of the mRNAs for hypoxia-inducible factor 1α (Hif1α), Cav3.1, Cav3.2 and Bdnf, but not tropomyosin-related kinase receptor B (TrkB). The upregulation of Cav3.1 and Cav3.2 caused by hypoxia was completely halted by small interfering RNA (siRNA) targeting Hif1a (Hif1a-siRNA) or Bdnf (Bdnf-siRNA). Immunocytochemical staining data revealed a distinct upregulation of Cav3.1- and Cav3.2-proteins caused by hypoxia in cardiomyocytes, which was markedly suppressed by Bdnf-siRNA. These results unveiled a novel regulatory action of BDNF on the T-type Ca2+ channels expression through the HIF-1α-dependent pathway in cardiomyocytes.

Keywords:  BDNF; Cav3.1; Cav3.2; HIF-1α; T-type Ca2+ channel; TrkB; hypoxia

DOI:  https://doi.org/10.3390/membranes11070470
Pharmacol Res. 2021 Jun 25. pii: S1043-6618(21)00326-1. [Epub ahead of print] 105742

Hypoxia-inducible factor-1: regulatory mechanisms and drug development in stroke.

Zirong Pan, Guodong Ma, Linglei Kong, Guanhua Du.

  Stroke is an acute cerebrovascular disease caused by sudden rupture of blood vessels in the brain or blockage of blood vessels, which has now become one of the main causes of adult death. During stroke, hypoxia-inducible factor-1 (HIF-1), as an important regulator under hypoxia conditions, is involved in the pathological process of stroke by regulating multi-pathways, such as glucose metabolism, angiogenesis, erythropoiesis, cell survival. However, the roles of HIF-1 in stroke are still controversial, which are related with ischemic time and degree of ischemia. The regulatory mechanisms of HIF-1 in stroke include inflammation, autophagy, oxidative stress, apoptosis and energy metabolism. The potential drugs targeting HIF-1 have attracted more attention, such as HIF-1 inhibitors, HIF-1 stabilizers and natural products. Based on the role of HIF-1 in stroke, HIF-1 is expected to be a potential target for stroke treatment. Resolving when and what interventions for HIF-1 to take during stroke will provide novel strategies for stroke treatment.

Keywords:  drug development; hypoxia-inducible factor 1; stroke

DOI:  https://doi.org/10.1016/j.phrs.2021.105742
Cancers (Basel). 2021 Jun 09. pii: 2883. [Epub ahead of print]13(12):

Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL.

Candida Vitale, Valentina Griggio, Chiara Riganti, Maria Todaro, Joanna Kopecka, Rebecca Jones, Chiara Salvetti, Elia Boccellato, Francesca Perutelli, Claudia Voena, Laura Godio, Mario Boccadoro, Marta Coscia.

  The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells.

Keywords:  CXCL12/CXCR4 axis; chronic lymphocytic leukemia; drug resistance; hypoxia inducible factor-1α; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13122883
Shock. 2021 Jul 01. 56(1): 80-91

HIF-1α and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes From Survivors and Non-Survivors Patients During Clinical Sepsis.

Bianca Lima Ferreira, Giuseppe Gianini Figueirêdo Leite, Milena Karina Colo Brunialti, Murillo Assuncao, Luciano Cesar Pontes Azevedo, Flávio Freitas, Reinaldo Salomao.

ABSTRACT: Hypoxia inducible factor 1 alpha (HIF-1α) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1α by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation, and apoptosis. Here, we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1α and other hypoxia responsive genes in peripheral blood mononuclear cells from patients with sepsis secondary to community acquired infections. Samples were collected at intensive care unit admission (D0, n=29) and after 7 days follow-up (D7, n = 18); healthy volunteers (n = 10) were included as controls. Hypoxia and glycolysis were among the top scored molecular signatures in the transcriptome datasets. PCR array showed that 24 out of 78 analyzed genes were modulated in septic patients compared with healthy volunteers; most of them (23/24) were downregulated at admission. This same pattern was observed in surviving patients, while non-survivors presented more upregulated genes. EGLN1, EGLN2, and HIF1AN, inhibitors of HIF-1α activation were downregulated in patients, regardless of the outcome, while HIF-1α and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO2 ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis.

DOI: https://doi.org/10.1097/SHK.0000000000001694
Redox Biol. 2021 Jun 17. pii: S2213-2317(21)00206-8. [Epub ahead of print]45 102047

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia.

Prasad Sulkshane, Jonathan Ram, Anita Thakur, Noa Reis, Oded Kleifeld, Michael H Glickman.

  The contribution of the Ubiquitin-Proteasome System (UPS) to mitophagy has been largely attributed to the E3 ubiquitin ligase Parkin. Here we show that in response to the oxidative stress associated with hypoxia or the hypoxia mimic CoCl2, the damaged and fragmented mitochondria are removed by Parkin-independent mitophagy. Mitochondria isolated from hypoxia or CoCl2-treated cells exhibited extensive ubiquitination, predominantly Lysine 48-linked and involves the degradation of key mitochondrial proteins such as the mitofusins MFN1/2, or the import channel component TOM20. Reflecting the critical role of mitochondrial protein degradation, proteasome inhibition blocked CoCl2-induced mitophagy. The five conserved ubiquitin-binding autophagy receptors (p62, NDP52, Optineurin, NBR1, TAX1BP1) were dispensable for the ensuing mitophagy, suggesting that the mitophagy step itself was independent of ubiquitination. Instead, the expression of two ubiquitin-independent mitophagy receptor proteins BNIP3 and NIX was induced by hypoxia or CoCl2-treatment followed by their recruitment to the oxidation-damaged mitochondria. By employing BNIP3/NIX double knockout and DRP1-null cell lines, we confirmed that mitochondrial clearance relies on DRP1-dependent mitochondrial fragmentation and BNIP3/NIX-mediated mitophagy. General antioxidants such as N-Acetyl Cysteine (NAC) or the mitochondria-specific Mitoquinone prevented HIF-1α stabilization, ameliorated hypoxia-related mitochondrial oxidative stress, and suppressed mitophagy. We conclude that the UPS and receptor-mediated autophagy converge to eliminate oxidation-damaged mitochondria.

Keywords:  HIF-1α; Hypoxia; Mitochondria; Mitophagy; Oxidative stress; Proteasome; Ubiquitin

DOI:  https://doi.org/10.1016/j.redox.2021.102047
J Transl Med. 2021 Jun 30. 19(1): 283

STAT3/HIF-1α signaling activation mediates peritoneal fibrosis induced by high glucose.

Xiaoxiao Yang, Manchen Bao, Yi Fang, Xiaofang Yu, Jun Ji, Xiaoqiang Ding.

   BACKGROUND: Epithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.
METHODS: Firstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.
RESULTS: Compared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.
CONCLUSIONS: Taken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.

Keywords:  Epithelial-mesenchymal transition; HIF-1α; Peritoneal dialysis; Peritoneal fibrosis; STAT3

DOI:  https://doi.org/10.1186/s12967-021-02946-8
Cancers (Basel). 2021 Jun 04. pii: 2813. [Epub ahead of print]13(11):

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor.

Yukari Shirai, Christalle C T Chow, Gouki Kambe, Tatsuya Suwa, Minoru Kobayashi, Itsuki Takahashi, Hiroshi Harada, Jin-Min Nam.

  Hypoxia, a characteristic feature of solid tumors, is associated with the malignant phenotype and therapy resistance of cancers. Hypoxia-inducible factor 1 (HIF-1), which is responsible for the metazoan adaptive response to hypoxia, has been recognized as a rational target for cancer therapy due to its critical functions in hypoxic regions. In order to efficiently inhibit its activity, extensive efforts have been made to elucidate the molecular mechanism underlying the activation of HIF-1. Here, we provide an overview of relevant research, particularly on a series of HIF-1 activators identified so far and the development of anticancer drugs targeting them.

Keywords:  HIF-1 inhibitor; cancer; chemoresistance; hypoxia-inducible factor 1 (HIF-1); radioresistance; tumor hypoxia

DOI:  https://doi.org/10.3390/cancers13112813
J Family Med Prim Care. 2021 May;10(5): 1852-1855

Study to identify predictor of hypoxia in COVID-19 infection: A single-center, retrospective study.

Deependra K Rai, Somesh Thakur.

   Background: Given the limited availability of critical care resources in our country, it is important to identify reliable predictors of hypoxia in patients with COVID-19 infection. We thus sought to compare differential predictive values of demographic, clinical, and laboratory measures and identify predictor for hypoxia in COVID-19 infection.
Materials and Methods: This is single-center retrospective analysis of patient admitted at AIIMS Patna between 15th June and 15th Aug. All the patients who had oxygen saturation less than 94% grouped under hypoxic group while ≥94% in non-hypoxic group at room air. Statistical analysis: Logistic regression model used to determine the predictor of hypoxia in COVID-19 infection.
Results: Total 73 were used for analysis. Study patients had a mean age of 55.05 ± 12.7 year, of whom 78.08% were male (57/73). 39 (53.42%) patients were found hypoxic at time of admission while 34 (46.56%) were non-hypoxic. Presence of dyspnoea significantly found more frequently in hypoxic patients (P = 0.0003). Patients with O2 saturation of less than 94% have more likely to have diabetes (P = 0.002) and hypertension (P = 0.02). Analysis of laboratory variables showed that leucocytosis (P = 0.007) and neutrophilia (P = 0.01) were significantly higher in hypoxic group compare to non-hypoxic group. Univariate regression model showed patient with any one comorbidities, diabetes, or hypertension was found as strong risk factor for hypoxia after COVID-19 infection (P < 0.05).
Conclusion: This is the first study to identify predictor of hypoxia in COVID-19 infection. Patient with any one comorbidities, diabetes, or hypertension was found strong risk factor for hypoxia after COVID-19 infection. Among lab variable, leucocytosis, neutrophilia, lymphocytopenia, and CRP (>27.5 mg/L) were found as predictor of hypoxia in COVID infection.

Keywords:  COVID-19; Comorbidity; hypoxia; inflammatory marker

DOI:  https://doi.org/10.4103/jfmpc.jfmpc_2252_20
Cancers (Basel). 2021 Jun 04. pii: 2809. [Epub ahead of print]13(11):

Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma.

Paolo Uva, Maria Carla Bosco, Alessandra Eva, Massimo Conte, Alberto Garaventa, Loredana Amoroso, Davide Cangelosi.

  Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.

Keywords:  PI3K/Akt/mTOR inhibitors; hypoxia; neuroblastoma; treatment

DOI:  https://doi.org/10.3390/cancers13112809