bims-hypoxi 2021-07-18 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021–07–18
forty papers selected by
Ashish Kaul, University of Tsukuba

Regulation of humoral immune response by HIF-1α-dependent metabolic reprogramming of the germinal center reaction.
Upregulation of the long noncoding RNA UBOX5 antisense RNA 1 (UBOX5-AS1) under hypoxic conditions promotes epithelial-mesenchymal transition in endometriosis.
Correlation between hypoxia-inducible factor-1α C1772T/G1790A polymorphisms and head and neck cancer risk: a meta-analysis.
HIF-1α affects sensitivity of murine squamous cell carcinoma to boron neutron capture therapy with BPA.
Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys.
Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.
Hypoxia Signaling in Cancer: From Basics to Clinical Practice.
Hypoxic Signaling in Skeletal Muscle Maintenance and Regeneration: A Systematic Review.
Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages.
Enhanced anti-tumor efficacy by inhibiting HIF-1α to reprogram TAMs via core-satellite upconverting nanoparticles with curcumin mediated photodynamic therapy.
The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury.
N-Acetylcysteine Improves Inflammatory Response in COPD Patients by Regulating Th17/Treg Balance through Hypoxia Inducible Factor-1α Pathway.
A positive feedback regulatory loop involving the lncRNA PVT1 and HIF-1α in pancreatic cancer.
NOX4-Derived ROS Mediates TGF-β1-Induced Metabolic Reprogramming during Epithelial-Mesenchymal Transition through the PI3K/AKT/HIF-1α Pathway in Glioblastoma.
HIF-1: structure, biology and natural modulators.
Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels.
Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly-LDL-induced HUVECs through inhibiting TLR4/HIF-1α.
CBL aggravates Ang II-induced cardiac hypertrophy via the VHL/HIF-1α pathway.
Sevoflurane exerts improved protective effects than propofol on hypoxia-reoxygenation injury by regulating the microRNA-221-5p/ADAM8 axis in cardiomyocytes.
Yi-Qi-Jian-Pi formula modulates the PI3K/AKT signaling pathway to attenuate acute-on-chronic liver failure by suppressing hypoxic injury and apoptosis in vivo and in vitro.
USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis.
Isorhamnetin Promotes MKN-45 Gastric Cancer Cell Apoptosis by Inhibiting PI3K-Mediated Adaptive Autophagy in a Hypoxic Environment.
A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.
Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.
Analysis of the Internal Hypoxic Environment in Solid Tumor Tissue Using a Folding Paper System.
The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.
The Clinicopathological Significance of YAP/TAZ Expression in Hepatocellular Carcinoma with Relation to Hypoxia and Stemness.
Hypoxia and chronic kidney disease: Possible mechanisms, therapeutic targets, and relevance to cats.
Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.
FoxO4 negatively modulates USP10 transcription to aggravate the apoptosis and oxidative stress of hypoxia/reoxygenation-induced cardiomyocytes by regulating the Hippo/YAP pathway.
Testosterone attenuates hypoxia-induced hypertension by affecting NRF1-mediated transcriptional regulation of ET-1 and ACE.
Effects of alcohol on brain oxygenation and brain hypoxia induced by intravenous heroin.
Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.
Circ_0124644 Serves as a ceRNA for miR-590-3p to Promote Hypoxia-Induced Cardiomyocytes Injury via Regulating SOX4.
Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer.
Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury's Biological Network Based on Systematic Pharmacology.
Microbiota Modulates Cardiac Transcriptional Responses to Intermittent Hypoxia and Hypercapnia.
Overexpression of Neutrophil MMP-9 and HIF-1α May Contribute to the Finger-Like Projections Formation and Histo-Pathogenesis in Nasal Inverted Papilloma.
Silent hypoxia in COVID-19: a gut microbiota connection.
Hypoxic induction of atrial natriuretic peptide (factor) secretion. An inflammatory IL-18 pathway is involved in the control of cardioprotective molecule.

Cell Immunol. 2021 Jul 01. pii: S0008-8749(21)00128-3. [Epub ahead of print]367 104409

Regulation of humoral immune response by HIF-1α-dependent metabolic reprogramming of the germinal center reaction.

Lingyun Li, Chunlei Feng, Jun Qin, Dali Li, Mingyao Liu, Shuhua Han, Biao Zheng.

  Hypoxia-inducible factor-1α (HIF-1α) has been implicated in the regulation of many genes responsible for aerobic glycolysis; however, the role of HIF-1α in B-cell metabolism has not been well defined. Here, we analyzed patterns of gene expression and oxygen consumption rates in B-cell subpopulations from humans and mice and described a model of HIF-1α-mediated B-cell metabolic reprogramming during the germinal center (GC) reaction. Importantly, we found that HIF-1α was highly expressed in GC B-cells, and HIF-1α deficiency in B-cells impaired a functional GC reaction, resulting in defective class-switch recombination and generation of high-affinity plasma cells. These results identified an important role of HIF-1α in regulating humoral immunity through metabolic reprogramming during the GC response. This newly discovered metabolic character of GC B-cells will advance our understanding of GC biology and B-cell lymphomagenesis.

Keywords:  Aerobic glycolysis; Germinal center; HIF-1α; Humoral immunity

DOI:  https://doi.org/10.1016/j.cellimm.2021.104409
Ann Transl Med. 2021 May;9(9): 790

Upregulation of the long noncoding RNA UBOX5 antisense RNA 1 (UBOX5-AS1) under hypoxic conditions promotes epithelial-mesenchymal transition in endometriosis.

Hengwei Liu, Haitang He, Zhibing Zhang, Lili Wang, Ling Zhang, Yi Liu, Wenqian Xiong.

   Background: Endometriosis is a debilitating gynecological condition that manifests many common malignant features, including migration and invasion. Hypoxia is a hallmark of endometriosis, characterized by endometrial cell metastasis via epithelial-mesenchymal transition (EMT). The long noncoding RNA (lncRNA) UBOX antisense RNA 1 (UBOX5-AS1) has been shown to be upregulated in ovarian endometriosis. However, the molecular mechanisms and biological functions of lncRNA UBOX5-AS1 in hypoxia-induced endometriosis EMT remain to be explored.
Methods: Normal, eutopic, and ectopic endometrium from ovarian endometriosis tissues were collected, and the expressions of hypoxia inducible factor (HIF)-1α, lncRNA UBOX5-AS1, E-cadherin, and vimentin were analyzed by quantitative real time polymerase chain reaction (qRT-PCR) and western blotting analysis. Primary human endometrial epithelial cells and human endometrial epithelial adenocarcinoma Ishikawa cell lines were cultured under hypoxic conditions, and western blotting analysis and immunocytochemistry were performed to investigate hypoxia-induced EMT. Moreover, HIF-1α and lncRNA UBOX5-AS1 were overexpressed and knocked down in endometrial epithelial cells to explore the role and mechanisms of lncRNA UBOX5-AS1 in hypoxia-triggered EMT. The migration and invasion potential of human endometrial epithelial cells was detected by Transwell migration/invasion assays.
Results: In ovarian endometriosis, the expression of hypoxia-inducible factor-1α (HIF-1α) and lncRNA UBOX5-AS1 were significantly increased, and this was accompanied by EMT. Furthermore, endometrial epithelial cells cultured under hypoxic conditions exhibited elevated lncRNA UBOX5-AS1 expression, as well as migration, invasion, and an EMT-like phenotype. This data indicated that HIF-1α signaling was crucial for hypoxia-induced lncRNA UBOX5-AS1 upregulation and the EMT process. Moreover, downregulation of lncRNA UBOX5-AS1 inhibited the hypoxia-induced EMT and attenuated cell migration and invasion.
Conclusions: The present research demonstrated that hypoxia upregulated the expression of lncRNA UBOX5-AS1 via HIF-1α-dependent signaling. The increased expression of lncRNA UBOX5-AS1 plays a vital role in mediating the hypoxia-regulated EMT and invasiveness of endometriosis, suggesting that lncRNA UBOX5-AS1 may be an important potential therapeutic target for endometriosis.

Keywords:  Hypoxia; endometriosis; epithelial-mesenchymal transition (EMT); hypoxia-inducible factor-1α (HIF-1α); long noncoding RNA UBOX antisense RNA 1 (lncRNA-UBOX5-AS1)

DOI:  https://doi.org/10.21037/atm-20-4546
World J Surg Oncol. 2021 Jul 13. 19(1): 210

Correlation between hypoxia-inducible factor-1α C1772T/G1790A polymorphisms and head and neck cancer risk: a meta-analysis.

Ting Wu, Zhong-Ti Zhang, Lin Li, Ru-Yue Liu, Bao-Ting Bei.

   OBJECTIVE: This meta-analysis was implemented to evaluate the association between hypoxia-inducible factor-1α (HIF-1α) C1772T/G1790A polymorphisms and susceptibility to head and neck cancer (HNC).
MATERIAL AND METHODS: This meta-analysis has been registered on PROSPERO platform ( CRD42021257309 ). The PubMed, Embase and Web of Science databases were searched to retrieve eligible published papers. STATA software was used to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the correlation strength.
RESULTS: Our results demonstrated that the HIF-1α C1772T polymorphism was significantly related to an increased HNC risk (OR = 2.27, 95% CI = 1.17-4.42 for the homozygous model; OR = 11.53, 95% CI = 1.11-120.4 for the recessive model), especially in Caucasians (OR = 2.16, 95% CI = 1.09-4.27 for the homozygous model; OR = 2.28, 95% CI = 1.15-5.51 for the recessive model). Similarly, a remarkable correlation was discovered between the G1790A polymorphism and HNC risk (OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 58.05, 95% CI = 1.70-1985.77 for the recessive model). Moreover, in the subgroup analysis by source of controls, a statistically significant correlation was discovered in the population-based (PB) subgroup (OR = 9.43, 95% CI = 1.20-73.9 for allelic model; OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 3.22, 95% CI = 1.28-8.08 for the heterozygous model; OR = 7.83, 95% CI = 1.48-41.37 for the dominant model; OR = 58.05, 95% CI = 1.70-1985.8 for the recessive model) but not in the hospital-based (HB) subgroup.
CONCLUSION: Our study found that both HIF-1α C1772T and G1790A polymorphisms might be a higher risk of HNC, especially in the Caucasian group with the C1772T polymorphism.

Keywords:  HIF-1α; Head and neck cancer; Meta-analysis; Polymorphism; Risk

DOI:  https://doi.org/10.1186/s12957-021-02324-0
Int J Radiat Biol. 2021 Jul 15. 1-24

HIF-1α affects sensitivity of murine squamous cell carcinoma to boron neutron capture therapy with BPA.

Yu Sanada, Takushi Takata, Hiroki Tanaka, Yoshinori Sakurai, Tsubasa Watanabe, Minoru Suzuki, Shin-Ichiro Masunaga.

  Purpose To examine whether hypoxia and Hif-1α affect sensitivity of murine squamous cell carcinoma cells to boron neutron capture therapy (BNCT).Materials and methods SCC VII and SCC VII Hif-1α-deficient mouse tumor cells were incubated under normoxic or hypoxic conditions, and cell survival after BNCT was assessed. The intracellular concentration of the 10B-carrier, boronophenylalanine-10B (BPA), was estimated using an autoradiography technique. The expression profile of SLC7A5, which is involved in the uptake of BPA, and the amount of DNA damage caused by BNCT with BPA were examined. A cell survival assay was performed on cell suspensions prepared from tumor-bearing mice.Results Hypoxia ameliorated SCC VII cell survival after neutron irradiation with BPA, but not BSH. Hypoxia-treated SCC VII cells showed decreased intracellular concentrations of BPA and the down-regulated expression of the SLC7A5 protein. BPA uptake and the SLC7A5 protein were not decreased in hypoxia-treated Hif-1α-deficient cells, the survival of which was lower than that of SCC VII cells. More DNA damage was induced in SCC VII Hif-1α-deficient cells than in SCC VII cells. In experiments using tumor-bearing mice, the survival of SCC VII Hif-1α-deficient cells was lower than that of SCC VII cells.Conclusion. Hypoxia may decrease the effects of BNCT with BPA, whereas the disruption of Hif-1α enhanced sensitivity to BNCT with BPA.

Keywords:  HIF-1α; boron neutron capture reaction; boron neutron capture therapy (BNCT); hypoxia

DOI:  https://doi.org/10.1080/09553002.2021.1956004
Front Physiol. 2021 ;12 690496

Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys.

Yaya Xu, Xiangmei Kong, Jiru Li, Tiantian Cui, Yifan Wei, Jiayue Xu, Yueniu Zhu, Xiaodong Zhu.

   Background: Hypoxia contributes to a cascade of inflammatory response mechanisms in kidneys that result in the development of renal interstitial fibrosis and subsequent chronic renal failure. Nonetheless, the kidney possesses a self-protection mechanism under a certain degree of hypoxia and this mechanism its adaptation to hypoxia. As the hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF) axis is a key pathway for neovascularization, the activation of this axis is a target for renal hypoxia therapies.
Methods: Sprague-Dawley rats were exposed to normobaric hypoxia and subdivided into three groups, namely group A (21% O2), group B (10% O2), and group C (7% O2). Renal tissue samples were processed and analyzed to determine pathological morphological changes, the expression of HIF, VEGF, inflammation factor and vascular density.
Results: We found that as the duration of hypoxia increased, destructive changes in the kidney tissues became more severe in group C (7% O2). In contrast, the increased duration of hypoxia did not exacerbate kidney damage in group B (10% O2). As the hypoxia was prolonged and the degree of hypoxia increased, the expression of HIF-1α increased gradually. As hypoxia time increased, the expression of VEGF increased gradually, but VEGF expression in group B (10% O2) was the highest. Group C (7% O2) had higher levels of IL-6, IL-10, and TNF-alpha. Additionally, the highest vascular density was observed in group B.
Conclusion: These findings suggest that activating the HIF-VEGF signaling pathway to regulate angiogenesis after infliction of hypoxic kidney injury may provide clues for the development of novel CKD treatments.

Keywords:  HIF-1; VEGF; chronic hypoxia; kidney injury; vascularization

DOI:  https://doi.org/10.3389/fphys.2021.690496
PLoS One. 2021 ;16(7): e0249103

Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.

Dingxia Feng, Zhiwei Zhai, Zhiyong Shao, Yi Zhang, Jo Anne Powell-Coffman.

During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57::GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57::GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat or gsk-3 RNAi, increases expression of a Pegl-9::GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

DOI: https://doi.org/10.1371/journal.pone.0249103
Pathol Oncol Res. 2021 ;27 1609802

Hypoxia Signaling in Cancer: From Basics to Clinical Practice.

Anna Sebestyén, László Kopper, Titanilla Dankó, József Tímár.

  Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.

Keywords:  angiogenesis; cancer; hypoxia; metabolism; therapy

DOI:  https://doi.org/10.3389/pore.2021.1609802
Front Physiol. 2021 ;12 684899

Hypoxic Signaling in Skeletal Muscle Maintenance and Regeneration: A Systematic Review.

Tamara Pircher, Henning Wackerhage, Attila Aszodi, Christian Kammerlander, Wolfgang Böcker, Maximilian Michael Saller.

  In skeletal muscle tissue, oxygen (O2) plays a pivotal role in both metabolism and the regulation of several intercellular pathways, which can modify proliferation, differentiation and survival of cells within the myogenic lineage. The concentration of oxygen in muscle tissue is reduced during embryogenesis and pathological conditions. Myogenic progenitor cells, namely satellite cells, are necessary for muscular regeneration in adults and are localized in a hypoxic microenvironment under the basal lamina, suggesting that the O2 level could affect their function. This review presents the effects of reduced oxygen levels (hypoxia) on satellite cell survival, myoblast regeneration and differentiation in vertebrates. Further investigations and understanding of the pathways involved in adult muscle regeneration during hypoxic conditions are maybe clinically relevant to seek for novel drug treatments for patients with severe muscle damage. We especially outlined the effect of hypoxia-inducible factor 1-alpha (HIF1A), the most studied transcriptional regulator of cellular and developmental response to hypoxia, whose investigation has recently been awarded with the Nobel price.

Keywords:  HIF1A; fusion; hypoxia-inducible factor 1 alpha; muscle regeneration; satellite cells

DOI:  https://doi.org/10.3389/fphys.2021.684899
Sleep Breath. 2021 Jul 12.

Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages.

Yuanling Liu, Minzhen Lu, Jianan Chen, Siqi Li, Yiyu Deng, Shifang Yang, Qiong Ou, Jing Li, Ping Gao, Zeru Luo, Ping Yuan, Jianlong Tan, Xinglin Gao.

   PURPOSE: Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), compromises immune surveillance through the upregulation of programmed cell death-1 ligand (PD-L1). Tumor-released extracellular vesicles (EVs) have been reported to modulate immunosuppressive activities. We investigated whether or not EVs derived from intermittent hypoxic lung cancer cells can alter the expression of PD-L1 in macrophages.
METHODS: The expression of PD-L1+monocytes from 40 patients with newly diagnosed non-small-cell lung cancer (NSCLC) and with (n=21) or without (n=19) OSA were detected. Plasma EVs isolated from NSCLC patients with moderate-severe OSA (n=4) and without OSA (n=4) were co-cultured with macrophages. A549 cells were exposed to normoxia or IH (48 cycles of 5 min of 1% O2 hypoxia, followed by 5 min of normoxia). EVs were isolated from cell supernatant and were co-cultured with macrophages differentiated from THP-1. PD-L1 and hypoxia-inducible factor-1 α (HIF-1α) expressions were measured by flow cytometry, immunofluorescence, and Western blot analysis.
RESULTS: PD-L1+monocytes were elevated in NSCLC patients with OSA and increased with the severity of OSA and nocturnal desaturation. PD-L1+ macrophages were induced by EVs from NSCLC patients with OSA and positively correlated with HIF-1α expressions. EVs from IH-treated A549 can promote PD-L1 and HIF-1α expression in macrophages and the upregulation of PD-L1 expression was reversed by specific HIF-1α inhibitor.
CONCLUSION: IH can enhance the function of EVs derived from lung cancer cells to aggravate immunosuppressive status in macrophages. HIF-1α may play an important role in this process.

Keywords:  Extracellular vesicle; Macrophage; Non-small-cell lung cancer; Obstructive sleep apnea; Programmed cell death-1 ligand

DOI:  https://doi.org/10.1007/s11325-021-02369-1
Biomater Sci. 2021 Jul 13.

Enhanced anti-tumor efficacy by inhibiting HIF-1α to reprogram TAMs via core-satellite upconverting nanoparticles with curcumin mediated photodynamic therapy.

Li-Jun Zhang, Rui Huang, Yi-Wen Shen, Jie Liu, Ye Wu, Jin-Mei Jin, Hong Zhang, Yun Sun, Hong-Zhuan Chen, Xin Luan.

Tumor hypoxic stress after photodynamic therapy (PDT) will be inevitably exacerbated by the vascular blocking effects and oxygen consumption in the tumor microenvironment (TME) which usually leads to compromised efficacy and clinical performance. Increasing evidence links the hypoxia induced up-regulation of hypoxia inducible factor 1α (HIF-1α) with immunosuppressive TME, including the polarization of M2 phenotype tumor associated macrophages (TAMs), which promote the recurrence and metastasis. Here, we reported NIR-triggered core-satellite upconverting nanoparticles (CSNPs) with curcumin (Cur) embedded as a difunctional photosensitizer, which could realize PDT in deep tumors with long excitation wavelength (980 nm) and reverse the immunosuppressive TME induced by up-regulated HIF-1α at the same time. This Cur-loaded CSNPs (Cur-CSNPs)-mediated PDT could successfully induce the immunogenic cell death (ICD) of triple negative breast cancer (TNBC) cell lines (4T1 and MDA-MB-231) in vitro and repolarize the 4T1 cells co-cultured TAMs from pro-tumor M2 to the anti-tumor M1 phenotype. Furthermore, Cur-CSNPs-mediated PDT could suppress the 4T1 tumor growth in primary and distant sites through the synergistic immunotherapeutic effects in vivo by priming M1 type TAMs and CD4+/CD8+ T cells' infiltration. Our data highlight the novel application of CSNPs-embedded Cur as a difunctional photosensitizer to enhance the anti-tumor efficacy of PDT.

DOI: https://doi.org/10.1039/d1bm00675d
Cell Commun Signal. 2021 Jul 13. 19(1): 76

The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury.

Yang Sun, Jin Tan, Yuyang Miao, Qiang Zhang.

  Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract.

Keywords:  Hypoxia; Immune dysfunction; Multiple organ injuries; PD-1; PD-L1

DOI:  https://doi.org/10.1186/s12964-021-00742-x
Biomed Res Int. 2021 ;2021 6372128

N-Acetylcysteine Improves Inflammatory Response in COPD Patients by Regulating Th17/Treg Balance through Hypoxia Inducible Factor-1α Pathway.

Xiaopeng Liu, Zhixiong Hu, Haiying Zhou.

Introduction: This study was aimed to investigate the effects of N-acetylcysteine (NAC) on chronic obstructive pulmonary disease (COPD) and the change of Th17/Treg cytokine imbalance. Material and Methods. A total of 121 patients with stable COPD at the stage of C or D were consecutively enrolled and randomly divided into 2 groups. Patients in the treatment group received NAC granules (0.2 g × 10 bags, 0.4 g each time, 3 times/d) for half a year. The control group was treated with the same amount of placebo therapy. The peripheral blood of the patient was collected and the cytokine, T lymphocyte subsets were detected.
Results: We found the oral administration of NAC could regulate Th17/Treg balance to resist inflammation in COPD patients. Serum testing showed that the proportion of Treg in CD4+ T cells has increased and the Th17/Treg ratio has decreased during the NAC treatment. In vitro studies, we found that NAC regulated Th17/Treg balance through Hypoxia Inducible Factor-1α pathway.
Conclusions: Our result could provide new diagnosis and treatment for elderly patients with COPD from the perspective of immunity ideas.

DOI: https://doi.org/10.1155/2021/6372128
J Mol Cell Biol. 2021 Jul 10. pii: mjab042. [Epub ahead of print]

A positive feedback regulatory loop involving the lncRNA PVT1 and HIF-1α in pancreatic cancer.

Yiping Zhu, Fang Wu, Weiwei Gui, Nan Zhang, Erik Matro, Linghua Zhu, Daniel Turunen Eserberg, Xihua Lin.

  Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer (PC). Both the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and hypoxic inducible factor-1α (HIF-1α) are highly expressed in PC patients and play a crucial role in disease progression. Reciprocal regulation involving PVT1 and HIF-1α in PC, however, is poorly understood. Here, we report that PVT1 binds to the HIF-1α promoter and activates its transcription. In addition, we found that PVT1 could bind to HIF-1α and increases HIF-1α post-translationally. Our findings suggest that the PVT1‒HIF-1α positive feedback loop is a potential therapeutic target in the treatment of PC.

Keywords:  HIF-1α; PVT1; feedforward regulatory loop; pancreatic cancer

DOI:  https://doi.org/10.1093/jmcb/mjab042
Oxid Med Cell Longev. 2021 ;2021 5549047

NOX4-Derived ROS Mediates TGF-β1-Induced Metabolic Reprogramming during Epithelial-Mesenchymal Transition through the PI3K/AKT/HIF-1α Pathway in Glioblastoma.

Xiangsheng Su, Yihang Yang, Changfa Guo, Rui Zhang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Yibing Fu, Qi Pang.

Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-β1 (TGF-β1) released from TME plays a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-β1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-β1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-β1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-β1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1α (HIF-1α) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-β1-induced metabolic changes and tumorigenesis. Moreover, TGF-β1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1α signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-β1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.

DOI: https://doi.org/10.1155/2021/5549047
Chin J Nat Med. 2021 Jul;pii: S1875-5364(21)60051-1. [Epub ahead of print]19(7): 521-527

HIF-1: structure, biology and natural modulators.

Chao Yang, Zhang-Feng Zhong, Sheng-Peng Wang, Chi-Teng Vong, Bin Yu, Yi-Tao Wang.

  Hypoxia-inducible factor 1 (HIF-1), as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment, participates in many physiological and pathological processes in the body, and is closely related to the pathogenesis of many diseases. This review outlines the mechanisms of HIF-1 activation, its signaling pathways, natural inhibitors, and its roles in diseases. This article can provide new insights in the diagnosis and treatment of human diseases, and recent progress on the development of HIF-1 inhibitors.

Keywords:  Human disease; Hypoxia; Inhibitor; Natural product

DOI:  https://doi.org/10.1016/S1875-5364(21)60051-1
Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2023868118. [Epub ahead of print]118(29):

Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels.

Marie-Anne Goyette, Islam E Elkholi, Chloé Apcher, Hellen Kuasne, Carla V Rothlin, William J Muller, Darren E Richard, Morag Park, Jean-Philippe Gratton, Jean-François Côté.

  Hypoxia is an important phenomenon in solid tumors that contributes to metastasis, tumor microenvironment (TME) deregulation, and resistance to therapies. The receptor tyrosine kinase AXL is an HIF target, but its roles during hypoxic stress leading to the TME deregulation are not well defined. We report here that the mammary gland-specific deletion of Axl in a HER2+ mouse model of breast cancer leads to a normalization of the blood vessels, a proinflammatory TME, and a reduction of lung metastases by dampening the hypoxic response in tumor cells. During hypoxia, interfering with AXL reduces HIF-1α levels altering the hypoxic response leading to a reduction of hypoxia-induced epithelial-to-mesenchymal transition (EMT), invasion, and production of key cytokines for macrophages behaviors. These observations suggest that inhibition of Axl generates a suitable setting to increase immunotherapy. Accordingly, combining pharmacological inhibition of Axl with anti-PD-1 in a preclinical model of HER2+ breast cancer reduces the primary tumor and metastatic burdens, suggesting a potential therapeutic approach to manage HER2+ patients whose tumors present high hypoxic features.

Keywords:  AXL; HER2; hypoxia; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2023868118
J Cell Mol Med. 2021 Jun 10.

Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly-LDL-induced HUVECs through inhibiting TLR4/HIF-1α.

Wenjun Sha, Meizhi Liu, Dusang Sun, Junhui Qiu, Bilin Xu, Lin Chen, Tian Shen, Cheng Chen, Hongping Wang, Cuiping Zhang, Tao Lei.

  To explore the effects of resveratrol on the levels of inflammatory cytokines and Toll-like receptor-4/ hypoxia-inducible transcription factors-1α (TLR4/HIF-1α) signalling pathway in diabetes mellitus. C57BL/6 mice received intraperitoneal injection of streptozocin for constructing diabetic mice models. Human umbilical vein endothelial cells (HUVECs) were treated with 50 µg/mL Gly-LDL for inducing injury models. 10, 100 and 1000 mmol/L resveratrol were obtained and added into each group. Haematoxylin-eosin (H&E) staining was used for histological evaluation. CCK8 assay was performed for determination of cell viability, and Transwell assay was implemented for detecting cell migration ability. Cell apoptosis was analysed using flow cytometry. The content of inflammatory factors including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), vascular adhesion molecule-1 (VCAM-1) and vascular endothelial growth factor (VEGF) were measured by ELISA. GST pull-down assay was employed for determining interactions between TLR4 and HIF-1α. The protein expression of TLR4 and HIF-1α was detected using Western blotting and immunohistochemistry, while relative mRNA expression was measured by RT-qRCR. Resveratrol could reduce bodyweight and ameliorate endothelial injury of thoracic aorta in diabetic mice. Both in vivo and in vitro results revealed that the level of IL-6, TNF-α, VCAM-1 and VEGF was significantly down-regulated after being treated with resveratrol. Resveratrol inhibited the increase of MDA and ROS and increased the level of SOD in diabetic mice. Western blotting, IHC and RT-qPCR results showed that the levels of TLR4 and HIF-1α were significantly down-regulated in resveratrol group. Overexpression of TLR4 or HIF-1α could reverse the effect of resveratrol. GST pull-down elucidated that there might be a close interaction between TLR4 and HIF-1α. Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly-LDL-induced HUVECs through inhibiting TLR4/HIF-1α signalling pathway.

Keywords:  TLR4/HIF-1α; resveratrol; thoracic aorta

DOI:  https://doi.org/10.1111/jcmm.16584
Exp Cell Res. 2021 Jul 07. pii: S0014-4827(21)00262-7. [Epub ahead of print]405(2): 112730

CBL aggravates Ang II-induced cardiac hypertrophy via the VHL/HIF-1α pathway.

Yuting Yang, Pengtao Zou, Lin He, Jun Shao, Yanhua Tang, Juxiang Li.

  CBL (Casitas B cell lymphoma), an important ubiquitin protein ligase, is involved in protein folding, protein maturation, and proteasome-dependent protein catabolism in different cells. However, its role in cardiac hypertrophy is still unclear. In this study, we found that expression of CBL is increased in an Ang II-induced mouse cardiac hypertrophy animal model and in Ang II-treated H9C2 cells. Interference with CBL expression attenuates the degree of myocardial hypertrophy as well as the expression of hypertrophy-related genes in H9C2 cells. Further research found that CBL aggravates myocardial hypertrophy by activating HIF-1α, which is an aggravating factor for hypertrophy. The effect of CBL on promoting myocardial hypertrophy was reversed by interference with HIF-1α. Mechanistically, we found that CBL directly interacted with and degraded VHL by increasing its ubiquitination level, which is a widely accepted regulatory factor of HIF-1α. Finally, our results showed that CBL was partially dependent on degradation of VHL and that activation of HIF-1α promoted myocardial hypertrophy. Collectively, these findings suggest that strategies based on activation of the CBL/HIF-1α axis might be promising for the treatment of hypertrophic cardiomyopathy.

Keywords:  CBL; HIF-1α; Pathological myocardial hypertrophy; Ubiquitination; VHL

DOI:  https://doi.org/10.1016/j.yexcr.2021.112730
Exp Ther Med. 2021 Aug;22(2): 893

Sevoflurane exerts improved protective effects than propofol on hypoxia-reoxygenation injury by regulating the microRNA-221-5p/ADAM8 axis in cardiomyocytes.

Dan Xie, Huifei Deng, Hao Feng.

  Myocardial ischemia-reperfusion (I/R) injury is a leading cause of heart disease and death. Decreasing the detrimental effect of I/R remains an urgent issue in clinical practice. The present study examined the interaction of the anesthetics (sevoflurane and propofol), ADAM8, and microRNA (miR)-221-5p in myocardial tissue protection in the hypoxia-reoxygenation (H/R) model. H9C2 cells were cultured and subjected to H/R stimulation for further verifications in vitro. Reverse transcription-quantitative PCR or western blotting was performed to evaluate mRNA or protein expression levels. Cell Counting Kit-8, BrdU, and caspase-3 activity assays were performed to investigate cell viability, proliferation and apoptosis. A dual-luciferase reporter assay was performed to verify the association between miR-221-5p and ADAM8. Sevoflurane had greater protective effects on the life of cardiomyocytes with H/R injury compared with propofol by promoting cell viability, proliferation and inhibiting apoptosis. Concurrently, compared with propofol-treated H/R injured cardiomyocytes, the expression level of ADAM8 in sevoflurane-treated H/R injured cardiomyocytes was higher. In addition, overexpression of ADAM8 promoted the cell viability and proliferation of sevoflurane-treated cardiomyocytes with H/R injury but inhibited cell apoptosis, while the downregulation of miR-221-5p showed an opposite trend to that of ADAM8 overexpression. The present data provide evidence that sevoflurane can mediate the miR-221-5p/ADAM8 axis, playing a better protective role compared with propofol in cardiomyocytes with H/R injury.

Keywords:  ADAM8; cardiomyocytes; hypoxia-reoxygenation; microRNA-221-5p; propofol; sevoflurane

DOI:  https://doi.org/10.3892/etm.2021.10325
J Ethnopharmacol. 2021 Jul 12. pii: S0378-8741(21)00640-1. [Epub ahead of print] 114411

Yi-Qi-Jian-Pi formula modulates the PI3K/AKT signaling pathway to attenuate acute-on-chronic liver failure by suppressing hypoxic injury and apoptosis in vivo and in vitro.

Li Tang, Feixia Wang, Lingyan Xiao, Min Shen, Siwei Xia, Zili Zhang, Feng Zhang, Shizhong Zheng, Shanzhong Tan.

   ETHNOPHARMACOLOGICAL RELEVANCE: Acute-on-chronic liver failure (ACLF) is a key complication of chronic hepatitis, with a relatively high mortality rate and limited treatment options, which dramatically threatens human lives. Yi-Qi-Jian-Pi formula (YQJPF) is a herbal compound commonly used to treat liver failure.
AIM OF THE STUDY: The purpose of this research is to discuss the potential molecular biological effect and mechanism of YQJPF in ACLF.
MATERIALS AND METHODS: In this study, we created a rat model of ACLF by CCl4-, LPS- and D-Galactosamine (D-Gal) and an in vitro model of LPS-induced hepatocyte damage. The specific components of YQJPF and potential mechanism were explored based on bioinformatics analyses. Furthermore, we verified the effect of YQJPF on ACLF using immunohistochemistry, RT-qPCR, western blotting, and flow cytometry.
RESULTS: Our research demonstrated that, after YQJPF treatment, hepatocyte injury in rats was relieved. Bioinformatics analysis showed that PI3K/AKT, HIF-1, mitochondrial apoptosis pathways played prominent roles. YQJPF promoted HIF-1α protein expression and exerted protective effects against hypoxic injury, simultaneously reducing mitochondrial ROS production, suppressing hepatocyte apoptosis. Furthermore, we showed that YQJPF accelerates PI3K/AKT pathway activation, a known broad-spectrum inhibitor of PI3K. LY294002, which was used for reverse verification, suppressed the effect of YQJPF on hypoxic injury and ROS-mediated hepatocyte apoptosis.
CONCLUSIONS: YQJPF ameliorates liver injury by suppressing hypoxic injury and ROS-mediated hepatocyte apoptosis by modulating the PI3K/AKT pathway.

Keywords:  Apoptosis; Hypoxic liver injury; Liver failure; Network pharmacology; Yi-Qi-Jian-Pi formula

DOI:  https://doi.org/10.1016/j.jep.2021.114411
Oncogenesis. 2021 Jul 16. 10(7): 52

USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis.

Ruize Gao, David Buechel, Ravi K R Kalathur, Marco F Morini, Mairene Coto-Llerena, Caner Ercan, Salvatore Piscuoglio, Qian Chen, Tanja Blumer, Xueya Wang, Eva Dazert, Markus H Heim, Michael N Hall, Fengyuan Tang, Gerhard Christofori.

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

DOI: https://doi.org/10.1038/s41389-021-00338-7
J Agric Food Chem. 2021 Jul 16.

Isorhamnetin Promotes MKN-45 Gastric Cancer Cell Apoptosis by Inhibiting PI3K-Mediated Adaptive Autophagy in a Hypoxic Environment.

Chenghao Li, Jiawei Li, Yan Li, Ling Li, Yali Luo, Junjie Li, Yiming Zhang, Yanru Wang, Xiuzhu Liu, Xiaotian Zhou, Hongxia Gong, Xiaojie Jin, Yongqi Liu.

  A tumor-related hypoxic microenvironment can promote the proliferation of gastric cancer cells, and hypoxic-induced autophagy is the main mechanism of protection against hypoxia in gastric cancer cells. Isorhamnetin (ISO) is a chemical substance derived from plants, mainly from the sea buckthorn. Previous studies have shown that ISO has antitumor effects, but the effects of ISO against gastric cancer in a hypoxic environment are still unknown. In this study, we investigated the effects of ISO against gastric cancer in a hypoxic environment and the mechanisms underlying ISO-induced gastric cancer cell death. The results show that ISO targeted PI3K and blocked the PI3K-AKT-mTOR signaling pathway, significantly inhibiting gastric cancer cell autophagy in a hypoxic environment, inhibiting cell proliferation, decreasing mitochondrial membrane potential, and promoting mitochondria-mediated apoptosis. ISO, a functional food component, is a promising candidate for the treatment of gastric cancer.

Keywords:  PI3K; apoptosis; autophagy; gastric cancer; isorhamnetin

DOI:  https://doi.org/10.1021/acs.jafc.1c02620
Cancer Immunol Immunother. 2021 Jul 15.

A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.

Anneloes van Duijn, Karin J Willemsen, Nathalie O P van Uden, Lieke Hoyng, Sterre Erades, Jan Koster, Rosalie M Luiten, Walbert J Bakker.

  Cancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.

Keywords:  HIF1; Hypoxia; IFNγ; Immunotherapy; Melanoma; PD-L1

DOI:  https://doi.org/10.1007/s00262-021-03007-1
Cell Death Dis. 2021 Jul 15. 12(7): 711

Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.

Junyi Yan, Chun-Ling Sun, Seokyung Shin, Marc Van Gilst, C Michael Crowder.

Mitochondria are the main oxygen consumers in cells and as such are the primary organelle affected by hypoxia. All hypoxia pathology presumably derives from the initial mitochondrial dysfunction. An early event in hypoxic pathology in C. elegans is disruption of mitochondrial proteostasis with induction of the mitochondrial unfolded protein response (UPRmt) and mitochondrial protein aggregation. Here in C. elegans, we screen through RNAis and mutants that confer either strong resistance to hypoxic cell death or strong induction of the UPRmt to determine the relationship between hypoxic cell death, UPRmt activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA). We find that resistance to hypoxic cell death invariantly mitigated HIMPA. We also find that UPRmt activation invariantly mitigated HIMPA. However, UPRmt activation was neither necessary nor sufficient for resistance to hypoxic death and vice versa. We conclude that UPRmt is not necessarily hypoxia protective against cell death but does protect from mitochondrial protein aggregation, one of the early hypoxic pathologies in C. elegans.

DOI: https://doi.org/10.1038/s41419-021-03979-z
ACS Appl Mater Interfaces. 2021 Jul 14.

Analysis of the Internal Hypoxic Environment in Solid Tumor Tissue Using a Folding Paper System.

Chia-Hao Huang, Kowit-Yu Chong, Kin Fong Lei.

  Hypoxia is a nonphysiological oxygen tension which is common in most malignant tumors. Hypoxia stimulates complicated cell signaling networks in cancer cells, e.g., the HIF, PI3K, MAPK, and NFκB pathways. Then, cells release a number of cytokines such as VEGFA to promote the growth of peripheral blood vessels and lead to metastasis. In the current work, understanding of the internal hypoxic environment in solid tumor tissue was attempted by developing a folding paper system. A paper-based solid tumor was constructed by folding a filter paper cultured with cancer cells. The cellular response in each layer could be analyzed by disassembling the folded paper after the culture course. The result showed that an internal hypoxic environment was successfully reproduced in the paper-based solid tumor. The cells in the inner layer expressed high levels of HIF1-α and VEGFA. Hence, proliferation and migration of endothelial cells were shown to be induced by the cells located in the internal hypoxic environment. Moreover, the paper-based solid tumor was transplanted into nude mice for the study of hypoxic response and angiogenesis. The crosstalk between internal and external parts of solid tumor tissue could be analyzed by sectioning each layer of the paper-based solid tumor. This approach provides a favorable analytical method for the discovery of the interaction between cancer cells, hypoxia, and peripheral angiogenesis.

Keywords:  angiogenesis; cancer cells; cancer metastasis; hypoxia; paper-based microfluidics; solid tumor

DOI:  https://doi.org/10.1021/acsami.1c08857
Nat Commun. 2021 07 14. 12(1): 4308

The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.

Eui Jung Moon, Stephano S Mello, Caiyun G Li, Jen-Tsan Chi, Kaushik Thakkar, Jacob G Kirkland, Edward L Lagory, Ik Jae Lee, Anh N Diep, Yu Miao, Marjan Rafat, Marta Vilalta, Laura Castellini, Adam J Krieg, Edward E Graves, Laura D Attardi, Amato J Giaccia.

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

DOI: https://doi.org/10.1038/s41467-021-24631-6
Pathol Oncol Res. 2021 ;27 604600

The Clinicopathological Significance of YAP/TAZ Expression in Hepatocellular Carcinoma with Relation to Hypoxia and Stemness.

Hyunjin Park, Yangkyu Lee, Kiryang Lee, Hyejung Lee, Jeong Eun Yoo, Soomin Ahn, Young Nyun Park, Haeryoung Kim.

  Background/Aims: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) activation has been implicated in hepatocarcinogenesis and hepatic progenitor cell differentiation, and hypoxia has been shown to induce nuclear translocation of YAP in cancer cells. Here, we aimed to investigate the relationship between hypoxia, YAP and TAZ expression and stemness-related marker expression in human hepatocellular carcinomas (HCCs) and its clinical implications. Methods: Immunohistochemical stains were performed on tissue microarrays from 305 surgically resected HCCs, and the expression status of YAP and TAZ were correlated with CAIX, stemness markers (K19, EpCAM) and epithelial-mesenchymal transition (EMT)-related markers (uPAR, ezrin). The clinicopathological significance of YAP/TAZ expression was analyzed with relation to CAIX expression status. Results: YAP and TAZ expression were seen in 13.4 and 4.3% of HCCs, respectively. YAP/TAZ-positive HCCs frequently demonstrated higher serum AFP levels, microvascular invasion, advanced tumor stage, increased proliferative activity and expression of stemness- and EMT-related markers, CAIX, p53 and Smad2/3 (p < 0.05, all). Interestingly, YAP/TAZ-positivity was associated with microvascular invasion, higher serum AFP levels, stemness and EMT-related marker expression only in tumors expressing CAIX (p < 0.05, all), while these associations were not seen in CAIX-negative HCCs. Conclusions: YAP/TAZ expression is associated with vascular invasion, stemness and EMT in HCCs with hypoxia marker expression. The effect of Hippo signaling pathway deregulation in HCC may depend on the presence or absence of a hypoxic microenvironment, and hypoxia marker expression status should be taken into account when considering the use of YAP/TAZ as markers of aggressive biologic behavior in HCC.

Keywords:  Hippo pathway; hepatocellular carcinoma; hypoxia; immunohistochemistry; stemness

DOI:  https://doi.org/10.3389/pore.2021.604600
Vet J. 2021 Jul 09. pii: S1090-0233(21)00109-X. [Epub ahead of print] 105714

Hypoxia and chronic kidney disease: Possible mechanisms, therapeutic targets, and relevance to cats.

Sarah Spencer, Caroline Wheeler-Jones, Jonathan Elliott.

  There is mounting evidence that kidney ischaemia/hypoxia plays an important role in feline chronic kidney disease (CKD) development and progression, as well as in human disease and laboratory animal models. Ischaemic acute kidney injury is widely accepted as a cause of CKD in people and data from laboratory species has identified some of the pathways underlying this continuum. Experimental kidney ischaemia in cats results in morphological changes, namely chronic tubulointerstitial inflammation, tubulointerstitial fibrosis, and tubular atrophy, akin to those observed in naturally-occurring CKD. Multiple situations are envisaged that could result in acute or chronic episodes of kidney hypoxia in cats, while risk factors identified in epidemiological studies provide further support that kidney hypoxia contributes to spontaneously occurring feline CKD. This review evaluates the evidence for the role of kidney ischaemia/hypoxia in feline CKD and the proposed mechanisms and consequences of kidney hypoxia. As no effective treatments exist that substantially slow or prevent feline CKD progression, there is a need for novel therapeutic strategies. Targeting kidney hypoxia is one such promising approach, with therapies including those that attenuate the hypoxia-inducible factor (HIF) pathway already being utilised in human CKD.

Keywords:  Hypoxia-inducible factor; Ischaemia; Tubulointerstitial fibrosis

DOI:  https://doi.org/10.1016/j.tvjl.2021.105714
Neural Regen Res. 2022 Feb;17(2): 318-319

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Alfredo Garcia-Alix, Juan Arnaez.

DOI: https://doi.org/10.4103/1673-5374.317972
J Bioenerg Biomembr. 2021 Jul 12.

FoxO4 negatively modulates USP10 transcription to aggravate the apoptosis and oxidative stress of hypoxia/reoxygenation-induced cardiomyocytes by regulating the Hippo/YAP pathway.

Jingwen Huang, Yu Liu, Mei Wang, Rong Wang, Huifen Ling, Yan Yang.

  Acute myocardial infarction (AMI) is the main cause of death in the whole world. This study aimed to investigate whether forkhead box O4 (FoxO4) could negatively modulate ubiquitin specific peptidase 10 (USP10) transcription to aggravate the apoptosis and oxidative stress of hypoxia/reoxygenation (H/R)-induced cardiomyocytes through Hippo/YAP pathway. mRNA expression as well as protein expressions of USP10 and FoxO4 in H9C2 cells after H/R induction or transfection were respectively detected by Reverse transcription-quantitative (RT-q) PCR analysis and Western blot. The viability and apoptosis of H9C2 cells after H/R induction or transfection were respectively detected by CCK-8 and TUNEL assays. The expressions of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in H9C2 cells after H/R induction or transfection were analyzed using appropriate kits and intracellular reactive oxygen species (ROS) levels were detected using a ROS Assay Kit. Dual luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) have adopted to confirm the combination of USP10 and FoxO4. Western blot was also used to analyze the expression of apoptosis-related proteins and Hippo/YAP pathway-related proteins. As a result, USP10 expression was decreased in H/R-induced H9C2 cells in a time-dependent manner. USP10 overexpression increased the viability and suppressed the apoptosis and oxidative stress of H/R-induced H9C2 cells. In addition, FoxO4 modulated USP10 transcription. FoxO4 expression was increased in H9C2 cells induced by H/R. FoxO4 overexpression could reverse the protective effects of USP10 overexpression on H/R-induced H9C2 cells by regulating the Hippo/YAP signaling pathway. In conclusion, FoxO4 negatively modulated USP10 transcription to aggravate the apoptosis and oxidative stress of H/R-induced H9C2 cells via blocking Hippo/YAP pathway.

Keywords:  Cardiomyocytes; FoxO4; Hippo/YAP pathway; Oxidative stress; USP10

DOI:  https://doi.org/10.1007/s10863-021-09910-7
Hypertens Res. 2021 Jul 13.

Testosterone attenuates hypoxia-induced hypertension by affecting NRF1-mediated transcriptional regulation of ET-1 and ACE.

Shan Jiang, Guijuan Chen, Zhihui Yang, Dan Wang, Yapeng Lu, Li Zhu, Xueting Wang.

  Hypertension induced by hypoxia at high altitude is one of the typical symptoms of high-altitude reactions (HARs). Emerging evidence indicates that endothelial abnormalities, including increases in angiotensin-2 (Ang-2) and endothelin-1 (ET-1), are closely associated with hypertension. Thus, low blood oxygen-induced endothelial dysfunction through acceleration of Ang-2 and ET-1 synthesis may alleviate HARs. In this study, we investigated the effects of hypoxia on rat blood pressure (BP) and endothelial injury. We found that BP increased by 10 mmHg after treatment with 10% O2 (~5500 m above sea level) for 24 h. Consistently, serum Ang-2 and ET-1 levels were increased along with decreases in NO levels. In endothelial cells, angiotensin-1-converting enzyme (ACE) and ET-1 expression levels were upregulated. Interestingly, nuclear respiratory factor 1 (NRF1) levels were also upregulated, consistent with the changes in ACE and ET-1 levels. We further demonstrated that NRF1 transcriptionally activated ACE and ET-1 by directly binding to their promoter regions, suggesting that the endothelial cell dysfunction induced by hypoxia was due to NRF1-dependent upregulation of ACE and ET-1. Surprisingly, testosterone supplementation showed significant protective effects on BP, while castration induced even higher BPs in rats exposed to hypoxia. We further showed that physiological testosterone repressed NRF1 expression in vivo and in vitro and thereby reduced Ang-2 and ET-1 levels, which was dependent on hypoxia. In summary, we have identified that physiological testosterone protects against hypoxia-induced hypertension through inhibition of NRF1, which transcriptionally regulates ACE and ET-1 expression.

Keywords:  Hypertension; Hypoxia; Nuclear respiratory factor 1; Testosterone; Vascular endothelial cells

DOI:  https://doi.org/10.1038/s41440-021-00703-4
Neuropharmacology. 2021 Jul 13. pii: S0028-3908(21)00268-9. [Epub ahead of print] 108713

Effects of alcohol on brain oxygenation and brain hypoxia induced by intravenous heroin.

Shruthi A Thomas, Carlos M Curay, Eugene A Kiyatkin.

  Alcohol is the most commonly used psychoactive drug, often taken in conjunction with opioid drugs. Since both alcohol and opioids can induce CNS depression, it is often assumed that alcohol potentiates the known hypoxic effects of opioid drugs, thus contributing to coma and death during opioid overdose. To address this supposition, we used oxygen sensors to examine the effects of alcohol on brain oxygenation and hypoxic responses induced by intravenous heroin in awake, freely moving rats. To eliminate robust sensory effects of alcohol following its oral or intraperitoneal delivery, alcohol was administered directly into the stomach via chronically implanted intragastric catheters at human relevant doses. Alcohol delivered at a 0.5 g/kg dose did not affect brain oxygen levels, except for a weak transient increase during drug delivery. This phasic oxygen increase was stronger at a 2.0 g/kg alcohol dose and followed by a weaker tonic increase. Since alcohol absorption from intragastric delivery is much slower and more prolonged than with intraperitoneal or intravenous injections, the rapid rise of brain oxygen levels suggests direct action of alcohol on sensory afferents in the stomach well before the drug physically reaches brain tissue via circulation. Despite slow tonic increases in brain oxygen, alcohol at the 2.0 g/kg dose strongly potentiates heroin-induced oxygen responses, increasing both the magnitude and duration of oxygen decrease. Therefore, under the influence of alcohol, the use of opioid drugs becomes much more dangerous, increasing brain hypoxia and enhancing the probability of serious health complications, including coma and death.

Keywords:  Brain oxygen; Brain temperature; Central vasodilation; Neural activation; Opioid drugs; Peripheral vasoconstriction; Rats

DOI:  https://doi.org/10.1016/j.neuropharm.2021.108713
Sci Adv. 2021 Jul;pii: eabi4822. [Epub ahead of print]7(29):

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.

Juha Auvinen, Joona Tapio, Ville Karhunen, Johannes Kettunen, Raisa Serpi, Elitsa Y Dimova, Dipender Gill, Pasi Soininen, Tuija Tammelin, Juha Mykkänen, Katri Puukka, Mika Kähönen, Emma Raitoharju, Terho Lehtimäki, Mika Ala-Korpela, Olli T Raitakari, Sirkka Keinänen-Kiukaanniemi, Marjo-Riitta Järvelin, Peppi Koivunen.

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

DOI: https://doi.org/10.1126/sciadv.abi4822
Front Genet. 2021 ;12 667724

Circ_0124644 Serves as a ceRNA for miR-590-3p to Promote Hypoxia-Induced Cardiomyocytes Injury via Regulating SOX4.

Juan Tan, Weinan Pan, Huilin Chen, Yafang Du, Peiyong Jiang, Dianmei Zeng, Jie Wu, Kuang Peng.

  Circular RNA (circRNA) is an important factor for regulating the progression of many cardiovascular diseases, including acute myocardial infarction (AMI). However, the role of circ_0124644 in AMI progression remains unclear. Hypoxia was used to induce cardiomyocytes injury. The expression of circ_0124644, microRNA (miR)-590-3p, and SRY-box transcription factor 4 (SOX4) mRNA was measured by qRT-PCR. Cell counting kit 8 (CCK8) assay and flow cytometry were utilized to detect cell viability, cell cycle progression, and apoptosis. The protein levels of apoptosis markers and SOX4 were determined by western blot (WB) analysis, and the levels of oxidative stress markers were assessed using commercial Assay Kits. Dual-luciferase reporter assay, RIP assay, and RNA pull-down assay were employed to confirm the interaction between miR-590-3p and circ_0124644 or SOX4. Circ_0124644 was upregulated in AMI patients and hypoxia-induced cardiomyocytes. Hypoxia could inhibit cardiomyocytes viability, cell cycle process, and promote apoptosis and oxidative stress, while silencing circ_0124644 could alleviate hypoxia-induced cardiomyocytes injury. In terms of mechanism, circ_0124644 could target miR-590-3p. MiR-590-3p overexpression could relieve hypoxia-induced cardiomyocytes injury. Also, the suppressive effect of circ_0124644 knockdown on hypoxia-induced cardiomyocytes injury could be reversed by miR-590-3p inhibitor. Moreover, SOX4 was found to be a target of miR-590-3p, and its overexpression also could reverse the regulation of miR-590-3p on hypoxia-induced cardiomyocytes injury. Circ_0124644 silencing could alleviate hypoxia-induced cardiomyocytes injury by regulating the miR-590-3p/SOX4 axis, suggesting that it might be a target for alleviating AMI.

Keywords:  SOX4; acute myocardial infarction; circ_0124644; hypoxia; miR-590-3p

DOI:  https://doi.org/10.3389/fgene.2021.667724
Front Immunol. 2021 ;12 705511

Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer.

Jun-Peng Pei, Chun-Dong Zhang, Maimaititusun Yusupu, Cheng Zhang, Dong-Qiu Dai.

   Background: Hypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia.
Methods: We screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis.
Results: We developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits.
Conclusions: The hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.

Keywords:  gastric cancer; hypoxia; nomogram; prognosis; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.705511
Front Pharmacol. 2021 ;12 601846

Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury's Biological Network Based on Systematic Pharmacology.

Kailin Yang, Liuting Zeng, Anqi Ge, Yi Chen, Shanshan Wang, Xiaofei Zhu, Jinwen Ge.

  Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound (HCC) has definite curative effect on cerebral ischemic diseases, such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its mechanism for treating cerebral ischemia is still not fully explained. Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC's potential targets. The CIR genes were obtained from Genecards and OMIM and the protein-protein interaction (PPI) data of HCC's targets and IS genes were obtained from String database. After that, the DAVID platform was applied for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Finally, a series of animal experiments were carried out to further explore the mechanism of HCC intervention in CIR. Results: The prediction results of systematic pharmacology showed that HCC can regulate CIR-related targets (such as AKT1, MAPK1, CASP3, EGFR), biological processes (such as angiogenesis, neuronal axonal injury, blood coagulation, calcium homeostasis) and signaling pathways (such as HIF-1, VEGF, Ras, FoxO signaling). The experiments showed that HCC can improve the neurological deficit score, decrease the volume of cerebral infarction and up-regulate the expression of HIF-1α/VEGF and VEGFR protein and mRNA (p < 0.05). Conclusion: HCC may play a therapeutic role by regulating CIR-related targets, biological processes and signaling pathways found on this study.

Keywords:  HIF-VEGF pathway; Ischemic stroke; cerebral ischemia; cerebral ischemia-reperfusion injury; chinese medicine; hedysarum multijugum maxim-chuanxiong rhizoma compound; systematic pharmacology

DOI:  https://doi.org/10.3389/fphar.2021.601846
Front Physiol. 2021 ;12 680275

Microbiota Modulates Cardiac Transcriptional Responses to Intermittent Hypoxia and Hypercapnia.

Dan Zhou, Jin Xue, Yukiko Miyamoto, Orit Poulsen, Lars Eckmann, Gabriel G Haddad.

  The microbiota plays a critical role in regulating organismal health and response to environmental stresses. Intermittent hypoxia and hypercapnia, a condition that represents the main hallmark of obstructive sleep apnea in humans, is known to induce significant alterations in the gut microbiome and metabolism, and promotes the progression of atherosclerosis in mouse models. To further understand the role of the microbiome in the cardiovascular response to intermittent hypoxia and hypercapnia, we developed a new rodent cage system that allows exposure of mice to controlled levels of O2 and CO2 under gnotobiotic conditions. Using this experimental setup, we determined the impact of the microbiome on the transcriptional response to intermittent hypoxia and hypercapnia in the left ventricle of the mouse heart. We identified significant changes in gene expression in both conventionally reared and germ-free mice. Following intermittent hypoxia and hypercapnia exposure, we detected 192 significant changes in conventionally reared mice (96 upregulated and 96 downregulated) and 161 significant changes (70 upregulated and 91 downregulated) in germ-free mice. Only 19 of these differentially expressed transcripts (∼10%) were common to conventionally reared and germ-free mice. Such distinct transcriptional responses imply that the host microbiota plays an important role in regulating the host transcriptional response to intermittent hypoxia and hypercapnia in the mouse heart.

Keywords:  gnotobiotics; heart; intermittent hypoxia and hypercapnia; mice; transcriptome

DOI:  https://doi.org/10.3389/fphys.2021.680275
J Inflamm Res. 2021 ;14 2979-2991

Overexpression of Neutrophil MMP-9 and HIF-1α May Contribute to the Finger-Like Projections Formation and Histo-Pathogenesis in Nasal Inverted Papilloma.

Tao Li, Kai Sen Tan, Yan Yi Tu, Li Zhao, Jing Liu, Hsiao Hui Ong, De Yun Wang, Li Shi.

   Background: Nasal inverted papilloma (NIP) is defined based on its histological characteristic of inverted epithelium growth into the stroma. The inversion can result in epithelial growth in the underlying connective tissue stroma when the basement membrane completely separates from the epithelial layer. To date, such inversion mechanism underlying NIP's pathological phenomenon is unknown. Therefore, we hypothesized that mediators and soluble proteins released by neutrophils, the most predominant infiltrating cells in NIP, is vital in causing the epithelial changes and pathogenesis of NIP.
Methods: We collected 37 NIP tissues from patients who underwent surgical removal of NIP and performed hematoxylin-eosin (HE), immunohistochemical, and immunofluorescence staining to analyze in-depth the basic characteristics of NIP, including detecting the expression and distribution of MMPs and associated factors in NIP. Western blotting and quantitative real-time PCR were further performed to analyze the protein and mRNA expression levels of specific factors including MMPs, HIF-1α, and tissue inhibitors of metalloproteinases (TIMPs).
Results: We observed finger-like projections that insert into the epithelium in NIP tissue as its main characteristics. The projections contain fibroblasts, extracellular matrix, capillaries, and infiltrating inflammatory cells. We found abundant neutrophils clustered at the finger-like projection of NIP, and also noted MMP-1 and MMP-9 were up-regulated in NIP (p<0.05), whereas TIMP-1/3 was decreased. The expression level of HIF-1α was also found to be increased in NIP tissue. We further showed that MMP-9 and HIF-1α were mainly expressed by neutrophils and were predominantly observed in the finger-like projections that contribute to the NIP pathology.
Conclusion: Upregulation and release of MMP-9 and HIF-1α from infiltrating neutrophils may cause damage to the epithelial basement membrane and epithelial clefts, forming finger-like projections with angiogenesis and fibroblasts insertion, resulting in epithelial growth in the tissue stroma, a typical histo-pathological characteristic in NIP.

Keywords:  HIF-1α; MMP-9; finger-like projection; nasal inverted papilloma; neutrophils; pathogenesis

DOI:  https://doi.org/10.2147/JIR.S312605
Curr Opin Physiol. 2021 Jul 06.

Silent hypoxia in COVID-19: a gut microbiota connection.

Akshita Baiju Gopal, Soumyadeep Chakraborty, Pratyush Kumar Padhan, Alok Barik, Pragyesh Dixit, Debashish Chakraborty, Indrajit Poirah, Supriya Samal, Arup Sarkar, Asima Bhattacharyya.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has triggered the COVID-19 pandemic. Several factors induce hypoxia in COVID-19. Despite being hypoxic, some SARS-CoV-2-infected individuals do not experience any respiratory distress, a phenomenon termed "silent/happy hypoxia". Prolonged undetected hypoxia is dangerous, sometimes leading to death. A few studies attempted to unravel what causes silent hypoxia, however, the exact mechanisms are still elusive. Here, we aim to understand how SARS-CoV-2 causes silent hypoxia.

DOI: https://doi.org/10.1016/j.cophys.2021.06.010
Kardiol Pol. 2021 Jul 16.

Hypoxic induction of atrial natriuretic peptide (factor) secretion. An inflammatory IL-18 pathway is involved in the control of cardioprotective molecule.

Mikko Nikinmaa.

DOI: https://doi.org/10.33963/KP.a2021.0065