Hypoxia-inducible Factor Signaling Research Articles

Hypoxia and viral infectious diseases.

Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.

A structural analysis of the hypoxia response network.

BackgroundThe hypoxia-inducible factor-1 (HIF-1) signaling pathway is an important topic in high-altitude medicine. Network analysis is a novel method for integrating information on different aspects and levels of biological networks. However, this method has not been used in research on the HIF-1 signaling pathway network. To introduce this method into HIF-1-related research fields and verify its feasibility and effectiveness, we used a network analytical method to explore the structural attributes of the HIF-1 signaling pathway network.MethodsFirst, we analyzed the overall network of the HIF-1 signaling pathway using information retrieved from the Kyoto Encyclopedia of Genes and Genomes (KEGG). We performed topology analysis, centrality analysis, and subgroup analysis of the network. Then, we analyzed the core network based on the overall network analysis. We analyzed the properties of the topology, the bow-tie structure, and the structural complexity of the core network.ResultsWe obtained topological structure diagrams and quantitative indicators of the overall and core networks of the HIF-1 signaling pathway. For the structure diagrams, we generated topology diagrams of the network and the bow-tie structure of the core network. As quantitative indicators, we identified topology, centrality, subgroups, the bow-tie structure, and structural complexity. The topology indicators were the number of nodes, the number of lines, the network diameter, and the network density. The centrality indicators were the degree, closeness, and betweenness. The cohesive subgroup indicator was the components of the network. The bow-tie structure indicators included the core, input, and tendril-like structures. The structural complexity indicators included a power-law fitting model and its scale parameter.ConclusionsThe core network could be extracted based on the subgroup analysis of the overall network of the HIF-1 signaling pathway. The critical elements of the network could be identified in the centrality analysis. The results of the study show the feasibility and effectiveness of the network analytical method used to explore the network properties of the HIF-1 signaling pathway and provide support for further research.

Hypoxic and Pharmacological Activation of HIF Inhibits SARS-CoV-2 Infection of Lung Epithelial Cells

COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 1 million fatalities to date. Understanding how host factors modify the viral life cycle could inform susceptibility to viral infection and the design of new therapies. Viral replication is shaped by the cellular microenvironment and one important factor is local oxygen tension, where hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via a HIF-1α dependent signalling pathway. Further, hypoxia and Roxadustat inhibit viral replication in SARS-CoV-2 infected cells, showing that post-entry steps in the viral life cycle are oxygen-sensitive. This study highlights the importance of hypoxia and HIF signalling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention and/or treatment of COVID-19.Funding: The McKeating laboratory is funded by a Wellcome Investigator Award (IA) 200838/Z/16/Z, UK Medical Research Council (MRC) project grant MR/R022011/1 and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002). The Ratcliffe laboratory is funded by the Oxford Branch of the Ludwig Institute for Cancer Research; Wellcome IA 106241/Z/14/Z; the Francis Crick Institute, which receives core funding from Cancer Research UK (FC001501), UK MRC (FC001501) and Wellcome (FC001501); the Paradifference Foundation. PJR, EJH and TB are additionally funded by the COVID-19 Research Response Fund, University of Oxford. SK is funded by the Clarendon Scholarships Fund and the Christopher Welch Trust. The Davis laboratory is funded by Wellcome IA 209412/Z/17/Z and Wellcome Strategic Awards 091911/B/10/Z and 107457/Z/15/Z. JYL is funded by the Medial Sciences Graduate Studentship, University of Oxford. The Hinks laboratory is funded by grants from the Wellcome (104553/z/14/z, 211050/Z/18/z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre; the views expressed are those of the authors and not those of the NHS or NIHR. Conflict of Interest: EJH is employed under the Cambridge Experimental Medicine Initiative, which is partly funded by AstraZeneca although they have not been involved in this project. The other authors declare no financial interests.Ethical Approval: The study was reviewed by the Oxford Research Ethics Committee B (18/SC/0361).

Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells.

SummaryCOVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.

PHD3 mediates denervation skeletal muscle atrophy through Nf-κB signal pathway.

Skeletal muscle is the largest organ of the body, the development of skeletal muscle is very important for the health of the animal body. Prolyl hydroxylases (PHDs) are the classical regulator of the hypoxia inducible factor (HIF) signal pathway, many researchers found that PHDs are involved in the muscle fiber type transformation, muscle regeneration, and myocyte differentiation. However, whether PHDs can impact the protein turnover of skeletal muscle is poorly understood. In this study, we constructed denervated muscle atrophy mouse model and found PHD3 was highly expressed in the atrophic muscles and there was a significant correlation between the expression level of PHD3 and skeletal muscle weight which was distinct from PHD1 and PHD2. Then, the similar results were getting from the different weight muscles of normal mice. To further verify the relationship between PHD3 and skeletal muscle protein turnover, we established a PHD3 interference model by injecting PHD3 sgRNA virus into tibialis anterior muscle (TA) muscle of MCK-Cre-cas9 mice and transfecting PHD3 shRNA lentivirus into primary satellite cells. It was found that the Knock-out of PHD3 in vivo led to a significant increase in muscle weight and muscle fiber area (P<.05). Besides, the activity of protein synthesis signal pathway increased significantly, while the protein degradation pathway was inhibited evidently (P<.05). In vitro, the results of 5-ethynyl-2'-deoxyuridine (EdU) and tetramethylrhodamine ethyl ester (TMRE) fluorescence detection showed that PHD3 interference could lead to a decrease in cell proliferation and an increase of cell apoptosis. After the differentiation of satellite cells, the production of puromycin in the interference group was higher than that in the control group, and the content of 3-methylhistidine in the interference group was lower than that in the control group (P<.05) which is consistent with the change of protein turnover signal pathway in the cell. Mechanistically, there is an interaction between PHD3, NF-κB, and IKBα which was detected by immunoprecipitation. With the interfering of PHD3, the expression of the inflammatory signal pathway also significantly decreased (P<.05). These results suggest that PHD3 may affect protein turnover in muscle tissue by mediating inflammatory signal pathway. Finally, we knocked out PHD3 in denervated muscle atrophy mice and LPS-induced myotubes atrophy model. Then, we found that the decrease of PHD3 protein level could alleviate the muscle weight and muscle fiber reduction induced by denervation in mice. Meanwhile, the protein level of the inflammatory signal pathway and the content of 3-methylhistidine in denervated atrophic muscle were also significantly reduced (P<.05). In vitro, PHD3 knock-out could alleviate the decrease of myotube diameter induced by LPS, and the expression of protein synthesis pathway was also significantly increased (P<.05). On the contrary, the expression level of protein degradation and inflammatory signal pathway was significantly decreased (P<.05). Through these series of studies, we found that the increased expression of PHD3 in denervated muscle might be an important regulator in inducing muscle atrophy, and this process is likely to be mediated by the inflammatory NF-κB signal pathway.

Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications.

Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, and a clinically malignant phenotype. At the nexus of these interconnected pathways are hypoxia-inducible factors (HIFs) which orchestrate transcriptional responses under hypoxia. The following review summarizes current literature regarding effects of hypoxia on DNA repair, metastasis, epithelial-to-mesenchymal transition, the cancer stem cell phenotype, and therapy resistance. We also discuss mechanisms and pathways, such as HIF signaling, mitochondrial dynamics, exosomes, and the unfolded protein response, that contribute to hypoxia-induced phenotypic changes. Finally, novel therapeutics that target the hypoxic tumor microenvironment or interfere with hypoxia-induced pathways are reviewed.

Regulation of lysyl oxidase expression in THP-1 cell-derived M2-like macrophages.

Lysyl oxidase (LOX) is a copper-containing enzyme and its overexpression in tumor tissues promote tumor metastasis through the crosslinking of extracellular matrix. Our previous report demonstrated that LOX expression is significantly increased in human leukemic THP-1 cell-derived M2-like macrophages, and histone modification plays a key role in its induction. However, the rigorous mechanism of LOX regulation remains unclear. In this study, we investigated the role of functional transcription factors, hypoxia-inducible factor 1α (HIF1α), signal transducer and activator of transcription 3 (STAT3) and forkhead box O1 (FOXO1) in LOX regulation in M2-like macrophages. HIF1α expression was significantly increased in M2-like macrophages, and HIF1α inhibitor, TX402, suppressed LOX induction. The significant STAT3 activation was also observed in M2-like macrophages. Additionally, LOX induction was canceled in the presence of STAT3 inhibitor, S3I-201, suggesting that HIF1α and STAT3 pathways play a critical role in LOX induction. On the other hand, our ChIP results clearly indicated that the enrichment of FOXO1 within the lox promoter region was dramatically decreased in M2-like macrophages. In this context, knockdown of FOXO1 further enhanced LOX induction. LOX induction and HIF1α binding to the lox promoter region were suppressed in FOXO1-overexpressed cells, suggesting that the FOXO1 binding to the lox promoter region counteracted HIF1α binding to that region. Overall, the present data suggested that both of HIF1α and STAT3 were required for LOX induction in M2-like macrophages, and loss of FOXO1 within the lox promoter region facilitated HIF1α binding to that region which promoted LOX induction.

Correction to: Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression

Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a key role in cancer progression by enhancing glycolysis through activating the transcription of glycolytic genes. JMJD2D, a histone demethylase that specifically demethylates H3K9me2/3, can promote colorectal cancer (CRC) progression. However, it is unknown whether JMJD2D could promote CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. In this study, we found that downregulation of JMJD2D inhibited the glycolysis in CRC cells through suppressing HIF1 signaling pathway to downregulate glycolytic gene expression. Restoring HIF1 signaling by enforced expression of HIF1α in JMJD2D-knockdown CRC cells partially recovered CRC cell glycolysis, proliferation, migration, invasion, xenograft growth, and metastasis, suggesting that JMJD2D promotes CRC progression by enhancing glycolysis through activating HIF1 signaling pathway. JMJD2D activated HIF1 signaling pathway through three different mechanisms: JMJD2D cooperated with the transcription factor SOX9 to enhance mTOR expression and then to promote HIF1α translation; JMJD2D cooperated with the transcription factor c-Fos to enhance HIF1β transcription; JMJD2D interacted and cooperated with HIF1α to enhance the expression of glycolytic gene. The demethylase-defective mutant of JMJD2D could not induce the expression of mTOR, HIF1α, HIF1β, and glycolytic genes, suggesting that the demethylase activity of JMJD2D is important for glycolysis through activating HIF1 signaling. Clinically, a highly positive correlation between the expression of JMJD2D and mTOR, HIF1β, and several glycolytic genes in human CRC specimens was identified. Collectively, our study reveals an important role of JMJD2D in CRC progression by enhancing glycolysis through activating HIF1 signaling pathway.

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer.

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.

Angiotensin II blockers improve cardiac coronary flow under hemodynamic pressure overload.

Coronary flow velocity (CFV) is reduced in pathologic cardiac hypertrophy. This functional reduction is linked to adverse cardiac remodeling, hypertension and fibrosis, and angiotensin II (AngII) is a key molecular player. Angiotensin receptor blockers (ARBs) are known to attenuate adverse cardiac remodeling and fibrosis following increased afterload, while the mechanism by which these drugs offer clinical benefits and regulate hemodynamics remains unknown. To establish a direct connection between coronary flow changes and angiotensin-induced hypertension, we used a Doppler echocardiographic method in two distinct disease models. First, we performed serial echocardiography to visualize coronary flow and assess heart function in patients newly diagnosed with hypertension and currently on ARBs or calcium channel blockers (CCBs). CFV improved significantly in the hypertensive patients after 12 weeks of ARB treatment but not in those treated with CCBs. Second, using murine models of pressure overload, including Ang II infusion and aortic banding, we mimicked the clinical conditions of Ang II- and mechanical stress-induced hypertension, respectively. Both Ang II infusion and aortic banding increased the end-systolic pressure-volume relationship and cardiac fibrosis, but interestingly, only Ang II infusion resulted in a significant reduction in CFV and corresponding activation of pressure-sensitive proteins, including connective tissue growth factor, hypoxia-inducible factor 1α and signal transducer and activator of transcription 3. These data support the existence of a molecular and functional link between AngII-induced hemodynamic remodeling and alterations in coronary vasculature, which, in part, can explain the clinical benefit of ARB treatment in hypertensive patients.

Uncovering the Anti-Lung-Cancer Mechanisms of the Herbal Drug FDY2004 by Network Pharmacology.

With growing evidence on the therapeutic efficacy and safety of herbal drugs, there has been a substantial increase in their application in the lung cancer treatment. Meanwhile, their action mechanisms at the system level have not been comprehensively uncovered. To this end, we employed a network pharmacology methodology to elucidate the systematic action mechanisms of FDY2004, an anticancer herbal drug composed of Moutan Radicis Cortex, Persicae Semen, and Rhei Radix et Rhizoma, in lung cancer treatment. By evaluating the pharmacokinetic properties of the chemical compounds present in FDY2004 using herbal medicine-associated databases, we identified its 29 active chemical components interacting with 141 lung cancer-associated therapeutic targets in humans. The functional enrichment analysis of the lung cancer-related targets of FDY2004 revealed the enriched Gene Ontology terms, involving the regulation of cell proliferation and growth, cell survival and death, and oxidative stress responses. Moreover, we identified key FDY2004-targeted oncogenic and tumor-suppressive pathways associated with lung cancer, including the phosphatidylinositol 3-kinase-Akt, mitogen-activated protein kinase, tumor necrosis factor, Ras, focal adhesion, and hypoxia-inducible factor-1 signaling pathways. Overall, our study provides novel evidence and basis for research on the comprehensive anticancer mechanisms of herbal medicines in lung cancer treatment.

Gain of HIF1 Activity and Loss of miRNA let-7d Promote Breast Cancer Metastasis to the Brain via the PDGF/PDGFR Axis.

Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA let-7d concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM2), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM2 and MDA231-BrM2). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM2 model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis. SIGNIFICANCE: These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/594/F1.large.jpg.See related article by Thies et al., p. 606.

Network Pharmacology Integrated Molecular Docking Reveals the Anti-COVID-19 Mechanism of Yinma Jiedu Granules

To investigate the mechanism of action of components of Yinma Jiedu granules in the treatment of coronavirus disease 2019 (COVID-19) using network pharmacology and molecular docking. The main chemical components of Yinma Jiedu granules were collected in the literature and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. Using the SwissTargetPrediction database, the targets of the active component were identified and further correlated to the targets of COVID-19 through the GeneCards database. The overlapping targets of Yinma Jiedu granules components and COVID-19 were identified as the research target. Using the Database for Annotation, Visualization and Integrated Discovery database to carry out the target gene function Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway annotation and Cytoscape 3.6.1 software was used to construct a “component-target-pathway” network. The protein-protein interaction network was built using Search Tool for the Retrieval of Interacting Genes/Proteins database. Using Discovery Studio 2016 Client software to study the virtual docking of key protein and active components. One hundred active components were screened from the Yinma Jiedu Granules that involved 67 targets, including mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor, tumor necrosis factor, tumor protein 53, and MAPK1. These targets affected 109 signaling pathways including hypoxia-inducible factor-1, apoptosis, and Toll-like receptor signaling pathways. Molecular docking results showed that the screened active components have a strong binding ability to the key targets. In this study, through network pharmacology and molecular docking, we justified the multicomponent, multitarget, and multipathways of Yinma Jiedu Granules in the treatment of COVID-19.

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Background & AimsHypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication.MethodsUsing cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle.ResultsCulturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family.ConclusionsIdentifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection.Lay summaryViral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets.

SARS-CoV-2 Proteins Exploit Host's Genetic and Epigenetic Mediators for the Annexation of Key Host Signaling Pathways.

The constant rise of the death toll and cases of COVID-19 has made this pandemic a serious threat to human civilization. Understanding of host-SARS-CoV-2 interaction in viral pathogenesis is still in its infancy. In this study, we utilized a blend of computational and knowledgebase approaches to model the putative virus-host interplay in host signaling pathways by integrating the experimentally validated host interactome proteins and differentially expressed host genes in SARS-CoV-2 infection. While searching for the pathways in which viral proteins interact with host proteins, we discovered various antiviral immune response pathways such as hypoxia-inducible factor 1 (HIF-1) signaling, autophagy, retinoic acid-inducible gene I (RIG-I) signaling, Toll-like receptor signaling, fatty acid oxidation/degradation, and IL-17 signaling. All these pathways can be either hijacked or suppressed by the viral proteins, leading to improved viral survival and life cycle. Aberration in pathways such as HIF-1 signaling and relaxin signaling in the lungs suggests the pathogenic lung pathophysiology in COVID-19. From enrichment analysis, it was evident that the deregulated genes in SARS-CoV-2 infection might also be involved in heart development, kidney development, and AGE-RAGE signaling pathway in diabetic complications. Anomalies in these pathways might suggest the increased vulnerability of COVID-19 patients with comorbidities. Moreover, we noticed several presumed infection-induced differentially expressed transcription factors and epigenetic factors, such as miRNAs and several histone modifiers, which can modulate different immune signaling pathways, helping both host and virus. Our modeling suggests that SARS-CoV-2 integrates its proteins in different immune signaling pathways and other cellular signaling pathways for developing efficient immune evasion mechanisms while leading the host to a more complicated disease condition. Our findings would help in designing more targeted therapeutic interventions against SARS-CoV-2.

FAM13A promotes proliferation of bovine preadipocytes by targeting Hypoxia-Inducible factor-1 signaling pathway

ABSTRACT The family with sequence similarity 13 member A (FAM13A) gene has been discovered in recent years and is related to metabolism. In this study, the function of FAM13A in precursor adipocyte proliferation in Qinchuan cattle was investigated using fluorescence quantitative polymerase chain reaction (PCR), western blotting, 5-ethynyl-2′-deoxyuridine staining, and other tests. FAM13A promoted precursor adipocyte proliferation. To determine the pathway FAM13A was involved in, transcriptome sequencing, fluorescence quantitative PCR, western blotting, and other tests were used, which identified the hypoxia inducible factor-1 (HIF-1) signalling pathway. Finally, cobalt chloride, a chemical mimic of hypoxia, was used to treat precursor adipocytes. mRNA and protein levels of FAM13A were significantly increased after hypoxia. Thus, FAM13A promoted bovine precursor adipocyte proliferation by inhibiting the HIF-1 signalling pathway, whereas chemically induced hypoxia negatively regulated FAM13A expression, regulating cell proliferation.

Role of Herbal Medicines in the Management of Brain Injury.

Brainis susceptible to oxidative stress due to its increased oxygen consumption and low antioxidant levels. Oxidative stress plays a crucial role in the pathogenesis of various neurological diseases. This review on the role of herbal medicines in the management of brain injury was performed by searching Web of Science, PubMed, Google Scholar, Scopus, and Iran Medex between 1976 to January 2020. The search words contained brain injury, and the total number of publications for the review study was 32. Studies with various medicinal plants such as Acanthopanax senticosus, Bacopa monnieri, carnosol, Cassia mimosoides, Centella asiatica, Crocus sativus, Cuminum cyminum, curcumin, Feronia limonia, Gardenia jasminoides, Ginkgo biloba, Kaempferia parviflora, Mentha longifolia, Nigella sativa, olive, orientin, pomegranate, quercetin, rice bran, Rosa damascena, Thymus vulgaris, Viola odorata, Withania coagulans, Zingiber officinale, and Ziziphus spina-christi show a significant improvement in brain injury. The different mechanisms for improvement in brain injury by these medicinal plants include HIF-1 (hypoxia-inducible factor 1) signaling, free-radical scavenging, reduction of nitric oxide (NO) toxicity and acetylcholine esterase (AChE) activity, decrease of pAkt and its downstream targets, downregulation of the aquaporin-4 (AQP-4) and TLR4/NF-ĸB/TNF-α signal, reduction in malondialdehyde and NO levels, increasing neuronal density in the hippocampus, and inhibition of oxidative stress. In this review, the neuroprotective actions and molecular mechanisms of herbal medicines are evaluated by reviewing available studies.

Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation

Hypoxia-induced inflammation is the critical pathological feature of acute kidney injury (AKI). Activation of hypoxia-inducible factor (HIF) signaling is considered as a central mechanism of body adapting to hypoxia. Hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 (Roxadustat) is a first-in-class HIF stabilizer for the treatment of patients with renal anemia. The current study aimed to investigate whether FG-4592 could protect against ischemia/reperfusion (I/R)-induced kidney injury via inhibiting inflammation. Here, efficacy of FG-4592 was evaluated in a mice model of I/R-induced AKI. Interestingly, improved renal function and renal tubular injuries, combined with reduced kidney injury molecule-1 were observed in the mice with FG-4592 administration. Meanwhile, inflammation responses in FG-4592-treated mice were also strikingly attenuated, as evidenced by the decreased infiltration of macrophages and neutrophils and down-regulated expression of inflammatory cytokines. In vitro, FG-4592 treatment significantly protected the tubular epithelial cells against hypoxia-induced injury, with suppressed inflammation and cell injuries. In summary, FG-4592 treatment could protect against the I/R-induced kidney injury possibly through diminishing tubular cells injuries and suppression of sequence inflammatory responses. Thus, our findings definitely offered a clinical potential approach in treating AKI.

The role of hypoxia-inducible factor 1 in tumor immune evasion.

Hypoxia-inducible factor 1 (HIF-1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF-1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF-1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF-1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2 , and programmed death-ligand 1/programmed death-1. Moreover, HIF-1 blocks tumor-associated antigen presentation via major histocompatibility complex class I chain-related/natural killer group 2, member D signaling. Tumor-associated autophagy and the release of tumor-derived exosomes contribute to HIF-1-mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF-1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF-1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF-1 in the regulation of tumor-derived exosomes, as well as the roles of HIF-1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF-1-mediated tumor immune evasion, leading to the development of effective HIF-1-targeting drugs and immunotherapies.

Mechanism of Salviae Miltiorrhizae Radix et Rhizoma in the Treatment of Knee Osteoarthritis Based on Network Pharmacology

ObjectiveThe molecular mechanism of Salviae Miltiorrhizae Radix et Rhizoma (SMRR) in the treatment of knee osteoarthritis (KOA) was analyzed based on network pharmacology.MethodsActive components and potential targets of SMRR were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. KOA targets were obtained from the OMIM, DisGeNET, DrugBank, PharmGKB, and GeneCards Databases. The potential targets of SMRR in the treatment of KOA were identified by the Venn diagram. A protein-protein interaction network was generated with the STRING database. Visualization of the interactions in a potential pharmacodynamic component-target network was accomplished with Cytoscape software. The Database for Annotation, Visualization, and Integrated Discovery database and R software were used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway annotation analyses of common targets. Molecular docking of the potential leading components, as determined by efficacy with the core target molecules, was performed with Discovery Studio.ResultsFifty-seven potential pharmacodynamic components and 58 potential targets of SMRR in the treatment of KOA were found. Bioinformatics analyses showed that the interleukin (IL)-17, hypoxia-inducible factor-1 (HIF-1), and tumor necrosis factor (TNF) signaling pathways, as well as the advanced glycation end product-receptor for advanced glycation end product signaling pathway in cases of diabetic complications, are related to the molecular mechanism of SMRR in the treatment of KOA. Molecular docking results showed that luteolin, tanshinone IIA, cryptotanshinone, and other components of SMRR had a strong affinity for MYC, signal transducer and activator of transcription 3, caspase-3 (CASP3), JUN, cyclin D1, prostaglandin endoperoxide synthase 2 (PTGS2), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), protein kinase B, vascular endothelial growth factor A, and other targets.ConclusionSMRR indirectly regulates IL-17, HIF-1, TNF, and other signal transduction pathways by regulating the expression of proteins, including PTGS2, MAPK1, EGFR, and CASP3, thus playing a role in promoting chondrocyte proliferation, improving microcirculation, eliminating free radicals, and inhibiting inflammatory factors.