Redoxisome Update: TRX and TXNIP/TBP2-Dependent Regulation of NLRP-1/NLRP-3 Inflammasome.

Recent studies have provided evidence for the direct binding of thioredoxin-1 (TRX1) to a component of inflammasome complex NLR family pyrin domain containing 1 (NLRP-1). This interaction suggests a potential role for TRX1 in the regulation of the NLRP-1 inflammasome. Furthermore, the NLRP-3 inflammasome is known to bind TRX1 and its inhibitor, TRX-binding protein-2/TRX-interacting protein/vitamin D3 upregulated protein-1 (TBP2/TXNIP/VDUP-1). This binding forms a redox-sensitive complex, termed the "Redoxisome," as described previously. However, the specific functions of NLRP-1 within the redoxisome complex remain undefined. Antioxid. Redox Signal. 40, 595-597.

Using nanopore sequencing to identify fungi from clinical samples with high phylogenetic resolution.

The study of microbiota has been revolutionized by the development of DNA metabarcoding. This sequence-based approach enables the direct detection of microorganisms without the need for culture and isolation, which significantly reduces analysis time and offers more comprehensive taxonomic profiles across broad phylogenetic lineages. While there has been an accumulating number of researches on bacteria, molecular phylogenetic analysis of fungi still remains challenging due to the lack of standardized tools and the incompleteness of reference databases limiting the accurate and precise identification of fungal taxa. Here, we present a DNA metabarcoding workflow for characterizing fungal microbiota with high taxonomic resolution. This method involves amplifying longer stretches of ribosomal RNA operons and sequencing them using nanopore long-read sequencing technology. The resulting reads were error-polished to generate consensus sequences with 99.5-100% accuracy, which were then aligned against reference genome assemblies. The efficacy of this method was explored using a polymicrobial mock community and patient-derived specimens, demonstrating the marked potential of long-read sequencing combined with consensus calling for accurate taxonomic classification. Our approach offers a powerful tool for the rapid identification of pathogenic fungi and has the promise to significantly improve our understanding of the role of fungi in health and disease.

Impact of neoadjuvant therapy on gut microbiome in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: /Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications. METHODS: Twenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences. RESULTS: Of the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and ß-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01). CONCLUSIONS: The diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC.

Inflammatory Cytokine-Induced HIF-1 Activation Promotes Epithelial-Mesenchymal Transition in Endometrial Epithelial Cells.

The endometrium undergoes repeated proliferation and shedding during the menstrual cycle. Significant changes to this environment include fluctuations in the partial pressure of oxygen, exposure to a high-cytokine environment associated with intrauterine infection, and inflammation. Chronic endometritis is a condition wherein mild inflammation persists in the endometrium and is one of the causes of implantation failure and miscarriage in early pregnancy. It is thought that the invasion of embryos into the endometrium requires epithelial-mesenchymal transition (EMT)-associated changes in the endometrial epithelium. However, the effects of inflammation on the endometrium remain poorly understood. In this study, we investigated the effects of the intrauterine oxygen environment, hypoxia-inducible factor (HIF), and inflammation on the differentiation and function of endometrial epithelial cells. We elucidated the ways in which inflammatory cytokines affect HIF activity and EMT in an immortalized cell line (EM-E6/E7/TERT) derived from endometrial epithelium. Pro-inflammatory cytokines caused significant accumulation of HIF-1α protein, increased HIF-1α mRNA levels, and enhanced hypoxia-induced accumulation of HIF-1α protein. The combined effect of inflammatory cytokines and hypoxia increased the expression of EMT-inducing factors and upregulated cell migration. Our findings indicate that pro-inflammatory factors, including cytokines and LPS, work synergistically with hypoxia to activate HIF-1 and promote EMT in endometrial epithelial cells.

Clinical impact of physician staffing transition in intensive care units: a retrospective observational study.

BACKGROUND: Intensivists play an essential role in improving the outcomes of critically ill patients in intensive care units (ICUs). The transition of ICU physician staffing from low-intensity ICUs (elective intensivist or no intensivist consultation) to high-intensity ICUs (mandatory intensivist consultation or a closed ICU) improves clinical outcomes. However, whether a transition from high-intensity to low-intensity ICU staffing affects ICU outcomes and quality of care remains unknown. METHODS: A retrospective observational study was conducted to examine the impact of high- versus low-intensity staffing models on all-cause mortality in a suburban secondary community hospital with 400 general beds and 8 ICU beds. The ICU was switched from a high-intensity staffing model (high-former period) to low-intensity staffing in July 2019 (low-mid period) and then back to high-intensity staffing in March 2020 (high-latter period). Patients admitted from the emergency department, general ward, or operating room after emergency surgery were enrolled in these three periods and compared, balancing the predicted mortality and covariates of the patients. The primary outcome was all-cause mortality analyzed using hazard ratios (HRs) from Cox proportional hazards regression. An interrupted time-series analysis (ITSA) was also conducted to evaluate the effects of events (level change) and time. RESULTS: There were 962 eligible admissions, of which 251, 213, and 498 occurred in the high-former, low-mid, and high-latter periods, respectively. In the matched group (n = 600), the all-cause mortality rate comparing the high-former period with the low-mid period showed an HR of 0.88 [95% confidence interval (CI), 0.56, 1.39; p = 0.58] and that comparing the high-latter period with the low-mid period showed an HR of 0.84 [95% CI, 0.54, 1.30; p = 0.43]. The result for comparison between the three periods was p = 0.80. ITSA showed level changes of 4.05% [95% CI, -13.1, 21.2; p = 0.63] when ICU staffing changed from the high-former to the low-mid period and 1.35% [95% CI, -13.8, 16.5; p = 0.86] when ICU staffing changed from the low-mid to the high-latter period. CONCLUSION: There was no statistically significant difference in all-cause mortality among the three ICU staffing periods. This study suggests that low-intensity ICU staffing might not worsen clinical outcomes in the ICU in a medium-sized community hospital. Multiple factors, including the presence of an intensivist, other medical staff, and practical guidelines, influence the prognosis of critically ill patients.

Sevoflurane Does Not Promote the Colony-Forming Ability of Human Mesenchymal Glioblastoma Stem Cells In Vitro.

Background and Objectives: Clinically used concentrations of sevoflurane, an inhaled anesthetic, have been reported to significantly inhibit tumor growth. We investigated the effects of sevoflurane on sphere formation and the proliferation of human glioblastoma stem cells (GSCs) to determine whether sevoflurane exerts short- and long-term effects on human tumor cells. Materials and Methods: High-grade patient-derived GSCs (MD13 and Me83) were exposed to 2% sevoflurane. To evaluate the effect of sevoflurane on viability, proliferation, and stemness, we performed a caspase-3/7 essay, cell proliferation assay, and limiting dilution sphere formation assays. The expression of CD44, a cell surface marker of cancer stem-like cells in epithelial tumors, was evaluated using quantitative reverse transcription PCR. Differences between groups were evaluated with a one-way analysis of variance (ANOVA). Results: Sevoflurane exposure for 4 days did not significantly promote caspase 3/7 activity in MD13 and Me83, and cell proliferation was not observed after 5 days of exposure. Furthermore, prolonged exposure to sevoflurane for 6 days did not promote the sphere-forming and proliferative potential of MD13 and Me83 cells. These results suggest that sevoflurane does not promote either apoptosis, proliferative capacity, or the colony-forming ability of human mesenchymal glioblastoma stem cells in vitro. Conclusions: Sevoflurane at clinically used concentrations does not promote the colony-forming ability of human mesenchymal glioblastoma stem cells in vitro. It is very important for neurosurgeons and anesthesiologists to know that sevoflurane, a volatile anesthetic used in surgical anesthesia, would not exacerbate the disease course of GSCs.

16S rRNA nanopore sequencing for the diagnosis of ocular infection: a feasibility study.

OBJECTIVE: We conducted a feasibility study to verify the effectiveness of 16S ribosomal RNA (rRNA) gene analysis using the nanopore sequencer MinION for identifying causative bacteria in several types of ocular infections. METHODS AND ANALYSIS: Four cases of corneal ulcers, one case of endophthalmitis and one case of a conjunctival abscess were included in this study. DNA was extracted from corneal scraping, vitreous samples and secretions from the conjunctival abscess. We conducted 16S rRNA gene amplicon sequencing using MinION and metagenomic DNA analysis. The efficacy of bacterial identification was verified by comparing the conventional culture method with smear observations. RESULTS: 16S rRNA gene sequencing analysis with MinION identified the causative organisms promptly with high accuracy in approximately 4 hours, from ophthalmic specimens. The results of the conventional culture method and 16S rRNA gene sequencing were consistent in all cases. In four of the six cases, a greater variety of organisms was found in the 16S rRNA gene analysis than in bacterial culture. CONCLUSION: Using our workflow, 16S rRNA gene analysis using MinION enabled rapid and accurate identification possible in various kinds of bacterial ocular infections.

AGE/RAGE axis regulates reversible transition to quiescent states of ALK-rearranged NSCLC and pancreatic cancer cells in monolayer cultures.

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.

Successful identification of Granulicatella adiacens in postoperative acute infectious endophthalmitis using a bacterial 16S ribosomal RNA gene-sequencing platform with MinION™: A case report.

Purpose: To evaluate the efficacy of identifying the bacteria by aqueous sampling and vitreous sampling in postoperative infectious endophthalmitis using 16S ribosomal RNA (rRNA) gene analysis with a nanopore sequencer (MinION™). Observation: A 55-year-old woman who underwent cataract surgery at an ophthalmology clinic 18 days ago was referred to our hospital for suspected endophthalmitis. She had light perception visual acuity in her right eye; however, the eye was severely inflamed, with a hypopyon and a fibrinous membrane in the anterior chamber. The fundus was not visible because of vitreous opacity on a B-scan image. Based on the diagnosis of postoperative acute infectious endophthalmitis, we performed a vitrectomy, intraocular lens extraction, and silicone oil tamponade. On postoperative day 14, the inflammation resolved. An aqueous sample was collected before surgical treatment, and the vitreous sample was collected during the operation. Both samples underwent 16S rRNA gene analysis with a nanopore sequencer MinION™ to identify the causative organism. Conclusions and Importance: In the aqueous humor, Granulicatella adiacens and Cutibacterium acnes were identified before the operation, while only Granulicatella adiacens was detected in the vitreous sample after the operation. Although the aqueous humor sample might contain commensal bacteria, it could provide a predictable result before the operation. It can also provide a substitute for a vitreous sample to allow earlier identification of the causative organism.

Activation of transcription factor HIF inhibits IL-1ß-induced NO production in primary cultured rat hepatocytes.

Roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have recently been approved for the treatment of chronic renal anemia. In macrophages and monocytes, the activation of HIF-1 by pro-inflammatory cytokines induces iNOS expression and activity through the NF-κB pathway to produce nitric oxide (NO), which causes liver injury when excessively produced. Few studies have reported a relationship between HIF activity and iNOS induction in hepatocytes. We investigated the effect of drug- and hypoxia-induced HIF activations on NO production in primary cultured rat hepatocytes. Roxadustat treatment and hypoxic conditions activated HIF. Contrary to expectations, HIF-PHI treatment and hypoxia inhibited IL-1ß-induced NO production. RNA-Seq analysis of mRNA expression in rat hepatocytes showed that roxadustat treatment decreased the expression of genes related to inflammation, and genes in the NF-κB signaling pathway were induced by IL-1ß. Moreover, roxadustat suppressed IL-1ß-activated signaling pathways in an HIF-dependent manner. GalN/LPS-treated rats were used as in vivo models of hepatic injury, and roxadustat treatment showed a tendency to suppress the death of rats. Therefore, exogenous HIF-1 activation, including HIF-PHI and hypoxia exposures, suppressed IL-1ß-induced iNOS mRNA expression and subsequent NO production in hepatocytes, by suppressing the NF-κB signaling pathway. Roxadustat treatment suppresses the expression of pro-inflammatory genes by activating HIF, and thus may exhibit hepatoprotective effects.

Establishment of a novel assessment of the quality of human spermatozoa measuring mitochondrial oxygen metabolism.

OBJECTIVE: We aimed to establish a novel sperm quality evaluation technology by measuring mitochondrial oxygen metabolism in human spermatozoa. RESULTS: Normozoospermic human sperm samples were used. After establishing the optimal parameters for measuring the oxygen metabolism of human sperm cells using the extracellular flux analyzer, we measured the oxygen consumption rate (OCR) of human spermatozoa exposed to different storage temperatures. Although sperm motility was significantly lower at 4 °C when compared with sperm motility at 37 °C, there were no significant differences in sperm vitality and the OCR under both conditions. The present study established a methodology for human sperm quality evaluation using extracellular flux analysis technology. The OCR evaluation could be a reliable measurement tool for assessing human sperm quality.

MinION, a portable long-read sequencer, enables rapid vaginal microbiota analysis in a clinical setting.

BACKGROUND: It has been suggested that the local microbiota in the reproductive organs is relevant to women's health and may also affect pregnancy outcomes. Analysis of partial 16S ribosomal RNA (rRNA) gene sequences generated by short-read sequencers has been used to identify vaginal and endometrial microbiota, but it requires a long time to obtain the results, making it unsuitable for rapid bacterial identification from a small specimen amount in a clinical context. METHODS: We developed a simple workflow using the nanopore sequencer MinION that allows high-resolution and rapid differentiation of vaginal microbiota. Vaginal samples collected from 18 participants were subjected to DNA extraction and full-length 16S rRNA gene sequencing with MinION. RESULTS: The principal coordinate analysis showed no differences in the bacterial compositions regardless of the sample collection method. The analysis of vaginal microbiota could be completed with a total analysis time of approximately four hours, allowing same-day results. Taxonomic profiling by MinION sequencing revealed relatively low diversity of the vaginal bacterial community, identifying the prevailing Lactobacillus species and several causative agents of bacterial vaginosis. CONCLUSIONS: Full-length 16S rRNA gene sequencing analysis with MinION provides a rapid means for identifying vaginal bacteria with higher resolution. Species-level profiling of human vaginal microbiota by MinION sequencing can allow the analysis of associations with conditions such as genital infections, endometritis, and threatened miscarriage.

Rapid detection of single nucleotide polymorphisms using the MinION nanopore sequencer: a feasibility study for perioperative precision medicine.

INTRODUCTION: Precision medicine is a phrase used to describe personalized medical care tailored to specific patients based on their clinical presentation and genetic makeup. However, despite the fact that several single nucleotide polymorphisms (SNPs) have been reported to be associated with increased susceptibility to particular anesthetic agents and the occurrence of perioperative complications, genomic profiling and thus precision medicine has not been widely applied in perioperative management. METHODS: We validated six SNP loci known to affect perioperative outcomes in Japanese patients using genomic DNA from saliva specimens and nanopore sequencing of each SNP loci to facilitate allele frequency calculations and then compared the nanopore results to those produced using the conventional dideoxy sequencing method. RESULTS: Nanopore sequencing reads clustered into the expected genotypes in both homozygous and heterozygous cases. In addition, the nanopore sequencing results were consistent with those obtained using conventional dideoxy sequencing and the workflow provided reliable allele frequency estimation, with a total analysis time of less than 4 h. CONCLUSION: Thus, our results suggest that nanopore sequencing is a promising and versatile tool for SNP genotyping, allowing for rapid and feasible risk prediction of perioperative outcomes.

Efficacy of active hexose correlated compound on survival of patients with resectable/borderline resectable pancreatic cancer: a study protocol for a double-blind randomized phase II study.

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma remains very poor. One possible reason for the short survival of patients with this disease is malnutrition, which can be present at the initial diagnosis, and continue after pancreatectomy. Then, it is important to improve nutritional status and to decrease adverse events during neoadjuvant and adjuvant chemotherapy. Active hexose correlated compound (AHCC) is a standardized extract of cultured Lentinula edodes mycelia, and is considered a potent biological response modifier in the treatment of cancer. To evaluate the survival impact of AHCC on the patients with pancreatic ductal adenocarcinoma, we plan to perform this trial. METHODS: This is a prospective multicenter phase II trial in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma to investigate the efficacy of AHCC regarding survival. Patients will begin taking AHCC or placebo on the first day of neoadjuvant therapy. AHCC or placebo will be continued until 2 years after surgery. The primary endpoint will be 2-year disease-free survival. The secondary endpoints are the completion rate, dose intensity, and adverse event profile of preoperative chemotherapy; response rate to preoperative chemotherapy; rate of decrease in tumor marker (carbohydrate antigen 19-9, carcinoembryonic antigen) concentrations during preoperative chemotherapy; entry rate, completion rate, dose intensity, and adverse event profile of adjuvant chemotherapy; safety of the protocol therapy (adverse effect of AHCC); 2-year overall survival rate; and nutrition score before and after preoperative chemotherapy, and before and after adjuvant chemotherapy. We will enroll 230 patients, and the study involves eight leading Japanese institutions that are all high-volume centers in pancreatic surgery. DISCUSSION: AHCC is expected to function as a supportive food in patients with pancreatic ductal adenocarcinoma, to reduce the proportion of severe adverse events related to neoadjuvant chemotherapy, and to increase the completion proportion of multimodal treatments, resulting in improved survival. TRIAL REGISTRATION: The trial protocol has been registered in the protocol registration system at the Japan Registry of Clinical Trials (Trial ID: jRCTs051200029 ). At the time of the submission of this paper (October 2020), the protocol version is 2.0. The completion date is estimated to be November 2024.

A chemoproteoinformatics approach demonstrates that aspirin increases sensitivity to MEK inhibition by directly binding to RPS5.

MEK inhibitors are among the most successful molecularly targeted agents used as cancer therapeutics. However, to treat cancer more efficiently, resistance to MEK inhibitor-induced cell death must be overcome. Although previous genetic approaches based on comprehensive gene expression analysis or RNAi libraries led to the discovery of factors involved in intrinsic resistance to MEK inhibitors, a feasible combined treatment with the MEK inhibitor has not yet been developed. Here, we show that a chemoproteoinformatics approach identifies ligands overcoming the resistance to cell death induced by MEK inhibition as well as the target molecule conferring this resistance. First, we used natural products, perillyl alcohol and sesaminol, which induced cell death in combination with the MEK inhibitor trametinib, as chemical probes, and identified ribosomal protein S5 (RPS5) as their common target protein. Consistently, trametinib induced cell death in RPS5-depleted cancer cells via upregulation of the apoptotic proteins BIM and PUMA. Using molecular docking and molecular dynamics (MD) simulations, we then screened FDA- and EMA-approved drugs for RPS5-binding ligands and found that acetylsalicylic acid (ASA, also known as aspirin) directly bound to RPS5, resulting in upregulation of BIM and PUMA and induction of cell death in combination with trametinib. Our chemoproteoinformatics approach demonstrates that RPS5 confers resistance to MEK inhibitor-induced cell death, and that aspirin could be repurposed to sensitize cells to MEK inhibition by binding to RPS5.

Special Issue: Hypoxia-Inducible Factors: Regulation and Therapeutic Potential.

Oxygen (O2) is an essential molecule [...].

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal.

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

Polysulfide inhibits hypoxia-elicited hypoxia-inducible factor activation in a mitochondria-dependent manner.

In cellular signaling, the diverse physiological actions of biological gases, including O2, CO, NO, and H2S, have attracted much interest. Hypoxia-inducible factors (HIFs), including HIF-1 and HIF-2, are transcription factors that respond to reduced intracellular O2 availability. Polysulfides are substances containing varying numbers of sulfur atoms (H2Sn) that are generated endogenously from H2S by 3-mercaptopyruvate sulfurtransferase in the presence of O2, and regulate ion channels, specific tumor suppressors, and protein kinases. However, the effect of polysulfides on HIF activation in hypoxic mammalian cells is largely unknown. Here, we have investigated the effect of polysulfide on cells in vitro. In established cell lines, polysulfide donors reversibly reduced cellular O2 consumption and inhibited hypoxia-induced HIF-1α protein accumulation and the expression of genes downstream of HIFs; however, these effects were not observed in anoxia. In Von Hippel-Lindau tumor suppressor (VHL)- and mitochondria-deficient cells, polysulfides did not affect HIF-1α protein synthesis but destabilized it in a VHL- and mitochondria-dependent manner. For the first time, we show that polysulfides modulate intracellular O2 homeostasis and regulate HIF activation and subsequent hypoxia-induced gene expression in a VHL- and mitochondria-dependent manner.

Hypoxia-dependent signaling in perioperative and critical care medicine.

A critical goal of patient management for anesthesiologists and intensivists is to maintain oxygen homeostasis in patients admitted to operation theaters and intensive care units. For this purpose, it is imperative to understand the strategies of the body against oxygen imbalance-especially oxygen deficiency (hypoxia). Adaptation to hypoxia and maintenance of oxygen homeostasis involve a wide range of responses that occur at different organizational levels in the body. These responses are greatly influenced by perioperative patient management including factors such as perioperative drugs. Herein, the influence of perioperative patient management on the body's response to oxygen imbalance was reviewed with a special emphasis on hypoxia-inducible factors (HIFs), transcription factors whose activity are regulated by the perturbation of oxygen metabolism. The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who made outstanding achievements in this field. While previous studies have reported the effect of perioperatively used drugs on hypoxia-induced gene expression mediated by HIFs, this review focused on effects of subacute or chronic hypoxia changes in gene expression that are mediated by the transcriptional regulator HIFs. The clinical implications and perspectives of these findings also will be discussed. Understanding the basic biology of the transcription factor HIF can be informative for us since anesthesiologists manage patients during the perioperative period facing the imbalances the oxygen metabolism in organ and tissue. The clinical implications of hypoxia-dependent signaling in critical illness, including Coronavirus disease (COVID-19), in which disturbances in oxygen metabolism play a major role in its pathogenesis will also be discussed.

HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review.

Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors.