Factor Hypoxia Research Articles

Impacts of different intensities of exercise on inflammation and hypoxia markers in low altitude

BackgroundThis study aims to determine and compare the effects of exercise modalities with different intensities on the secretion of key inflammation and hypoxia markers in amateur athletes.MethodsTwenty-three athletes with a mean age of 20.1 years, living at low altitude (1850 m) participated in this study. The participants' maximal oxygen consumption values (VO2 max) were determined with an incremental cycle exercise test as 54.15 ± 6.14 mL kg min−1. Athletes performed four protocols: at rest, 50% VO2 max, 75% VO2 max and 100% VO2 max (until exhaustion) with one-week intervals. 50% VO2 max, 75% VO2 max sessions were performed continuously for 30 min on a bicycle ergometer and 100% VO2 max session was performed by cycling until exhaustion. Blood samples were obtained at rest and immediately after each exercise session. Serum tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), interleukin-10 (IL-10), and hypoxia inducible factor-1 alpha (HIF-1α) levels were measured.ResultsThere were significant differences in serum TNF-α levels in 75% VO2 max and 100% VO2 max sessions (489.03 ± 368.37 and 472.70 ± 365.21 ng/L, respectively) compared to rest conditions (331.65 ± 293.52 ng/L). Serum CRP levels of 50% VO2 max and 75% VO2 max sessions (1.19 ± 0.50; 1.07 ± 0.52 mg/L) were significantly higher than the rest condition (0.74 ± 0.35 mg/L). There were significant differences in serum IL-10 levels of rest condition and 50% VO2 max; 50% VO2 max, and 100% VO2 max sessions (328.09 ± 128.87; 446.36 ± 142.84; 347.44 ± 135.69; 324.88 ± 168.06 pg/mL). Serum HIF-1α levels were significantly higher in 75% VO2 max session compared to rest (1.26 ± 0.16; 1.08 ± 0.19 ng/mL) (P < 0.05 for all comparisons).ConclusionsBoth inflammatory and anti-inflammatory pathway is induced on different exercise intensities. Exercise protocols performed until exhaustion may lead to activation of inflammatory pathways and hypoxia-induced damage.

HIF-1α Regulated WTAP Overexpression Promote Warburg Effect of Ovarian Cancer by m6A-Dependent Manner

N6-methyladenosine (m6A), the methylation of the N6 nitrogen on adenosine, acts as the most common internal modification of eukaryotic mRNA. The dynamic and reversible m6A RNA modification established and erased by N6-methyltransferases and demethylases regulates gene expression and determines cell fate. In this study, we find for the first time that exposure of ovarian cancer cells to hypoxia significantly increases the expression of WT1 associated protein(WTAP), a critical m6A methylase which proved to be induced by a hypoxia factor (HIF)-1α dependent manner, and expression of WTAP in ovarian cancer cells is significantly correlated with the clinicopathological characteristics and up-regulation of WTAP predicts poor prognosis of ovarian cancer patients. Knockdown/ Overexpress of WTAP in human ovarian cancer cells substantially reduces/enhances their proliferative and invasive capacity both in vitro and in vivo. Moreover, We discover that WTAP interacts with DGCR8, a vital microprocessor protein, regulating the primary microRNA 200 process in an m6A-dependent manner. Further experiments demonstrate that microRNA200 could positively regulate HK2 and promote Warburg effect. These studies reveal that HIF-1α upregulated WTAP expression mediates primary miRNA processing, accelerates the Warburg effect and promotes the occurrence and development of tumor, thus providing a novel perspective on m6A modification in ovarian cancer progression. Funding Information: This study was supported by grants from the Natural Science Foundation of Anhui Province (2008085QH422). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: All human ovary tissues were obtained with informed consent, and the ethical review committee approved all protocols of the World Health Organization Collaborating Center for Research in Human Production. Animal studies were approved by the Institutional Animal Care and Use Committee of Second Military Medical University, Shanghai, China.

HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury.

Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI.Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1α inhibitor 2ME and agonist DMOG were used to study the role of HIF-1α in TRAIL-induced neuronal death. Meanwhile, HIF-1α siRNA was used to investigate the role of HIF-1α in TRAIL-induced neuronal death in vitro.Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1α siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro.Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1α mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.

Acute Pulmonary Edema in Healthy Subjects.

INTRODUCTION: Healthy individuals may present with acute pulmonary edema when exposed to extreme environments (high-altitude or deep diving) or while performing strenuous exercises. Recent data support the hypothesis that these forms of acute pulmonary edema might be due to a limited number of stimuli, often overlapping each other, inducing pulmonary capillary stress failure.DISCUSSION: Pathophysiology of nontoxic pulmonary edema occurring in healthy people is still incompletely understood, but recent data suggest a role of three factors (hypoxia, increase in ambient pressure, and physical exercise) that, alone or in combination, may increase pulmonary capillary pressure up to a level overcoming the mechanical resistance of the blood-gas barrier. Evidence has been recently provided to support the existence of a genetic pattern predisposing healthy subjects to pulmonary edema. This paper reviews the evidence supporting a common background for pulmonary edema triggered by extreme environments or heavy effort; a preventive and therapeutic strategy will also be proposed. From these data, hypotheses on the pathophysiology of other forms of noncardiac related pulmonary edema, as those associated with obstructive sleep-apnea syndrome or during post-surgery intensive care, will be proposed.Marabotti C, Cialoni D, Pingitore A. Acute pulmonary edema in healthy subjects. Aerosp Med Hum Perform. 2020; 91(8):662-668.

BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer

Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of “failed apoptosis” where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed apoptosis induces DNA double-strand breaks generating mutations that facilitate tumorigenesis. Whether failed apoptosis is relevant to clinical disease is unknown. BCL-2 interacting killer (BIK) is a stress-induced BH3-only protein that stimulates apoptosis in response to hormone and growth factor deprivation, hypoxia, and genomic stress. It was unclear whether BIK promotes or suppresses tumor survival within the context of breast cancer. We investigated this and show that BIK induces failed apoptosis with limited caspase activation and genomic damage in the absence of extensive cell death. Surviving cells acquire aggressive phenotypes characterized by enrichment of cancer stem-like cells, increased motility and increased clonogenic survival. Furthermore, by examining six independent cohorts of patients (total n = 969), we discovered that high BIK mRNA and protein levels predicted clinical relapse of Estrogen receptor (ER)-positive cancers, which account for almost 70% of all breast cancers diagnosed but had no predictive value for hormone receptor-negative (triple-negative) patients. Thus, this study identifies BIK as a biomarker for tumor recurrence of ER-positive patients and provides a potential mechanism whereby failed apoptosis contributes to cancer aggression.

Autofagia: un processo fisiopatologico di autodigestione cellulare

Macroautophagy, commonly referred to as autophagy, is a self-degradation process through which virtually all eukaryotic cells sequester cytoplasmic components (macromolecules, but also entire organelles or microorganisms) into de novo formed, double-membrane vescicles (autophagosomes) and degrade them after lysosomal fusion. The degradation products released from lysosomes are recycled into metabolic and biosynthetic pathways. Autophagy, normally occurring for ordinary organelle and protein turnover, can be enhanced in stress conditions as an adaptive, survival response to microenvironmental and intracellular noxia, including glucose, amino acid or growth factors withdrawal, hypoxia, oxidative stress, mitochondrial or organelle dysfunction, infections, and cytotoxic drugs. However, an excessive or long-lasting activation of autophagy can culminate in a peculiar mode of cell death. An imbalanced autophagy (either unrestrained or deficient) plays a role in the pathogenesis of different diseases, including cancer, neurodegenerative diseases, cardiovascular and autoimmune pathologies. In tumor cells, however, autophagy proves to play an ambiguous dual role (protective or cytotoxic), possibly depending on tumor cell type, genetic background and tumor stage.

Abstract 2504: Sialylation of EGFR by the glycosyltransferase ST6Gal-I results in receptor activation and resistance to gefitinib mediated apoptosis

Abstract The Epidermal Growth Factor Receptor (EGFR) is one of the most commonly altered receptors in cancer. In the present study, we report that sialylation of EGFR by the tumor-associated sialyltransferase ST6Gal-I increases receptor activation resulting in resistance to the EGFR tyrosine kinase inhibitor gefitinib. ST6Gal-I adds an α2-6 sialic acid (a bulky, negatively charged sugar) to select cell surface receptors, thereby modulating receptor function. Previously our group has shown that ST6Gal-I activity confers hallmark cancer stem cell characteristics such as invasion, chemoresistance, and resistance to microenvironmental stressors such as growth factor deprivation and hypoxia. Kinomics data collected for this study reveal that in OV4 ovarian cancer cells, where ST6Gal-I has been overexpressed using a lentiviral construct, ST6Gal-I overexpressing cells have an increase in overall tyrosine kinase activity in comparison to cells without ST6Gal-I expression, whereas the overall serine/threonine kinase activity is largely unaffected by ST6Gal-I expression. Specifically, the receptor tyrosine kinase, EGFR, is one of the most significantly altered kinases in ST6Gal-I expressing cells, with ST6Gal-I expressing cells having an increase in overall activity in comparison to non-expressing cells. Based on these findings, we further interrogated the role of ST6Gal-I on EGFR function. To this end, we first confirmed the sialylation status of EGFR in cells with either forced ST6Gal-I overexpression or shRNA knockdown. Using OV4 and Skov3 cells, ovarian cancer cells, as well as BxPC3 pancreatic cancer cells, we conclude that not only is EGFR a substrate of ST6Gal-I, but that sialylation of EGFR by ST6Gal-I results in basal activation of the receptor, independent of EGF ligand treatment. Further, upon stimulation with EGF, receptor activation is increased in ST6Gal-I expressing versus non-expressing cells. To determine the functional significance of EGFR sialylation by ST6Gal-I, we treated cells with differential ST6Gal-I expression with gefitinib, an EGFR tyrosine kinase inhibitor widely used as an anti-cancer therapy. These studies revealed that ST6Gal-I expressing cells were protected from gefitinib mediated apoptosis. Finally, given that EGFR activation has been shown to promote epithelial to mesenchymal transition (EMT), we evaluated ST6Gal-I expressing cells treated with EGF for the EMT marker Slug. We report that while ST6Gal-I expressing cells inherently have elevated Slug expression versus cells without ST6Gal-I, treatment with EGF greatly enhances Slug expression in ST6Gal-I expressing versus non-expressing cells. Collectively, these results reveal a novel functional role for sialylated EGFR and suggest that the sialylation of EGFR may facilitate EMT as well as provide cells a mechanism to overcome chemoresistance. Citation Format: Colleen Britain, Andrew Holdbrooks, Susan Bellis. Sialylation of EGFR by the glycosyltransferase ST6Gal-I results in receptor activation and resistance to gefitinib mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2504.

Morphologic Substantiation of Distraction as a Preparatory Step for Bioactive Interphalangeal Hand Joint Arthroplasty in Fibrous Ankylosis

The work is dedicated to the study of the morphologic peculiarities of proximal interphalangeal joint capsule before and after distraction in order to substantiate the use of distraction technique as a preparatory step for proximal interphalangeal hand joints bioactive arthroplasty in fibrous ankylosis. The study was conducted on the samples of small fragments of proximal interphalangeal hand joint capsule (11 patients) before distraction and 2 months after distraction apparatus removal. Control group (conventional norm) was presented by 6 autopsy samples. Light microscopy using standard staining methods and immunohistochemical examination were performed. Activation of angiogenesis processes, i.e. 3.5 times increase of vascular bed, 3.4 times growth of mature labrocytes number, both partially and maximum degranulated, as compared with the nondistracted tissue and control group. Direct correlation between the growth of mature labrocytes number and fibroblasts, and the quantity of newly formed vessels per unit of tissue area was detected. Distraction enables to raise the vitality and resistance of pathologically changed joint tissues to damaging factors (hypoxia), activates functional status of joint surrounding tissues and could be considered as a preparatory step for fibrotically ankylosed interphalangeal hand joints bioactive arthroplasty.

Long‐term changes in hypoxia and soluble reactive phosphorus in the hypolimnion of a large temperate lake: consequences of a climate regime shift

The (Lower) Lake of Zurich provides an ideal system for studying the long-term impact of environmental change on deep-water hypoxia because of its sensitivity to climatic forcing, its history of eutrophication and subsequent oligotrophication, and the quality and length of its data set. Based on 39years (1972-2010) of measured profiles of temperature, oxygen concentration and phosphorus (P) concentration, the potentially confounding effects of oligotrophication and climatic forcing on the occurrence and extent of deep-water hypoxia in the lake were investigated. The time-series of Nürnberg's hypoxic factor (HF) for the lake can be divided into three distinct segments: (i) a segment of consistently low HF from 1972 to the late-1980s climate regime shift (CRS); (ii) a transitional segment between the late-1980s CRS and approximately 2000 within which the HF was highly variable; and (iii) a segment of consistently high HF thereafter. The increase in hypoxia during the study period was not a consequence of a change in trophic status, as the lake underwent oligotrophication as a result of reduced external P loading during this time. Instead, wavelet analysis suggests that changes in the lake's mixing regime, initiated by the late-1980s CRS, ultimately led to a delayed but abrupt decrease in the deep-water oxygen concentration, resulting in a general expansion of the hypoxic zone in autumn. Even after detrending to remove long-term effects, the concentration of soluble reactive P in the bottom water of the lake was highly correlated with various measures of hypoxia, providing quantitative evidence supporting the probable effect of hypoxia on internal P loading. Such climate-induced, ecosystem-scale changes, which may result in undesirable effects such as a decline in water quality and a reduction in coldwater fish habitats, provide further evidence for the vulnerability of large temperate lakes to predicted increases in global air temperature.

EEG spectral power of young schoolchildren with perinatal pathology of the CNS

The influence of perinatal risk factors (prematurity and hypoxia) on the spectral power values of individual EEG frequency bands (θ1, θ2, α1, α2, β1, β2, and γ) in the state of quiet wakefulness in young schoolchildren with educational problems was studied. The results of statistical analysis showed a significant predominance of the power in the θ1 (especially in the anterior and posterior associative areas), β, and γ (on the whole surface of the cortex, with a predominance of differences in the anterior associative areas) bands in children with a gestational age (GA) less than 38 weeks at birth compared to that in the control group (a GA of 38 weeks). The intergroup differences in the power of most frequency bands were most pronounced in the left temporal area. A relationship between the consequences of perinatal hypoxia and the GA, namely, an increase in the power (especially in the left-hemispheric areas) of all the EEG frequency components (except α2) in the group with a GA less than 38 weeks, in contrast to its slight inhibition in the control group (except the γ band), was found. The genesis of the specific features of the pattern of local EEG synchronization, as well as their functional significance in the formation of different structures of cognitive disorders in children with perinatal dysontogenesis, is discussed.

MR imaging of nephropathies

Acute and chronic nephropathies are responsible for morphologic and functional renal changes. However, radiologic techniques currently play a minor role in imaging of parenchymal nephropathies in native or transplanted kidneys. From a morphologic point of view, three-dimensional magnetic resonance (MR) volumetric biomarkers of kidney function, such as renal and cortical volumes or cystic volume, in polycystic kidney diseases play a growing role in nephrologic practice. From a functional point of view, if scintigraphic techniques remain the major sources of renal performance assessment, new MR imaging systems and specific MR contrast agents may soon provide significant developments in the evaluation of renal performance (glomerular filtration rate measurement), in the search for prognostic factors (hypoxia, inflammation, cell viability, degree of tubular function, and interstitial fibrosis), and for monitoring new cell therapies. New developments that have provided higher signal-to-noise ratio and higher spatial and/or temporal resolutions have the potential to direct new opportunities for obtaining morphologic and functional information on tissue characteristics that are relevant for various renal diseases with respect to diagnosis, prognosis, and treatment follow-up.

Principles of physiological regulation of body functions in incomplete adaptation

The main condition of completing the process of adaptation of the body to the effect of an external factor is the return of the homeostatic system parameters to their initial levels or their stabilization at a new level. The article considers the state of incomplete adaptation (IA) based on the process of the stabilization of systemic reactions (respiration and blood circulation) on repeated exposure to extreme environmental factors (hypoxia and cold) associated with the excitation of the central regulatory mechanisms of the respiratory center system performing a compensatory–protective function. It is postulated that a change in the afferent information flows (the thresholds of excitation and reactivity of the peripheral receptor systems) forms the basis of IA. The IA state is supposed to persist for an indefinitely long period of time due to insufficient functional reserves and to be the cause of psychosomatic pathology.

Transcription-Independent p53 Apoptosis Requires Caspase-8

The tumor suppressor p53 is involved in cell-cycle arrest and apoptosis in response to several intrinsic signals (DNA damage) and extrinsic signals (growth factor deprivation and hypoxia). Apoptosis triggered by p53 can occur through two mechanisms: one that requires the transcriptional activation of genes by p53 and one that is transcription-independent. Ding et al. explored the mechanisms by which p53 causes transcription-independent apoptosis (TI-apoptosis) using cell-free apoptosis assays and cell-based assays that relied on transfection experiments to trigger apoptosis by a mutant of p53 that lacked transcriptional regulatory activity. TI-apoptosis relied on the activation of caspase-8, which was found in a large (600-kD complex that did not contain the pro-apoptotic, death domain-containing protein FADD). In cells, TI-apoptosis required caspase-8 and caspase-9; however, in cell-free extracts, caspase-8 alone was sufficient to trigger cleavage of caspase-3. Finally, TI-apoptosis was blocked by cotransfection of the anti-apoptotic protein Bcl-2, and irradiation caused the cleavage of the pro-apoptotic protein BID. Thus, the authors propose that the p53-triggered TI-apoptosis involves the activation of caspase-8 during the formation of the novel 600-kD complex, which then leads to cleavage of BID and activation of the mitochondrial caspase-9 apoptotic pathway. Ding, H.-F., Lin, Y.-L., McGill, G., Juo, P., Zhu, H., Blenis, J., Yuan, J., and Fisher, D.E. (2000) Essential role for caspase-8 in transcription-independent apoptosis triggered by p53. J. Biol. Chem. 275 : 38905-38911. [Abstract] [Full Text]

Management of head injury.

Incidence Head trauma accounts for one-third of all admissions to accident units. The annual incidence of head injury in the United States is approximately 0,2 per cent. t-5 Most head injuries occur and present to the emergency room between 4 p.m. and midnight. The frequency is highest between Friday and Saturday. Males outnumber females by three to o n e ) -5 Younger age groups are especially affected and, in New York, 39 per cent of injuries occur in patients under 15 years of age. 6 In most communities, traffic accidents cause over 50 per cent of injuries but in some urban areas, violence and falls predominate. Alcohol consumption has been associated with over 50 per cent of fatal vehicular accidents. 7 Detectable blood alcohol levels have been found in more than 50 per cent of head injured patients in emergency rooms. 8'9 The annual mortality rate averages 0.03 per cent. lo Over 60 per cent of deaths occur during a therapeutic vacuum, i.e., the time before the patient receives medical assistance. Comprehensive studies have indicated that 43 per cent of fatalities might have been avoided had medical aid been available within ten minutes. Respiratory obstruction is the primary cause of death in at least 15 per cent of the casualties. ~1 In a review of 116 patients who talked following head injury but subsequently died (a clinical situation encountered in 38 per cent of deaths), Rose and Jennett concluded that in 75 per cent, one or more avoidable factors were present and, in at least 54 per cent, these factors (hypoxia, hypotension, delay in treatment, sepsis, seizures and iatrogenic complications) contributed to death, t2 Intracranial injuries Head injury is not a homogeneous disease. Therapy and prognosis depend on the underlying pathology.