scholarly journals Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature

2021 ◽  
Vol 22 (17) ◽  
pp. 9191
Author(s):  
Diego Rodriguez ◽  
Deepika Watts ◽  
Diana Gaete ◽  
Sundary Sormendi ◽  
Ben Wielockx
Keyword(s):  
Endothelial Cells ◽  
Oxygen Supply ◽  
Supply And Demand ◽  
Tumor Development ◽  
Oxygen Sensors ◽  
The Body ◽  
Hypoxia Inducible Factors ◽  
Negative Effects ◽  
Number Of Genes ◽  
Hif Prolyl Hydroxylase

Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.

scholarly journals HIF1α is an essential regulator of steroidogenesis in the adrenal gland

2020 ◽  
Author(s):  
Deepika Watts ◽  
Johanna Stein ◽  
Ana Meneses ◽  
Nicole Bechmann ◽  
Ales Neuwirth ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Oxygen Sensors ◽  
Multiple Organ ◽  
Hypoxia Inducible Factors ◽  
Adrenocortical Cells ◽  
Steroid Production ◽  
Hormone Synthesis ◽  
Organ Systems ◽  
Hif Prolyl Hydroxylase ◽  
Endogenous Steroid

AbstractEndogenous steroid hormones, especially glucocorticoids and mineralocorticoids, are essential for life regulating numerous physiological and pathological processes. These hormones derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although a role for hypoxia pathway proteins (HPP) in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia Inducible Factors) and oxygen sensors (HIF-prolyl hydroxylase domain-containing enzymes; PHDs) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids under steady state conditions. Specifically, mice deficient in HIF1α in a part of the adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression due to combined PHD2 and PHD3 deficiency in the adrenal cortex resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a central and vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. Additionally, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.

scholarly journals Effects of Esmolol on Vascular Waterfall Phenomenon in Septic Shock Patients by Bedside Measurement of Critical Closure Pressure and Mean Systemic Filling Pressure: A Prospective Observational Study

2021 ◽  
Author(s):  
Zehan Liu ◽  
Chuanliang Pan ◽  
Jianping Liu ◽  
Hui Liu ◽  
Hui Xie
Keyword(s):  
Heart Rate ◽  
Septic Shock ◽  
Rate Control ◽  
Oxygen Supply ◽  
Supply And Demand ◽  
Filling Pressure ◽  
The Body ◽  
Heart Rate Control ◽  
Hemodynamic Optimization ◽  
The Difference

Abstract Background To explore the effect of esmolol on the vascular waterfall phenomenon and body oxygen supply and demand in septic shock patients by bedside measurements of critical closure pressure (Pcc) and mean systemic circulation filling pressure (Pmsf). Methods Enrolled in the Intensive Care Medicine Unit (ICU) of the Third People's Hospital of Chengdu City/Southwest Jiaotong University Hospital from August 2019 to January 2021, admitted to our department for infectious shock. Adults with endotracheal intubation, invasive ventilator-assisted ventilation, pulse-indicated continuous cardiac output monitoring (PiCCO) catheters and deep venous catheters placed for medical reasons. Results After 24 hours of initial hemodynamic optimization, 56 patients were finally enrolled. After heart rate control with esmolol, patients had a significant decrease in cardiac index (CI) (4.0 vs. 3.3 L/min/m2, p < 0.001), a significant increase in stroke index (SI) (34.1 vs. 36.6 ml/m2, p < 0.01), and a significant decrease in heart rate (HR) (116.8 vs. 90.6 beats/min, p < 0.001). After 1 hour of treatment with esmolol, patients had a significant increase in Pcc (31.4 vs 36.7 mmHg, p < 0.01). The difference between Pcc and Pmsf before and after treatment was statistically different (4.0 vs 10.0 mmHg, p < 0.01). After heart rate control with esmolol, the patients had a significant increase in the body circulation vascular resistance indices (RIs) (15.14 vs 18.25 mmHg/min/m2-L-1, p < 0.001). There was an increase in ScvO2 in patients after treatment with esmolol, but the difference was not statistically significant (68.4% vs 69.8%, p > 0.05), while Pcv-aCO2 was significantly lower (6.3 vs 4.9 mmHg, p < 0.001) and patients had a significant decrease in blood lactate levels (4.0 vs 3.6 mmol/L, p < 0.05) . Conclusion Patients with septic shock whose heart rate was still greater than 95 beats/min after hemodynamic optimization were treated with esmolol, which could effectively control heart rate and reduce CI, as well as improve Pcc and increase the difference between Pcc and Pmsf, without affecting MAP, CVP, Pmsf and arteriovenous vascular resistance, and improve the balance of oxygen supply and demand in the body.

scholarly journals Mammalian oxygen sensing, signalling and gene regulation

2000 ◽  
Vol 203 (8) ◽  
pp. 1253-1263 ◽  
Author(s):  
R.H. Wenger
Keyword(s):  
Oxygen Supply ◽  
Oxygen Sensing ◽  
Beta Subunit ◽  
Hypoxia Inducible Factors ◽  
Cell Type ◽  
Hypoxic Conditions ◽  
Oxygen Homeostasis ◽  
Number Of Genes ◽  
Made In ◽  
Limited Oxygen

Oxygen is essential to the life of all aerobic organisms. Virtually every cell type is able to sense a limited oxygen supply (hypoxia) and specifically to induce a set of oxygen-regulated genes. This review summarizes current concepts of mammalian oxygen-sensing and signal-transduction pathways. Since the discovery of the hypoxia-inducible factors (HIFs), a great deal of progress has been made in our comprehension of how hypoxia induces the expression of oxygen-regulated genes. The alpha subunit of the heterodimeric transcription factors HIF-1, 2 and 3 is unstable under normoxia but is rapidly stabilized upon exposure to hypoxic conditions. Following heterodimerization with the constitutively expressed beta subunit, HIFs activate the transcription of an increasing number of genes involved in maintaining oxygen homeostasis at the cellular, local and systemic levels.

scholarly journals Esmolol response in septic shock patients in relation to vascular waterfall phenomenon measured by critical closure pressure and mean systemic filling pressure: a prospective observational study

2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zehan Liu ◽  
Chuanliang Pan ◽  
Jianping Liu ◽  
Hui Liu ◽  
Hui Xie
Keyword(s):  
Heart Rate ◽  
Septic Shock ◽  
Vascular Resistance ◽  
Oxygen Supply ◽  
Supply And Demand ◽  
Filling Pressure ◽  
The Body ◽  
Controlled Study ◽  
Hemodynamic Optimization ◽  
The Difference

Abstract Background Bedside measurements of critical closure pressure (Pcc) and mean systemic circulation filling pressure (Pmsf) were utilized to evaluate the response to esmolol in septic shock patients, in relation to the vascular waterfall phenomenon and body oxygen supply and demand. Methods This prospective observational self-controlled study included patients with septic shock, newly admitted to the intensive care unit, between August 2019 and January 2021. Pcc and Pmsf, along with the heart rate and other hemodynamic indicators were observed and compared before and 1 h after esmolol IV infusion. Results After 24 h of initial hemodynamic optimization, 56 patients were finally enrolled. After start of esmolol infusion, patients had a significant decrease in cardiac index (CI) (4.0 vs. 3.3 L/min/m2, P < 0.001), a significant increase in stroke index (SI) (34.1 vs. 36.6 mL/m2, P < 0.01), and a significant decrease in heart rate (HR) (116.8 vs. 90.6 beats/min, P < 0.001). After 1 h of treatment with esmolol, patients had a significant increase in Pcc (31.4 vs. 36.7 mmHg, P < 0.01). The difference between Pcc and Pmsf before and after treatment was statistically different (4.0 vs. 10.0 mmHg, P < 0.01). After heart rate control with esmolol, the patients had a significant increase in the body circulation vascular resistance indices (RIs) (15.14 vs. 18.25 mmHg/min/m2/L, P < 0.001). There was an increase in ScvO2 in patients after treatment with esmolol, but the difference was not statistically significant (68.4% vs. 69.8%, P > 0.05), while Pcv-aCO2 was significantly lower (6.3 vs. 4.9 mmHg, P < 0.001) and patients had a significant decrease in blood lactate levels (4.0 vs. 3.6 mmol/L, P < 0.05). Conclusion Patients with septic shock whose heart rate is greater than 95 beats/min after hemodynamic optimization were treated with esmolol, which could effectively control heart rate and reduce CI, as well as improve Pcc and increase the difference between Pcc and Pmsf (known as “vascular waterfall” phenomenon), without affecting MAP, CVP, Pmsf and arteriovenous vascular resistance, and improve the balance of oxygen supply and demand in the body.

scholarly journals The Genomics and Genetics of Oxygen Homeostasis

2020 ◽  
Vol 21 (1) ◽  
pp. 183-204 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Supply And Demand ◽  
Germline Mutations ◽  
The Body ◽  
Hypoxia Inducible Factors ◽  
Von Hippel Lindau ◽  
Oxygen Homeostasis ◽  
Continuous Delivery ◽  
Genes Encoding ◽  
Vhl Protein ◽  
Atp Generation

Human survival is dependent upon the continuous delivery of O2 to each cell in the body in sufficient amounts to meet metabolic requirements, primarily for ATP generation by oxidative phosphorylation. Hypoxia-inducible factors (HIFs) regulate the transcription of thousands of genes to balance O2 supply and demand. The HIFs are negatively regulated by O2-dependent hydrox-ylation and ubiquitination by prolyl hydroxylase domain (PHD) proteins and the von Hippel–Lindau (VHL) protein. Germline mutations in the genes encoding VHL, HIF-2α, and PHD2 cause hereditary erythrocytosis, which is characterized by polycythemia and pulmonary hypertension and is caused by increased HIF activity. Evolutionary adaptation to life at high altitude is associated with unique genetic variants in the genes encoding HIF-2α and PHD2 that blunt the erythropoietic and pulmonary vascular responses to hypoxia.

scholarly journals INFLUENCE OF UNILATERAL SCIATIC NERVE LIGATION ON THE TUMOR-BEARING RATS WITH THE FEATURES OF SYSTEMIC REGULATION

2021 ◽  
Vol 20 (5) ◽  
pp. 84-92
Author(s):  
O. I. Kit ◽  
G. V. Zhukova ◽  
A. I. Shikhlyarova ◽  
A. S. Goncharova ◽  
S. Yu. Tkachev ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Motor Activity ◽  
Tumor Growth ◽  
Tumor Development ◽  
The Body ◽  
Tumor Growth Rate ◽  
Control Group ◽  
Negative Effects ◽  
Tumor Bearing ◽  
The Individual

The issue of factors that modify the tumor process stays relevant. The effect of unilateral sciatic nerve ligation on the growth of Guerin's transplantable carcinoma and the lifespan of white outbred rats of the same age, which differed in adaptation status and aging rates, was studied.Material and Methods. The motor activity (open field test), the character and tension of the general nonspecific adaptional reactions of the body (AR) according to Garkavi–Kvakina–Ukolova, the dynamics of tumor sizes and the lifespan of rats after Guerin’s carcinoma transplantation were evaluated.Results. The effect of unilateral sciatic nerve ligation differed from the unidirectional negative effects known in tumor-bearing animals after bilateral ligation of the sciatic nerve. In groups with unilateral ligation of the sciatic nerve and a false operation, more than 40 % of animals showed an increase in lifespan compared with the maximum lifespan in the control group. At the same time, in the most cases, the tumor growth rate was similar to the control indicators or exceeded them (more 25 % of cases). A temporary inhibition of tumor growth was observed only in individual animals. There was no direct relationship between tumor growth or lifespan and the degree of decrease in the motor activity of animals 4 weeks after nerve ligation. A correlation between the changes in the ARs and lifespans of animals and, to a lesser extent, the dynamics of tumor growth was observed. The distinct negative effect of increased aging rate, measured by animal weight, on tumor development and lifespan in studied rats was shown, but not in the cases of sciatic nerve ligation. Unilateral sciatic nerve ligation had a multidirectional effect on tumor growth and lifespan in rats with different rates of aging, depending, probably, on the individual pain sensitivity and the individual features of systemic regulation of tumor-bearing animals.Conclusion. The results reflect the complex relationship between processes associated with chronic pain, oncogenesis, aging and features of neuroendocrine and immune regulation of experimental animals. The question of the reasons for the preservation of viability in animals that underwent surgery and ligation of the sciatic nerve, when the tumors reach large sizes, exceeding this indicator in the control group, needs to be clarified. 

Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

2018 ◽  
pp. 41-46
Author(s):  
А.А. Раецкая ◽  
С.В. Калиш ◽  
С.В. Лямина ◽  
Е.В. Малышева ◽  
О.П. Буданова ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Development ◽  
Significant Inhibition ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Solid Carcinoma ◽  
Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

Inspector Quadro - the complex of preparation for the treatment of ectoand endoparasitoses in cats and dogs

2018 ◽  
Vol 12 (2) ◽  
pp. 75-84
Author(s):  
M.V. Arisov ◽  
I.P. Belykh ◽  
V.V. Artemov
Keyword(s):  
Body Weight ◽  
Clinical Picture ◽  
High Efficiency ◽  
The Body ◽  
Negative Effects ◽  
Laboratory Methods ◽  
Diagnosis Of Infection

The purpose of the research: the study of the efficacy of the preparations for veterinary use "Inspector Quadro C" and "Inspector Quadro K" against ecto- and endoparasitoses of dogs and cats. Materials and methods. Studies were conducted on spontaneously infected dogs and cats of different sexes, age, weight and breed. The diagnosis of infection with ectoparasites was made based on the clinical picture and laboratory methods of investigation (microscopy of scrapings taken from ectoparasitized skin areas, examination of the coat for fleas, lice, worms, ixodids). Infection with helminths was established by detecting eggs of helminths in faeces of animals by the method of Füleleborn and mature segments of cestodes. Preparations were applied to the animals by drip application on dry undamaged skin in places inaccessible to licking in a dose of 0.1-0.4 ml per 1 kg of body weight. The results were statistically processed. Results and discussion. "Inspector Quadro S" and "Inspector Quadro K" showed 100% efficacy at sarcoptosis in dogs, notoedrosis in cats, otodectosis in dogs and cats, ixodidoses and entomoses. "Inspector Quadro C" showed a high efficiency (92.3%) at demodecosis in dogs. However, single mites were found in one dog. 100% efficacy of "Inspector Quadro C" and "Inspector Quadro K" has been established against intestinal nematodes and cestodes in dogs and cats. Negative effects of drugs on the body of animals have not been revealed.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Vascular endothelial cell specification in health and disease

Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Current Knowledge ◽  
Vascular Malformations ◽  
Immune Surveillance ◽  
Vascular Endothelial Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
The Body ◽  
Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

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