scholarly journals Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

JCI Insight ◽  
2021 ◽  
Vol 6 (8) ◽  
Author(s):  
Moritz J. Strowitzki ◽  
Gwendolyn Kimmer ◽  
Julian Wehrmann ◽  
Alina S. Ritter ◽  
Praveen Radhakrishnan ◽  
...  
Keyword(s):  
Intestinal Anastomoses ◽  
Prolyl Hydroxylases

RESULTS OF SURGICAL TREATMENT OF PATIENTS WITH CHRONIC PANCREATITIS AND THE RISK OF CANCER AFTER SURGICAL TREATMENT

2018 ◽  
Vol 64 (2) ◽  
pp. 228-233
Author(s):  
Vladimir Lubyanskiy ◽  
Vasiliy Seroshtanov ◽  
Ye. Semenova
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Surgical Treatment ◽  
Fibrous Tissue ◽  
Pancreatic Head ◽  
Head Region ◽  
Intestinal Anastomoses ◽  
Resection Of The Pancreas ◽  
Risk Of Cancer

The aim: To analyze results of surgical treatment of patients with chronic pancreatitis (CP) and to assess the causes of pancreatic cancer after surgical treatment. Materials and methods: 137 patients had duodenum-preserving resections of the pancreas. Results: In the histological examination of the pancreas it was established that the growth of fibrous tissue was registered in patients with CP., which in 19 (13.8%) almost completely replaced the acinar tissue. In the long term after the operation from 6 months to 2 years in 8 patients (5.8%) pancreatic cancer was detected. Possible causes of tumor origin were analyzed, the value of preservation of ductal hypertension, which affects the state of the duct’s epithelium, was established. The most commonly used for treatment of chronic pancreatitis the Frey surgery removed pancreatic hypertension but in two patients during the operation an insufficient volume of the pancreatic head was reconstructed. In the case of the abandonment of a large array of fibrous tissue, local hypertension was retained in the region of the ductal structures of the head, which led to the transformation of the duct epithelium. An essential factor in the problem of the preservation of pancreatic hypertension were the stenosis of pancreatic intestinal anastomoses, they arose in the long term in 4 operated patients. With stenosis of anastomosis after duodenum-preserving resection both the hypertension factor and the regeneration factor could be realized, which under certain circumstances might be significant. Conclusion: After resection of the pancreas for CP cancer was diagnosed in 5.8% of patients. The main method of preventing the risk of cancer was performing the Frey surgery for CP eliminating pancreatic hypertension in the head region of the pancreas. Diagnosis of stenosis in the late period after resection of the pancreas was an important element in the prevention of recurrence of cancer since a timely reconstructive operation could improve the drainage of duct structures.

HIF-1α Activation Reduces Expression of the microRNA hsa-miR-603 Host Gene KIAA1217 and Increases Expression of the Target CCND1 Gene in BeWo b30 Cells

2019 ◽  
Vol 35 (6) ◽  
pp. 80-86
Author(s):  
E.A. Knyazeva ◽  
S.V. Nikulin ◽  
A.Yu. Khristichenko ◽  
V.A. Petrov ◽  
A. Turchinovich ◽  
...  
Keyword(s):  
Target Gene ◽  
Ministry Of Education ◽  
Trophoblast Cells ◽  
Prolyl Hydroxylases ◽  
Ccnd1 Gene ◽  
Russian Scientific ◽  
Technological Complex ◽  
Bewo B30 ◽  
The Russian Federation ◽  
Choriocarcinoma Cell Line

The model of the placental barrier based on the human choriocarcinoma cell line BeWo b30 allows studying the effect of hypoxia on trophoblast cells. The effect of the oxyquinoline derivative inhibiting HIF-prolyl hydroxylases was studied on this model. Inhibition of these enzymes leads to an increase in the HIF-1α subunit in the cytoplasm, mimicking the cell response to hypoxia. Incubation of the cells with the drug at a concentration of 10 uM for 24 h did not affect the paracellular transport, but reduced the transport of glucose through the cell barrier. The transcriptome analysis after the exposure with oxyquinoline derivative revealed a decreased expression of the KIAA1217 gene and its intronic gene MIR603, which encodes microRNA hsa-miR-603. The expression of the target gene of this miRNA, CCND1 encoding cyclin D1, after oxyquinoline derivative exposition increased significantly, which may indicate a potential microRNA-mRNA regulatory mechanism in the response of trophoblast cells to hypoxia. BeWo b30, placenta, hypoxia, oxyquinoline, barrier, microRNA, cyclin The study was performed with the equipment of the «Postgenomic and Metabolomic Methods of Study in Molecular Biology» Common Use Center (BioClinicum Scientific and Technical Center). The study was supported by the Ministry of Education and Science of the Russian Federation in the framework of the Federal Targeted Program for Research and Development in Priority Areas of Advancement of the Russian Scientific and Technological Complex for 2014-2020 (Project no. RFMEFI58817X0007).

scholarly journals Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

2021 ◽  
Vol 52 (6) ◽  
pp. 450-466
Author(s):  
Matthew R. Weir
Keyword(s):  
Drug Targets ◽  
Iron Status ◽  
Therapeutic Option ◽  
Attractive Potential ◽  
Dialysis Modality ◽  
Erythroid Progenitors ◽  
Prolyl Hydroxylases ◽  
Erythropoiesis Stimulating Agents ◽  
Sustained Effects ◽  
Concomitant Medications

<b><i>Background:</i></b> Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. <b><i>Summary:</i></b> The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. <b><i>Key Messages:</i></b> Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

scholarly journals Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 350
Author(s):  
Julianty Frost ◽  
Mark Frost ◽  
Michael Batie ◽  
Hao Jiang ◽  
Sonia Rocha
Keyword(s):  
Gene Expression ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Regulator ◽  
Hydroxylase Activity ◽  
Control Of Gene Expression ◽  
Prolyl Hydroxylases ◽  
Chromatin Organisation ◽  
Sense And Respond ◽  
Almost All ◽  
And Function

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

scholarly journals Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy

Amino Acids ◽  
2021 ◽  
Author(s):  
Jerzy Palka ◽  
Ilona Oscilowska ◽  
Lukasz Szoka
Keyword(s):  
Cell Metabolism ◽  
Underlying Mechanism ◽  
Collagen Biosynthesis ◽  
Proline Metabolism ◽  
Proline Dehydrogenase ◽  
Histone Demethylases ◽  
Proline Oxidase ◽  
Prolyl Hydroxylases ◽  
Transport Chain ◽  
And Control

AbstractRecent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.

No detrimental effects of repeated laparotomies on early healing of experimental intestinal anastomoses

2005 ◽  
Vol 20 (6) ◽  
pp. 534-541 ◽  
Author(s):  
I. H. J. T. de Hingh ◽  
H. van Goor ◽  
B. M. de Man ◽  
R. M. L. M. Lomme ◽  
R. P. Bleichrodt ◽  
...  
Keyword(s):  
Intestinal Anastomoses ◽  
Early Healing

scholarly journals Novel assessment of intestinal anastomotic perfusion using ICG SPY in a continuous flow LVAD patient

2020 ◽  
Vol 2020 (11) ◽  
Author(s):  
Daniel Kaufman ◽  
Danny Sherwinter ◽  
Ron Kaleya ◽  
Paul C Saunders
Keyword(s):  
Continuous Flow ◽  
Axial Flow ◽  
Colon Resection ◽  
Left Ventricular ◽  
Heartmate Ii ◽  
Ventricular Assist ◽  
Intestinal Anastomoses ◽  
First Case ◽  
Left Ventricular Assist ◽  
Axial Flow Pump

Abstract HeartMate II left ventricular assist device (LVAD) assists heart failure patients by generating continuous flow via axial flow pump placed in the left ventricle. Little is known of the effect of continuous flow on intestinal anastomoses. This is the first case visually documenting altered perfusion patterns in patients with LVADs using indocyanine green (ICG). A 72-year-old male required a colon resection, for adenocarcinoma, following implantation of an LVAD. Perfusion of the anastomosis was evaluated using indocyanine. During the assessment, an unusual perfusion pattern was noticed. Normally, flow as measured by SPY is seen as an initial blush of contrast followed by a gradual, pulsatile increase in the progression of the indocyanine through the tissues. In this patient, instead of the usual initial blush, a continuous beam of ICG was seen to flow though the blood vessels. This novel perfusion pattern is consistent with flow generated from LVAD.

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