Search results for "HYPOXIA"
showing 10 items of 508 documents
Targeting a Targeted Drug: An Approach Toward Hypoxia-Activatable Tyrosine Kinase Inhibitor Prodrugs
2016
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of …
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
2019
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dr…
Adipose Tissue in Sleep Apnea
2015
Obesity is increasingly recognized as a very complex metabolic state. Besides visceral obesity and white adipose tissue (WAT) function, the most recent studies point to a major metabolic role of brown adipose tissue (BAT) in energy metabolism. Visceral obesity is associated with hypoxia of adipose tissue and inflammation, both these features being also present in patients with obstructive sleep apnea (OSA). Obesity and OSA may share some common pathogenetic mechanisms, since hypoxia and inflammation are major features of OSA as well. However, the unique pattern of intermittent hypoxia occurring in OSA patients during sleep may modify the response of WAT and BAT in both lean and obese subjec…
Nutritional Status in Aging and Lung Disease
2016
Abstract Lung diseases exert a negative impact on nutritional status, especially among older patients where aging per se is already associated with relevant changes in nutrient intake, metabolism, and body composition. Both respiratory (increased respiratory work, hypoxia, and local oxidative stress and inflammation) and nonrespiratory (sarcopenia, reduced mitochondrial biogenesis and anabolic hormones, balance of orexigenic/anorexigenic neuropeptides, and systemic inflammation and oxidative stress) contribute to the association between lung diseases and malnutrition. For these reasons, nutritional assessments are of paramount importance in older patients with lung diseases. Current evidenc…
Prenatal Brain Damage in Preeclamptic Animal Model Induced by Gestational Nitric Oxide Synthase Inhibition
2010
Cerebral palsy is a major neonatal handicap with unknown aetiology. There is evidence that prenatal brain injury is the leading cause of CP. Severe placental pathology accounts for a high percentage of cases. Several factors predispose to prenatal brain damage but when and how they act is unclear. The aim of this paper was to determine if hypoxia during pregnancy leads to damage in fetal brain and to evaluate the localization of this injury. An animal model of chronic hypoxia produced by chronic administration of a nitric oxide synthase inhibitor (L-NAME) was used to evaluate apoptotic activity in fetal brains and to localize the most sensitive areas. L-NAME reproduces a preeclamptic-like c…
Inhibition of Peripheral Dopamine Metabolism and the Ventilatory Response to Hypoxia in the Rat
2014
Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO – debrisoquine, or COMT – entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O2 in N2 were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. Ho…
Role of IP3 Receptors in Shaping the Carotid Chemoreceptor Response to Hypoxia But Not to Hypercapnia in the Rat Carotid Body: An Evidence Review
2020
This article addresses the disparity in the transduction pathways for hypoxic and hypercapnic stimuli in carotid body glomus cells. We investigated and reviewed the experimental evidence showing that the response to hypoxia, but not to hypercapnia, is mediated by 1,4,5-inositol triphosphate receptors (IP3R/s) regulating the intracellular calcium content [Ca2+]c in glomus cells. The rationale was based on the past observations that inhibition of oxidative phosphorylation leads to the explicit inhibition of the hypoxic chemoreflex. [Ca2+]c changes were measured using cellular Ca2+-sensitive fluorescent probes, and carotid sinus nerve (CSN) sensory discharge was recorded with bipolar electrode…
Tumor Oxygenation Under Normobaric and Hyperbaric Hyperoxia
1997
Tumor hypoxia is an important factor limiting the efficiency of sparsely ionizing ra-diation and O2-dependent chemotherapy. Since the tumor pO2 is the result of a dynamic steady state between oxygen supply and O2 consumption of the tumor tissue, hypoxia could be reduced either by increasing the O2-supply or by reducing the O2 demand of the tumor cells. The O2 supply can be improved for instance by (i) increasing the arterial oxy-gen partial pressure, (ii) improving (and homogenizing) the tumor perfusion, or (iii) en-hancing the O2 release from blood into the tissue by right-shifting the HbO2 dissociation curve. Theoretically, it should also be possible to improve tumor oxygenation by a rela…
Hyperlipidemia Prevalence and Cholesterol Control in OSA: Data from European Sleep Apnea Database (ESADA)
2019
European-Respiratory-Society (ERS) International Congress -- SEP 28-OCT 02, 2019 -- Madrid, SPAIN
The Role of Endothelium in COVID-19
2021
The 2019 novel coronavirus, known as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19), is causing a global pandemic. The virus primarily affects the upper and lower respiratory tracts and raises the risk of a variety of non-pulmonary consequences, the most severe and possibly fatal of which are cardiovascular problems. Data show that almost one-third of the patients with a moderate or severe form of COVID-19 had preexisting cardiovascular comorbidities such as diabetes mellitus, obesity, hypertension, heart failure, or coronary artery disease. SARS-CoV2 causes hyper inflammation, hypoxia, apoptosis, and a renin–angiotensin system imbalance …