Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human rhomboid family (RHBDF)1 gene is highly expressed in breast cancer under clinical conditions but not in normal mammary gland tissues. Silencing the RHBDF1 gene in breast cancer xenograft tumors leads to inhibition of tumor growth. We show in this study that artificially raising RHBDF1 protein levels in the mammary epithelial cells MCF-10A results in severe perturbations of the ability of the cells to form lumen-containing acini, either in 3-dimensional cell cultures or implanted in mouse mammary fat pads. Knocking down RHBDF1 with short hairpin (sh)RNA leads to restoration of acinus formation. Consistently, RHBDF1 overexpression gives rise to disordered distribution of polarity markers GM130 and laminin-5, which otherwise are located in apical and basal positions, respectively, in the acini. Further investigations reveal that RHBDF1 directly binds to Par6a, a component of a protein complex consisting of partitioning-defective scaffold protein (Par)6, Par3, renin-angiotensin system-related C3 botulinum toxin substrate (Rac)1, and cell-division cycle (Cdc)42, which is structurally critical to the formation of apicobasal polarity. RHBDF1 binding to Par6a results in collapse of the protein complex and thus disruption of polarity formation. Since early stages of breast cancer are characterized by the loss of mammary gland epithelial cell polarity, our findings indicate that perturbations of apicobasal polarity by high levels of RHBDF1 is a significant attribute in the development of breast neoplasia.-Peng, X.-M., Gao, S., Deng, H.-T., Cai, H.-X., Zhou, Z., Xiang, R., Zhang, Q.-Z., Li, L.-Y. Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression.
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PMID:Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression. 2972 9

Canine hypoadrenocorticism (HoAC) results from a loss of functional adrenal cortex, the most common etiology of which is an immune-mediated destruction leading to an inadequate production of glucocorticoids and mineralocorticoids. The term "atypical" HoAC is used for a subgroup of dogs with either an isolated glucocorticoid deficiency or a combined glucocorticoid and mineralocorticoid deficiency but normal electrolytes. Dogs with HoAC can present with a large variety of clinical signs, ranging from shaking, weakness, and mild gastrointestinal signs to seizures, hypovolemic shock, and collapse. Routine clinicopathologic and diagnostic imaging findings are usually nonspecific and frequently mimic those of other common diseases. However, the absence of a stress leukogram, eosinophilia, hyponatremia, hyperkalemia, and azotemia and small adrenal glands on abdominal ultrasound are characteristic findings in dogs with HoAC. The ACTH stimulation test is currently the gold standard method for diagnosing HoAC. Other endocrine laboratory diagnostics, including the quantification of endogenous ACTH, basal and ACTH-stimulated aldosterone levels, cortisol:ACTH ratio, and aldosterone:renin ratio, may further aid in differentiating between primary, secondary, and "atypical" HoAC. Aggressive intravenous fluid therapy is the cornerstone of treatment in paients with an acute Addisonian crisis because it restores normovolemia and normal blood electrolytes. Maintenance therapy consists of glucocorticoid (e.g., prednisolone) and mineralocorticoid (e.g., des- oxycortone pivalate) supplementation and aims for stable electrolyte concentrations and a clinically well dog. The optimal dose of desoxy- cortone pivalate for a specific dog is determined based on blood so- dium and potassium concentrations by using a standardized protocol. Regular reevaluation of blood electrolytes is required for early identifi- cation of a mineralocorticoid deficiency in dogs with "atypical" HoAC. The long-term prognosis for dogs with HoAC is excellent provided that patients receive adequate treatment and there is good owner com- pliance.
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PMID:[Canine hypoadrenocorticism - an update on pathogenesis, diagnosis and treatment]. 2989 78

Background Obstructive sleep apnoea (OSA) is an independent risk factor of hypertension and cardiovascular diseases. Recurrent episodes of upper airways collapse during sleep causing blood oxygen desaturation, hypercapnia, and micro-arousals, are known to activate the sympathetic nervous system (SNS). However, whether changes in the renin-angiotensin-aldosterone system and endothelial activation also occur remains contentious. Methods Based on routine use of drug-induced sleep endoscopy (DISE) for the work-up of OSA patients in our centre, we designed a prospective study to investigate the haemodynamic and humoral changes occurring during the apnoeic episodes reproduced in vivo in the course of DISE. Specifically, plasma aldosterone concentration and renin activity, C-terminal fragment of proendothelin-1, as a marker of endothelial damage, and free plasma catecholamines, will be measured at fixed times during DISE. The activity of catechol-O-methyltransferase (COMT), a key catecholamine-inactivating enzyme that has been scantly investigated thus far owing to the lack of commercially available kits, will be also determined by a newly developed high performance liquid chromatography method, which is herein described. Results and conclusions The aim of this study is to provide novel information on the haemodynamic, hormonal, and SNS changes, and also on COMT activity modification concomitantly occurring during apnoea, thus contributing substantively to the understanding of the pathophysiology of OSA.
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PMID:Design of a study to investigate the mechanisms of obstructive sleep apnoea by means of drug-induced sleep endoscopy. 3111 3

Although methidathion is an organophosphate insecticide, it is different from the other organophosphates in terms of toxicity. Because of its relatively high fat solubility, the apparent volume of methidathion distribution throughout the body is very high, indicating that hemoperfusion is not effective in removing this organophosphate from the body. Redistribution of methidathion from fat to blood can also occur when plasma levels diminish. Additionally, acetylcholinesterase aging, which is the loss of an alkyl side chain that prevents reactivation by oximes, is very rapid so that the effective reactivation by oximes is thwarted. Thus, methidathion's effect on acetylcholinesterase inhibition is long lasting, particularly with a high dose. In addition to its parasympatholytic effect and ability to induce muscle paralysis, methidathion poisoning is associated with a profound and long-lasting circulatory collapse due to sympathetic ganglion blockade. This report presents the case of a 55-year-old man who accidentally ingested a high dose of methidathion. He later developed enteroinvasive aspergillosis infection-induced multiple bowel perforations on two separate occasions while on mechanical ventilator support, resulting in a fatal outcome. The renin-angiotensin axis activated by sympathetic ganglion blockade may have reduced the patient's splanchnic blood flow, contributing to translocation of endotoxin. Also, the effect of excessive acetylcholine on non-neuronal acetylcholine receptors may have contributed to the development of fatal enteroinvasive aspergillosis in this patient.
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PMID:Methidathion Poisoning. 3172 59

Large conduit arteries and the microcirculation participate in the mechanisms of elevation of blood pressure (BP). Large vessels play roles predominantly in older subjects, with stiffening progressing after middle age leading to increases in systolic BP found in most humans with aging. Systolic BP elevation and increased pulsatility penetrate deeper into the distal vasculature, leading to microcirculatory injury, remodelling, and associated endothelial dysfunction. The result is target organ damage in the heart, brain, and kidney. In younger individuals genetically predisposed to high BP, increased salt intake or other exogenous or endogenous risk factors for hypertension, including overweight and excess alcohol intake, lead to enhanced sympathetic activity and vasoconstriction. Enhanced vasoconstrictor responses and myogenic tone become persistent when embedded in an increased extracellular matrix, resulting in remodelling of resistance arteries with a narrowed lumen and increased media-lumen ratio. Stimulation of the renin-angiotensin-aldosterone and endothelin systems and inflammatory and immune activation, to which gut microbiome dysbiosis may contribute as a result of salt intake, also participate in the injury and remodelling of the microcirculation and endothelial dysfunction. Inflammation of perivascular fat and loss of anticontractile factors play roles as well in microvessel remodelling. Exaggerated myogenic tone leads to closure of terminal arterioles, collapse of capillaries and venules, functional rarefaction, and eventually to anatomic rarefaction, compromising tissue perfusion. The remodelling of the microcirculation raises resistance to flow, and accordingly raises BP in a feedback process that over years results in stiffening of conduit arteries and systo-diastolic or predominantly systolic hypertension and, more rarely, predominantly diastolic hypertension. Thus, at different stages of life and the evolution of hypertension, large vessels and the microcirculation interact to contribute to BP elevation.
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PMID:How Structure, Mechanics, and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension. 3238 38

SARS-CoV-2, the agent of COVID-19, shares a lineage with SARS-CoV-1, and a common fatal pulmonary profile but with striking differences in presentation, clinical course, and response to treatment. In contrast to SARS-CoV-1 (SARS), COVID-19 has presented as an often bi-phasic, multi-organ pathology, with a proclivity for severe disease in the elderly and those with hypertension, diabetes and cardiovascular disease. Whilst death is usually related to respiratory collapse, autopsy reveals multi-organ pathology. Chronic pulmonary disease is underrepresented in the group with severe COVID-19. A commonality of aberrant renin angiotensin system (RAS) is suggested in the at-risk group. The identification of angiotensin-converting-enzyme 2 (ACE2) as the receptor allowing viral entry to cells precipitated our interest in the role of ACE2 in COVID-19 pathogenesis. We propose that COVID-19 is a viral multisystem disease, with dominant vascular pathology, mediated by global reduction in ACE2 function, pronounced in disease conditions with RAS bias toward angiotensin-converting-enzyme (ACE) over ACE2. It is further complicated by organ specific pathology related to loss of ACE2 expressing cells particularly affecting the endothelium, alveolus, glomerulus and cardiac microvasculature. The possible upregulation in ACE2 receptor expression may predispose individuals with aberrant RAS status to higher viral load on infection and relatively more cell loss. Relative ACE2 deficiency leads to enhanced and protracted tissue, and vessel exposure to angiotensin II, characterised by vasoconstriction, enhanced thrombosis, cell proliferation and recruitment, increased tissue permeability, and cytokine production (including IL-6) resulting in inflammation. Additionally, there is a profound loss of the "protective" angiotensin (1-7), a vasodilator with anti-inflammatory, anti-thrombotic, antiproliferative, antifibrotic, anti-arrhythmic, and antioxidant activity. Our model predicts global vascular insult related to direct endothelial cell damage, vasoconstriction and thrombosis with a disease specific cytokine profile related to angiotensin II rather than "cytokine storm". Our proposed mechanism of lung injury provides an explanation for early hypoxia without reduction in lung compliance and suggests a need for revision of treatment protocols to address vasoconstriction, thromboprophylaxis, and to minimize additional small airways and alveolar trauma via ventilation choice. Our model predicts long term sequelae of scarring/fibrosis in vessels, lungs, renal and cardiac tissue with protracted illness in at-risk individuals. It is hoped that our model stimulates review of current diagnostic and therapeutic intervention protocols, particularly with respect to early anticoagulation, vasodilatation and revision of ventilatory support choices.
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PMID:COVID-19 as a viral functional ACE2 deficiency disorder with ACE2 related multi-organ disease. 3275 71

A Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has become a pandemic disease named Coronavirus Disease-19 (COVID-19) of epochal dimension. The clinical spectrum of COVID-19 is wide, ranging from asymptomatic forms to severe pneumonia, sepsis and multiple organ dysfunction syndromes resulting in poor outcomes. Among the various consequences of severe COVID-19, cardiovascular (CV) collapse appears the most serious and potentially lethal. On the other hand, pre-existent CV comorbidities are also associated with higher mortality. The most reliable hypothetical pathogenetic mechanism for CV complications and cardiac injury in severe COVID-19 patients appears to be a sustained endothelial dysfunction, caused by the interplay of inflammation and coagulation. In this review, we survey papers addressing issues related to severe COVID-19, characterized by enhanced lung microvascular loss, hypercytokinemia, hypoxemia and thrombosis. We discuss about how the virus-induced downregulation of the angiotensin converting enzyme-2 (ACE2) receptor, used to enter the host cell, could affect the renin-angiotensin system, attempting to clarify the doubts about the use of ACE inhibitors and Angiotensin-II receptor blockers in COVID-19 patients. Finally, we point out how the delicate and physiological homeostatic function of the endothelium, which turns into a disastrous battlefield of the complex interaction between "cytokine and coagulative storms", can be irreparably compromised and result in systemic inflammatory complications.
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PMID:COVID-19 and cardiovascular consequences: Is the endothelial dysfunction the hardest challenge? 3287 6


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