Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins (PG) are highly unsaturated, cyclic fatty acids with 20 carbon atoms which are biosynthesized from dihomo-gamma-linolenic, arachidonic and eicosapentaenoic acids. These fatty acids are either ingested or are biosynthesized from linoleic and linolenic acids, respectively. The PG-precursor fatty acids are liberated from membrane phospholipids by phospholipase A and are converted to prostaglandins by the multienzyme complex PG-synthetase. The activity of the PG-system is influenced by extracellular hormonal, neural and mechanical stimuli and by intracellular factors such as ion-concentration and activity of the enzymes adenyl- and guanylcyclase. Prostaglandins are tissue hormones or autacoids which act on their receptors near their site of synthesis and degradation. The prostaglandin family constitutes a group of more than 10 natural occurring compounds showing a variety of biological actions. In arteries and veins the different PG:s have vasodilating as well as vasoconstricting effects. In addition, they are involved in the regulation of vascular smooth muscle proliferation. Within the kidney PG:s have vascular and tubular actions. They antagonize the effect of ADH, mediate renin secretion and are involved in the control of electrolyte balance. In the regulation of platelet aggregation and platelet adhesion PG:s have opposite functions: Prostacyclin which is synthesized in the vascular wall antagonizes the aggregating action of Thromboxane A2 which is formed in the platelets. A defect or an imbalance in the production of PG:s in the vascular wall, in platelets or in the kidney is assumed to play a pathogenetic role in a variety of cardiovascular and renal diseases such as in hypertension, atherosclerosis, persistent ductus arteriosus and Bartter's syndrome.
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PMID:[Prostaglandins in cardiovascular and renal function. Biochemical, physiological and clinical findings (author's transl)]. 10 97

The aging kidney suffers reduction both in mass and in glomerular filtration rate. These changes may be totally or partially due to atherosclerosis and hypertension, which reduce renal blood flow. Superimposed on these processes, and perhaps responsible for primary loss of renal mass irrespective of renal vascular disease, is glomerular damage and involution that is a consequence of adaptive increases in glomerular perfusion pressure that occurs as the number of nephrons decline with age. The data available at this time do not allow us to distinguish between these two potential mechanisms of renal senescence. The decline in GFR is in turn responsible for reduced renal acidification and the reduced renal clearance of drugs that are normally removed by the kidney. Certain renal functions, however, are depressed to a greater extent than is GFR. Both the ability to maximally dilute the urine and to maximally concentrate it are controlled by serum ADH concentrations and by the action of that hormone on the collecting duct. Aged rats do not maximally secrete ADH under conditions of dehydration and the effect of ADH on the kidney is also attenuated. Elderly humans also cannot maximally suppress ADH secretion when serum osmolality is reduced. Likewise, the renin-angiotensin-aldosterone axis is poorly responsive to volume depletion in aging subjects. As a result, elderly individuals cannot maximally retain sodium under conditions of plasma volume contraction out of proportion to reduction in GFR. The kidney is the site of vitamin D1 hydroxylation. Hydroxylation of vitamin D is reduced out of proportion to any reduction in GFR in the rat. There are no data as yet available on the effect of aging and the production of erythropoietin, a principal regulator of red blood cell mass. Neither are there data available on changes that might occur with advancing age in the ability of the aging kidney to metabolize various hormones, such as parathyroid hormone, glucagon, and insulin. The mechanisms and the full biochemical and physiologic consequences of renal senescence remain to be fully elucidated.
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PMID:The aging kidney. 391

The discovery of PCSK9 in 2003 and its identification as the third protagonist responsible for ADH opened many new avenues of research in the cardiovascular field. Liver PCSK9 binds the LDLR and promotes its degradation in the endosomal/lysosomal pathway. A higher activity of PCSK9 leads to lower liver LDLR levels, resulting in a reduction in LDL-uptake from circulation, and thus in hypercholesterolemia and associated atherosclerosis. Although PCSK9 mutations are rare, their associated phenotypes can be devastating. The most powerful PCSK9 gain-of-function mutation, D374Y, is responsible for LDL cholesterol (LDLc) levels of ~10 mmol/L versus ~3 mmol/L in normal subjects.The aim of this manuscript is to review the available literature on the identification and pharmacological applications of potent inhibitors of PCSK9 function and/or activity, and to present the latest data on the ongoing clinical trials, mostly related to the use of monoclonal antibodies (mAb) that interfere with PCSK9 function on the LDLR, resulting in a significant drop in circulating LDLc.The clinical data, so far, are very encouraging with Phase-2 trials from various pharmaceutical companies showing a drop of >60% in LDLc for at least 2 weeks after a single injection of a humanized PCSK9 mAb in the presence or absence of adjunct statin therapy. In view of the absence of overt toxicity associated with this treatment Phase-3 clinical trials have started with >20,000 individuals being tested and anticipated primary outcomes results should be forthcoming by 2016. Other approaches including the use of recombinant adnectins, antisense RNAi or small molecule inhibitors are also undergoing early pre-clinical testing or are already in Phase-1 clinical trials.Very recent data revealed that absence of PCSK9 can be protective against melanoma invasion in mouse liver, and that this is due to lower circulating LDLc. This opens the door to novel applications of PCSK9 inhibitors/silencers in cancer/metastasis.
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PMID:Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. 2331 4