Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy. Patients with WS frequently develop deafness, diabetes insipidus, renal tract abnormalities, and diverse psychiatric illnesses, among others. A gene responsible for WS was identified on 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein present in a wide spectrum of tissues. A new locus for WS has been located on 4q22-24, providing evidence for the genetic heterogeneity of this syndrome. Six Spanish families with a total of seven WS patients were screened for mutations in the WFS1-coding region by direct sequencing. We found three previously undescribed mutations c.873C > A, c.1949_50delAT, and c.2206G > C, as well as the duplication c.409_424dup16, formerly published as 425ins16. Several groups had detected deletions in the mitochondrial DNA (mtDNA) of WS patients. For this reason, we also studied the presence of mtDNA rearrangements as well as Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and A1555G point mutations in the WS families. No mtDNA abnormalities were detected.
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PMID:Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families. 1515 4

P-selectin is a transmembrane protein present in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells. Following activation, it is rapidly translocated to the cell surface. P-selectin expression in platelets has been shown to be elevated in disorders associated with arterial thrombosis such as coronary artery disease, acute myocardial infarction, stroke, and peripheral artery disease. P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells as well as interactions of platelets with leukocytes. Platelet P-selectin interacts with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes to form platelet-leukocyte aggregates. Furthermore, this interaction of P-selectin with PSGL-1 induces the upregulation of tissue factor, several cytokines in leukocytes and the production of procoagulant microparticles, thereby contributing to a prothrombotic state. P-selectin is also involved in platelet-platelet interactions, i. e. platelet aggregation which is a major factor in arterial thrombosis. P-selectin interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed by GPIIb/IIIa-fibrinogen bridges. Inhibtion of the P-selectin-sulfatide interaction leads to a reversal of platelet aggregation. Thus, P-selectin plays a significant role in platelet aggregation and platelet- leukocyte interactions, both important mechanisms in the development of arterial thrombosis.
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PMID:P-selectin in arterial thrombosis. 1556 45

The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) was initially described in a 1997 publication co-authored by investigators from the biotechnology company Biogen (now Biogen-Idec) and the University of Geneva. Four years later, researchers at the biotechnology company Immunex (now part of Amgen) reported the cloning and characterization of the human TWEAK receptor. A sequence database search revealed that the predicted TWEAK receptor amino acid sequence was identical to that of fibroblast growth factor-inducible 14 (Fn14), a small transmembrane protein described one year earlier in a publication from investigators at the American Red Cross Holland Laboratory. Recent studies have revealed that the TWEAK-Fn14 ligand-receptor pair likely plays an important role in a variety of cellular processes and in the pathogenesis of several human diseases, including atherosclerosis, stroke, rheumatoid arthritis and cancer. In this paper, we first summarize the general properties of these two proteins and then review the available data implicating TWEAK and Fn14 in multiple aspects of tumor biology.
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PMID:Role of TWEAK and Fn14 in tumor biology. 1712 78

Prolyl 4-hydroxylases (P4Hs) have central roles in the synthesis of collagens and the regulation of oxygen homeostasis. The 4-hydroxyproline residues generated by the endoplasmic reticulum (ER) luminal collagen P4Hs (C-P4Hs) are essential for the stability of the collagen triple helix. Vertebrate C-P4Hs are alpha2beta2 tetramers with three isoenzymes differing in their catalytic alpha subunits. Another P4H family, the HIF-P4Hs, hydroxylates specific prolines in the alpha subunit of the hypoxia-inducible transcription factor (HIF), a master regulator of hypoxia-inducible genes, and controls its stability in an oxygen-dependent manner. The HIF-P4Hs are cytoplasmic and nuclear enzymes, likewise with three isoenzymes in vertebrates. A third vertebrate P4H type is an ER transmembrane protein that can act on HIF-alpha but not on collagens. All P4Hs require Fe2+, 2-oxoglutarate, O2, and ascorbate. C-P4Hs are regarded as attractive targets for pharmacological inhibition to control excessive collagen accumulation in fibrotic diseases and severe scarring, while HIF-P4H inhibitors are believed to have beneficial effects in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, diabetes, and severe anemias. Studies with P4H inhibitors in various animal models of fibrosis, anemia, and ischemia and ongoing clinical trials with HIF-P4H inhibitors support this hypothesis by demonstrating efficacy in many applications.
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PMID:Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. 1916 May 70

Notch3 is a single pass transmembrane protein belonging to the Notch receptor family. Notch proteins are involved in a very conserved signaling system (Notch signaling) with a broad spectrum of functions, from cell proliferation and differentiation to apoptosis. Mutations in Notch3 gene are linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder characterized by stroke and dementia in young adults. Studies evaluating Notch3 expression in human differentiated cells and adult tissues have shown high Notch3 levels only in vascular smooth muscle cells (VSMC). However, it has been hypothesized that Notch3 is ubiquitously expressed in adult human tissues. Our aim was to evaluate Notch3 expression in human peripheral blood lymphocytes (PBLs) and fibroblasts from normal healthy subjects. In both cell types, we examined the expression of Notch3 by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, we assessed Notch3 protein expression by Western blot analysis. RT-PCR and qRT-PCR analysis showed the presence of Notch3 mRNA in both cell types. Western blot analysis confirmed Notch3 protein expression in PBLs and fibroblasts though showing different profiles. Our data support the expression of Notch3 in adult human cell types, and suggests that PBLs and fibroblasts could provide readily available cells for the study of the role of Notch3 expression in the pathogenetic mechanisms leading to different human disease.
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PMID:Human peripheral blood lymphocytes and fibroblasts as Notch3 expression models. 2170 48

Voltage-gated sodium channels are large transmembrane protein complexes responsible for the propagation and transmission of electrical impulses through nerve, muscle and endocrine cells and cell systems. Dysregulated expression and/or functional changes of ion channel isoforms are found in many associated pathological conditions. In such cases, modulation of voltage gated sodium channels (Na(V) channels) is a recognised approach in medicinal chemistry. Multiple small-molecule active compounds are used for a plethora of Na(V) channel-linked indications, for example epilepsy and CNS disorders, arrhythmia, stroke and pain states such as congenital analgesia/hyperalgesia and neuropathic pain. As existent Na(V) channel modulators suffer mainly from selectivity issues and thus exert significant side effects, novel and selective Na(V) channel modulators would be beneficial. Consequently, the increased research on voltage-gated sodium channels has led to a large number of novel compounds that exploit classic binding site selectivity with state-dependence or functional selectivity. Such compounds offer selective targeting and new possibilities for studying the physiology of Na(V) channels and pathophysiology of the associated ailment conditions. This review consolidates the recent literature on Na(V) 1.3, 1.7 and 1.8 channel isoform selective and/or state-dependent modulators. In particular, their structure-activity relationship is illustrated, especially in the context of selectivity on a particular isoform, and their applicability in the therapy of neuropathic pain is described.
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PMID:Isoform selective voltage-gated sodium channel modulators and the therapy of pain. 2405 40

Metastatic disease to the brain results in significant morbidity because of edema in the central nervous system. Current anti-edema therapies are either expensive or result in unwanted long-term side effects. Sulfonylurea receptor 1 (Sur1) is a transmembrane protein that, when activated in the central nervous system, allows for unregulated sodium influx into cells, a process that has been linked to cytotoxic edema formation in ischemic stroke, subarachnoid hemorrhage, spinal cord injury, traumatic brain injury, and, most recently, brain metastases. In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.
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PMID:Potential of glyburide to reduce intracerebral edema in brain metastases. 2455 76

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.
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PMID:High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. 2468 81

Dyshidrosiform pemphigoid is a rare variant of bullous pemphigoid localized to the hands and feet whose characteristic subepidermal blisters develop as a result of binding of the IgG autoantibodies to intracellular plaque and extracellular face of the hemidesmosome recognizing a 230-kDa plakin molecule (BP230, BPAg1or BPAg1e) and a 180-kDa transmembrane protein. Neurodegenerative processes (viz., stroke, dementia, Parkinsonism, epilepsy, etc) uncover BPAg1-n, an alternatively spliced form of BPAg1-e that stabilizes the cytoskeleton of sensory neurons, generating autoantibodies that may subsequently lead to BP by cross-reacting with BPAg1-e. We present a patient with Parkinsonism who later developed blisters, erosions and crusts localized to the palms and soles, confirmed histopathologically as bullous pemphigoid. To the best of our knowledge, ours is the first case report from India wherein Parkinsonism-generated autoantibodies led to the development of dyshidrosiform pemphigoid due to their cross-reactivity with BPAg1-e.
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PMID:Dyshidrosiform pemphigoid with Parkinsonism in a nonagenarian Maharashtrian female. 2539 35

Vitamin K epoxide reductase complex subunit 1 (VKORC1) is integral 163-amino acid long transmembrane protein which mediates recycling of vitamin K 2,3-epoxide to vitamin K hydroquinone and it is necessary for activation of vitamin K-dependent proteins (VKDPs). Herein, the association between G-1639A (rs9923231) and C1173T (rs9934438) single-nucleotide polymorphisms (SNPs) of the VKORC1 gene and ischemic stroke (IS) was tested in Ukrainian population. Genotyping was performed in 170 IS patients and 124 control subjects (total 294 DNA samples) using PCR-RFLP (polymerase chain reaction with following restriction fragment length polymorphism analysis) method. Our data showed that G-1639A but not C1173T polymorphism was related to IS, regardless of adjustment for age, sex, body mass index, smoking status, and arterial hypertension. The risk for IS in -1639A allele carriers (OR = 2.138, P = 0.015) was higher than in individuals with G/G genotype. Haplotype analysis demonstrated that -1639G/1173T and -1639A/1173C were related to increased risk for IS (OR = 3.813, P = 0.010, and OR = 2.189, P = 0.011, resp.), while -1639G/1173C was a protective factor for IS (OR = 0.548, P < 0.001). Obtained results suggested that -1639A allele can be a possible genetic risk factor for IS in Ukrainian population.
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PMID:G-1639A but Not C1173T VKORC1 Gene Polymorphism Is Related to Ischemic Stroke and Its Various Risk Factors in Ukrainian Population. 2770 68


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