Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atopic dermatitis (AD) is a familial inflammatory skin disorder, which is characterized by extreme pruritus, the typical morphology and distribution, the chronic or chronically relapsing course, and the personal or family case history of atopy (asthma, allergic rhinitis, atopic dermatitis); moreover, we find a variety of additional features, which are either less specific or relatively rare. Although this disease has been well-known since the beginning of the century, we have not clearly understood its pathogenesis so far. This article reviews the reported deviations of the immune system and the alterations of the mediators of inflammation as well as the abnormalities of cyclic nucleotide regulation. These findings are correlated to the clinical symptoms. The following topics have been dealt with in detail: association with HLA-antigens, elevation of serum IgE and generation of IgE immune complexes, numerical and functional deficiencies of T-suppressor cells, involvement of granulocytes, alterations of mediators of inflammation, and particularly, observations on the cAMP-phosphodiesterase. These extremely complex findings, which are based on the interaction between disregulation of the autonomous nervous system and alterations of the immune system, may provide a better understanding of the pathogenesis of atopic dermatitis.
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PMID:[Pathogenesis of atopic dermatitis]. 243 53

Throughout spermatogenesis, inter-Sertoli tight junctions (TJs) that constitute the blood-testis barrier must be disassembled and reassembled to permit the timely movement of preleptotene and leptotene spermatocytes from the basal to the adluminal compartment of the seminiferous epithelium. However, the mechanism and the participating molecules that regulate the bioavailability of TJ proteins are entirely unknown. Using Sertoli cell culture, it was shown that there was an increase in occludin level, concomitant with a reduction of an E3 ubiquitin ligase, Itch, at the time when inter-Sertoli TJs were assembled. By co-immunoprecipitation, occludin was shown to associate with Itch at the TJs. A novel interaction between Itch and UBC4 (an ubiquitin-conjugating enzyme) was identified. When TJs were disrupted by dibutyryl-cAMP (db-cAMP), an increase in protein levels of Itch and UBC4 along with a significant reduction in endogenous occludin was detected. These results seemingly suggest that the interaction of Itch and UBC4 on occludin is potentially involved in regulating Sertoli TJ dynamics. Addition of a proteasome inhibitor, MG-132, into Sertoli cells cultured with db-cAMP blocked the db-cAMP-induced occludin loss in vitro. Accumulations of ubiquitin-conjugated and Itch-conjugated occludin were detected in Sertoli cells cultured in the presence of both MG-132 and db-cAMP. These results suggest that MG-132 prevented db-cAMP-induced TJ disruption by altering the rate of occludin degradation. Taken collectively, the results reported herein support the notion that db-cAMP-induced TJ disruption was mediated by an induction of Itch protein expression, which in turn triggered the ubiquitination of occludin resulting in TJ disruption.
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PMID:cAMP perturbs inter-Sertoli tight junction permeability barrier in vitro via its effect on proteasome-sensitive ubiquitination of occludin. 1560 77

Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by severe intraepatic cholestasis. Pruritus often occurs during the course of the illness. We designed a study aimed at assessing whether pruritus is associated with dysfunction of signal transduction. Seventeen female patients affected by PBC were enrolled into the study and divided in two groups according to severity of liver disease. Leukocytes were isolated from peripheral blood and Gi, Go and Gs protein expressions were evaluated by western blotting, while G protein function was assessed by measuring cyclic adenosine phosphate formation. The expression of all types of G proteins was increased in leukocytes of PBC patients. The basal adenylate activity was significally higher than control in patients with less severe liver disease, while it was lower than normal in those with severe liver disease. Incubation of patient leukocytes with guanosine triphosphate-gamma-S and Gs protein activators failed to enhance cAMP production, while N-formyl-met-leu-phe was more effective in reducing cAMP production. The expression of all G proteins was non-selectively increased in PBC leukocytes, while adenylate cyclase activity was significantly modified. However, the observed changes in G proteins expression and in adenylate cyclase activity are not related to the presence of pruritus.
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PMID:G protein-mediated signal transduction is affected in primary biliary cirrhosis. 1656 23

Reduced production of antimicrobial peptides was proposed to contribute to susceptibility for skin infections in atopic dermatitis (AD). Focusing on the human cathelicidin protein, hCAP18, the aim of the present study was to explore whether reduced hCAP18 expression is a constitutive trait in AD and if established inducers affect the expression of hCAP18 in the skin of AD. First, we compared levels of hCAP18 mRNA between lesional skin in AD and psoriasis and verified significantly lower expression of hCAP18 mRNA in AD. In non-lesional skin, however, there was no difference between AD, psoriasis and healthy, indicating that there is no constitutive defect in the production of hCAP18 in AD patients. In healthy skin, hCAP18 was reported to be rapidly induced following wounding and here we verified this pattern in healthy controls and in psoriasis. In AD lesions, however, the expression of hCAP18 mRNA was markedly suppressed following wounding. Obviously, the inflammation in AD lesions neutralizes the expected induction of hCAP18 and even induces suppression. Notably, the mechanism to upregulate hCAP18 following vitamin D treatment was functional in lesional as well as in non-lesional AD indicating that the CAMP gene is normally regulated in this respect. In addition, cultured primary keratinocytes from non-lesional skin of psoriasis, AD and healthy skin, upregulated hCAP18mRNA following treatment with vitamin D. Itching is a hallmark of AD and scratching inevitably injures the skin. Failure to upregulate hCAP18 in eczema following injury is likely to affect antimicrobial protection and tissue repair in AD.
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PMID:Injury downregulates the expression of the human cathelicidin protein hCAP18/LL-37 in atopic dermatitis. 1964 25

Itch, an ubiquitin E3 ligase, has been implicated in the regulation of the permeability of tight junction (TJ) barriers in Sertoli cells. It is involved in cAMP-mediated TJ disruption by targeting occludin for proteasomal degradation in the testis. However, the molecular mechanisms governing its transcription remain enigmatic. By the transient transfection of Itch promoter luciferase construct in TM4 cells, we showed that the minimal Itch promoter was located between nucleotides -151 and -1 (relative to the translation start site). One E2F motif and two each of GATA and Nkx motifs were identified within the core promoter region. Mutation and overexpression analyses have shown that the E2F and GATA-a motifs are involved in Itch gene transcription, but play different roles. The E2F motif is the crucial cis-acting element that drives the basal gene transcription, while the GATA-a motif functionally co-operates with E2F motif. By electromobility shift assays, we confirmed that E2F1 and DP1 form heterodimers and binds to E2F and GATA-a motifs. Taken together, the GATA-a motif assists/strengthens the binding of E2F1/DP1 complex to the E2F motif, resulting in efficient looping of promoter region of Itch gene for transcription.
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PMID:Expression of Itch in Sertoli cells is controlled via the interaction of E2F1/DP1 complex with E2F and GATA motifs. 2231 64

Atopic dermatitis is a chronic inflammatory cutaneous disease with difficult-to-treat pruritus. Although phosphodiesterase (PDE) 4 inhibitors have an anti-inflammatory effect on inflammatory skin diseases, such as atopic dermatitis, their acute antipruritic activities remain unclear. Therefore, in this study, we examined whether E6005, a novel PDE4 inhibitor, has antipruritic activity in dermatitis, using a mouse model of atopic dermatitis (NC/Nga mice). A single topical application of E6005 inhibited spontaneous hind-paw scratching, an itch-associated response and spontaneous activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP was significantly decreased in mice with chronic dermatitis, and this decrease was reversed by topical E6005 application. These results suggest that E6005 increases the cutaneous concentration of cAMP to relieve dermatitis-associated itching. Thus, E6005 may be a useful therapy for pruritic dermatitis such as atopic dermatitis.
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PMID:Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis. 2464 35

This study aimed to investigate the roles of autophagy and the ubiquitin-proteasome system in the degradation of histone deacetylase 8 (HDAC8) and to clarify the mechanism by which cAMP signaling regulates this degradation. cAMP signaling was activated by treating H1299 non-small cell lung cancer cells with isoproterenol or forskolin/3-isobutyl-1-methylxanthine, and HDAC8 expression was assessed by western blot analysis. The inhibition of autophagy and ubiquitin-proteasome-dependent degradation increased HDAC8 expression. cAMP signaling inhibited JNK activation, which decreased the phosphorylation of Bcl-2, thereby reducing autophagy, and the phosphorylation of Itch, thereby reducing ubiquitination. These results suggest that the HDAC8 protein is degraded via autophagy and the ubiquitin-proteasome system and that cAMP signaling increases HDAC8 protein levels by reducing JNK-mediated autophagy and ubiquitin-proteasome-dependent degradation of the HDAC8 protein in H1299 lung cancer cells.
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PMID:cAMP signaling increases histone deacetylase 8 expression by inhibiting JNK-dependent degradation via autophagy and the proteasome system in H1299 lung cancer cells. 2679 31

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.
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PMID:Atopic dermatitis. 2993 Feb 42

Atopic dermatitis (AD) is a chronic inflammatory skin disease with the hallmark characteristics of pruritus, psychological stress, and sleep disturbance, all possibly associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD). However, the etiology of the possible association between AD and ADHD is still not well understood. 2,4-dinitrochlorobenzene or corticosterone was used to evaluate the atopic symptom and its psychologic stress in the atopic mice model. Melatonin, corticotropin-releasing hormone, corticotropin-releasing hormone receptor, urocortin, proopiomelanocortin, adrenocorticotropic hormone, corticosterone, cAMP, cAMP response element-binding protein, dopamine and noradrenaline were analyzed spectrophotometrically, and the expression of dopamine beta-hydroxylase and tyrosine hydroxylase were measured by Western blotting or immunohistochemistry. AD-related psychological stress caused an increase in the levels of dopamine beta-hydroxylase and tyrosine hydroxylase, degradation of melatonin, hyper-activity of the hypothalamic-pituitary-adrenal axis, and dysregulation of dopamine and noradrenaline levels (ADHD phenomena) in the locus coeruleus, prefrontal cortex, and striatum of the AD mouse brain. Notably, melatonin administration inhibited the development of ADHD phenomena and their-related response in the mouse model. This study demonstrated that AD-related psychological stress increased catecholamine dysfunction and accelerated the development of psychiatric comorbidities, such as ADHD.
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PMID:Melatonin inhibits attention-deficit/hyperactivity disorder caused by atopic dermatitis-induced psychological stress in an NC/Nga atopic-like mouse model. 3029 27