Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted serine proteases (KLK1-KLK15). Many KLKs have been identified in normal stratum corneum (SC) and sweat, and are candidate desquamation-related proteases. We report quantification by enzyme-linked immunosorbent assay (ELISA) of KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of atopic dermatitis (AD) patients by ELISA, and examine their variation with clinical phenotype, correlation with blood levels of eosinophils, lactate dehydrogenase (LDH) and immunoglobulin E. The overall SC serine protease activities were also measured. In the SC of AD, all KLKs, except KLK11, were significantly elevated. The elevation of chymotrypsin-like KLK7 was predominant, compared with trypsin-like KLKs. The SC overall plasmin- and furin-like activities were significantly elevated, while trypsin- and chymotrypsin-like activities did not differ significantly. In the serum of AD patients, KLK8 was significantly elevated and KLK5 and KLK11 were significantly decreased. However, their serum levels were not modified by corticosteroid topical agents. The alterations of KLK levels in the SC of AD were more pronounced than those in the serum. KLK7 in the serum was significantly correlated with eosinophil counts in the blood of AD patients, while KLK5, KLK8 and KLK11 were significantly correlated with LDH in the serum. In conclusion, we report abnormal kallikrein levels in the SC and the serum of AD patients. KLKs might be involved in skin manifestation and/or focal/systemic inflammatory reactions in AD. Our data may contribute to a better understanding of the pathogenesis of AD.
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PMID:Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. 1751 92

Kallikreins-related peptidases (KLKs) are serine proteases and have been implicated in the desquamation process of the skin. Their activity is tightly controlled by epidermal protease inhibitors like the lympho-epithelial Kazal-type inhibitor (LEKTI). Defects of the LEKTI-encoding gene serine protease inhibitor Kazal type (Spink)5 lead to the absence of LEKTI and result in the genodermatose Netherton syndrome, which mimics the common skin disease atopic dermatitis. Since many KLKs are expressed in human skin with KLK5 being considered as one of the most important KLKs in skin desquamation, we proposed that more inhibitors are present in human skin. Herein, we purified from human stratum corneum by HPLC techniques a new KLK5-inhibiting peptide encoded by a member of the Spink family, designated as Spink9 located on chromosome 5p33.1. This peptide is highly homologous to LEKTI and was termed LEKTI-2. Recombinant LEKTI-2 inhibited KLK5 but not KLK7, 14 or other serine proteases tested including trypsin, plasmin and thrombin. Spink9 mRNA expression was detected in human skin samples and in cultured keratinocytes. LEKTI-2 immune-expression was focally localized at the stratum granulosum and stratum corneum at palmar and plantar sites in close localization to KLK5. At sites of plantar hyperkeratosis, LEKTI-2 expression was increased. We suggest that LEKTI-2 contributes to the regulation of the desquamation process in human skin by specifically inhibiting KLK5.
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PMID:Identification of lympho-epithelial Kazal-type inhibitor 2 in human skin as a kallikrein-related peptidase 5-specific protease inhibitor. 1919 Jul 73

The metalloproteases meprin alpha and beta are expressed in several tissues, leukocytes, and cancer cells. In skin, meprins are located in separate layers of human epidermis indicating distinct physiological functions, supported by effects on cultured keratinocytes. Meprin beta induces a dramatic change in cell morphology and a significant reduction in cell number, whereas in vitro evidence suggests a role for meprin alpha in basal keratinocyte proliferation. Meprins are secreted as zymogens that are activated by tryptic proteolytical processing. Here, we identify human kallikrein-related peptidases (KLKs) 4, 5, and 8 to be specific activators of meprins. KLK5 is capable of activating both metalloproteases. Interestingly, KLK4 and 8 cleave off the propeptide of meprin beta only, whereas in contrast plasmin exclusively transforms meprin alpha to its mature form. Moreover, we show that proKLK7 is processed by meprins. N-terminal sequencing revealed cleavage by meprin beta two amino acids N-terminal to mature KLK7. Interestingly, this triggering led to an accelerated activation of the serine protease in the presence of trypsin, but not of other tryptic KLKs, such as KLK2, 4, 5, 8, or 11. In summary, we demonstrate a specific interaction between meprin metalloproteases and kallikrein-related peptidases, revealing possible interactions within the proteolytic web.
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PMID:Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. 2012 84

Kallikrein-related peptidases (KLKs) play a central role in skin desquamation. They are tightly controlled by specific inhibitors, including the lymphoepithelial Kazal-type inhibitor (LEKTI) encoded by SPINK5 and LEKTI-2 encoded by SPINK9. Herein, we identify SPINK6 as a selective inhibitor of KLKs in the skin. Unlike LEKTI but similar to LEKTI-2, SPINK6 possesses only one typical Kazal domain. Its mRNA was detected to be expressed at low levels in several tissues and was induced during keratinocyte differentiation. Natural SPINK6 was purified from human plantar stratum corneum extracts. Immunohistochemical analyses revealed SPINK6 expression in the stratum granulosum of human skin at various anatomical localizations and in the skin appendages, including sebaceous glands and sweat glands. SPINK6 expression was decreased in lesions of atopic dermatitis. Using KLK5, KLK7, KLK8, KLK14, thrombin, trypsin, plasmin, matriptase, prostasin, mast cell chymase, cathepsin G, neutrophil elastase, and chymotrypsin, inhibition with recombinant SPINK6 was detected only for KLK5, KLK7, and KLK14, with apparent K(i) values of 1.33, 1070, and 0.5 nm, respectively. SPINK6 inhibited desquamation of human plantar callus in an ex vivo model. Our findings suggest that SPINK6 plays a role in modulating the activity of KLKs in human skin. A selective inhibition of KLKs by SPINK6 might have therapeutic potential when KLK activity is elevated.
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PMID:Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases. 2066 19

Acute eczematous atopic dermatitis (AD) is associated with increases in stratum corneum (SC) serine protease activity. The purpose of this study was to examine whether the increased SC protease activities in acute eczematous atopic dermatitis were associated with increased mass levels of SC proteases. Six subjects with healthy skin and six patients with AD each with non-lesional skin or lesional acute eczematous skin had the mass levels of their extractable SC kallikreins (KLK), plasmin and urokinase quantified using Luminex multiplex bead-based assays from SC tape strippings. The mass levels of KLK5 and KLK14 together with urokinase were not elevated in the SC in atopic skin. However, the mass levels of KLK7 and KLK11 together with plasmin were greatly elevated compared with the extracts from the non-lesional and the healthy skin and correlated with the corresponding enzymatic activities.
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PMID:Increased mass levels of certain serine proteases in the stratum corneum in acute eczematous atopic skin. 2169 49

Eczema is widely considered to be an exacerbation of alkaline stress to the skin. Epidermal barrier dysfunction is a feature of eczema pathology, which predisposes affected individuals to distressing morbid symptoms. At least two serine proteases, stratum corneum chymotryptic enzyme (kallikrein 7 [KLK7]) and stratum corneum tryptic enzyme (kallikrien 5 [KLK5]), have increased activity levels in eczematous lesions and both have been implicated in the destruction of corneodesomosomes, which are crucial to epidermal integrity. The present in vitro study investigated whether transcriptional gene silencing after siRNA transfection could influence the activity of these signature enzymes in an in vitro model of eczema induced by alkaline shock. HaCaT epithelial cells were subjected to alkaline stress by the addition of 1,1,3,3-tetramethyl guanidine "superbase" (TMG) to the culture media. The culture media were subsequently tested for chymotryspin, trypsin, plasmin, and urokinase activity using colorimetric peptide assays and for reactive oxygen species using WST1 cell viability reagent. Cells that had been transfected with small interfering ribonucleic acid (siRNA) against KLK5 and KLK7 for 24 h before alkaline shock did not exhibit the increase in serine protease levels observed in untreated controls. Moreover, an endpoint MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) confirmed that detachment of cells from the culture substrate observed in alkaline-stressed cells did not occur in siRNA-treated cells. This in vitro study has established the proof-of-principle that siRNA therapy appears to mitigate the consequences of alkaline shock to the serine protease-associated fragility of epithelial cells that is characteristic of eczema.
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PMID:Transcriptional gene silencing of kallikrein 5 and kallikrein 7 using siRNA prevents epithelial cell detachment induced by alkaline shock in an in vitro model of eczema. 2209 88

Niacinamide-containing moisturisers are known be efficacious in alleviating dry skin conditions and improving stratum corneum (SC) barrier function. However, the mechanisms of action of niacinamide at the molecular level in the SC are still not well understood. Previously, we have reported the development of novel methods to probe SC barrier properties in vivo. The aim of the present study was to characterise changes in Trans Epidermal Water Loss (TEWL), corneocyte surface area and maturity, selected protease activities and SC thickness after repeated application of a simple vehicle containing niacinamide. A commercial formulation was also included as a reference. The left and right mid-volar forearms of 20 healthy volunteers were used as study sites, to which topical formulations were applied twice daily for 28 days. After successive tape-stripping, corneocyte maturity and surface area were assessed. In addition, activity of the desquamatory kallikrein (KLK) protease enzymes KLK5 and KLK7, and tryptase and plasmin (implicated in inflammatory process) were measured using a fluorogenic probe assay. The amount of protein removed and TEWL were also recorded. SC thickness before and after treatment was determined using Confocal Raman Spectroscopy (CRS). Overall (i) corneocyte maturity and surface area decreased with increasing number of tape strips, (ii) activity of both the desquamatory and inflammatory enzymes was highest in the outer layers of the SC and decreased with depth (iii) TEWL increased as more SC layers were removed. Furthermore, areas treated with formulations containing niacinamide were significantly different to pre-treatment baseline and untreated/vehicle-control treated sites, with larger and more mature corneocytes, decreased inflammatory activity, decreased TEWL and increased SC thickness. These data (a) confirm the utility of measures and metrics developed previously for the non-invasive assay of SC barrier function, (b) present an holistic picture of a SC compartment managing barrier function through dynamic optimisation of pathlength and quality of building materials used, and (c) shed new light on niacinamide as a topical formulation adjunct with unique SC barrier-augmentation properties.
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PMID:Influence of niacinamide containing formulations on the molecular and biophysical properties of the stratum corneum. 2322 80