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Pathophysiology of Atopic Dermatitis and Atopiform Dermatitis
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
Steinhoff et al. (2003) demonstrated staining for PAR-2 in lesional skin of patients with AD in keratinocytes, blood vessels, certain inflammatory cells, and nerve fiber-like structures (Fig 6.10). PAR-2 receptors provide an explanation for several phenomena occurring in AD. First, there is a pH-dependent increase in endogenous proteases in patients with barrier damage as in AD and, second, many allergens thought to be involved in AD as well as staphylococci have protease activity that can activate PAR-2 (Miedzobrodzki et al. 2002, Kato et al. 2009, Voegeli et al. 2009). Indeed, recent work suggests that the enhancement of protease activity through increased KLK7 expression by the Th2 cytokines IL-4 and IL-13 may be an important determinant of epidermal barrier dysfunction in patients with AD (Morizane et al. 2012). As PAR-2 activation by allergens with protease activity has been shown to delay barrier recovery and affect lamellar body secretion in barrier-disrupted skin in mice, it is not unreasonable to think that they might affect AD lesional skin similarly (Jeong et al. 2008). It is currently believed that upregulated proteases in AD stimulate PAR-2 and induce the production of cytokines and chemokines implicated in allergic inflammation, immune responses, pruritus, and ongoing barrier dysfunction, possibly allowing easier allergen penetration (Lee SE et al. 2010).
Kallikrein-related peptidases represent attractive therapeutic targets for ovarian cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Daniela Loessner, Peter Goettig, Sarah Preis, Johanna Felber, Holger Bronger, Judith A. Clements, Julia Dorn, Viktor Magdolen
The vast majority of reports describe KLK5–7 as an unfavorable marker for progression-free (PFS) and overall survival (OS) in ovarian cancer (Table 1). However, two ELISA-based studies suggest that increased KLK7 levels may serve as a protective marker [16,17]. In the case of KLK8, the clinical relevance is not yet fully resolved: some publications described KLK8 as favorable marker [18,19], whereas others showed an association of high KLK8 levels with shorter PFS and/or OS [20–22]. Elevated KLK10 levels were, in most cases, related to poor PFS and/or OS, whereas KLK11 may represent a strong protective factor in ovarian cancer (Table 1). Performing immunohistochemistry of ovarian cancer tissues, KLK5 and KLK7 were expressed in both stromal and tumor cells, with higher levels in tumor cells [16,23]. Interestingly, there was a co-expression of KLK5 and KLK7 in the stromal cell compartment in ovarian cancer tissues using the same patient cohort with advanced stage disease [23]. KLK6 was also positively stained in both stromal and cancer cells, with a higher staining intensity in tumor cells [24]. While stromal cell-associated expression of KLK5 was associated with prolonged survival of ovarian cancer patients [23], KLK6 and KLK7 were attributed to a more aggressive disease [16,24]. Another study reported KLK6 and KLK7 expression exclusively in the tumor epithelium and negative expression in the stroma [25]. These discrepancies in stromal and tumor cell staining patterns might be caused by different antibodies used for detection and mixed tumor stages within these patient cohorts as discussed in the previous sections.
Serine protease inhibitors to treat inflammation: a patent review (2011-2016)
Published in Expert Opinion on Therapeutic Patents, 2018
Feryel Soualmia, Chahrazade El Amri
SFTI (sunflower trypsin inhibitor) derivatives were engineered [148] (Figure 3). These inhibitors are developed to target KLK14, KLK7, and/or KLK5 protease inhibitors and their uses in the diagnosis, prevention, or treatment of a skin disease or pathology, or other undesirable skin condition [140]. R1, R2, R3, R4, R6, and R8 are each an amino acid residue, R5 is an amino acid residue other than Phe, and R7 is an amino acid residue other than Asp or Glu. In one embodiment, R1 is Trp or Tyr, R2 is Val or He, R3 is Arg, R5 is Gln, and R7 is Asn. There is no limitation on natural amino acids; however, unnatural ones’ amino acids include, without limitation, allyl glycine (AllylGly), biphenylalanine (Bip), citrulline (Cit), 4-guanidinophenylalanine (Phe(Gu)), homoarginine (hArg), homolysine (hLys), 2-napthylalanine (2-Nal), ornithine (Orn), and pentafluorophenylalanine (FsPhe). SFTI-WCVR F12 N14 was the most selective variant: complete inhibition of KLK14 was achieved with 2.5 μΜ inhibitor, with very weak effect on KLK5, trypsin, and matriptase. SFTI-YCVR F12 N14 was also relatively selective inhibitor of KLK14 with an IC50 1.75 μΜ inhibitor, with no effect seen on KLK5, trypsin, and matriptase. An ex vivo skin desquamation was performed and it has been shown that SFTI-WCVR Q12 N14 inhibits KLK14-mediated desmosome remodeling in these assays at two doses (1.75 and 3.5 µM). More precisely, SFTI-WCVR Q12 N14 attenuates KLK14-mediated cell detachment by inhibiting proteolysis of desmoglein-1, bringing thus the proof of concept that inhibiting KLK14 would be of a great interest in skin diseases involving epidermis disruption.
Advances in understanding of Netherton syndrome and therapeutic implications
Published in Expert Opinion on Orphan Drugs, 2020
Evgeniya Petrova, Alain Hovnanian
3. More specific treatments targeting the initial causative events, i.e. unopposed KLK5 and/or KLK7 activities have the greatest therapeutic potential. Several molecules inhibiting KLK5 and/or KLK7 are currently at different stages of development. These molecules have been designed for topical or systemic delivery. Their use in future clinical trials should provide very insightful information on their effectiveness to revert the disease phenotype via different modes of delivery.